Chemical Diversity of Ketosteroids as Potential Therapeutic Agents

Preprint

Review

Chemical Diversity of Ketosteroids as Potential Therapeutic Agents

Altmetrics

Downloads

109

Views

Comments

A peer-reviewed article of this preprint also exists.

Valery M Dembitsky^*

This version is not peer-reviewed

Submitted:

29 July 2024

Posted:

30 July 2024

You are already at the latest version

Alerts

Abstract

This article presents a comprehensive overview of recent discoveries and advancements in the field of steroid chemistry, highlighting the isolation and characterization of various steroidal compounds from natural sources. The paper discusses a wide range of steroids, including pregnane steroids, steroidal alkaloids, ketosteroids, and novel triterpenoids, derived from marine organisms, fungi, and plants. Significant findings include the isolation of bioactive compounds such as the cytotoxic erectsterates from microorganisms, soft corals, the unusual tetracyclic steroid penicillitone from a fungal culture, and innovative steroidal derivatives with potential anti-inflammatory and anticancer activities. The synthesis of steroids from microorganisms as a tool for pharmaceutical development is also explored, showcasing the role of microbial biotransformation in generating steroidal drugs. Additionally, the paper emphasizes the ecological and medicinal relevance of these compounds, which are often used in traditional medicine and have potential therapeutic applications in treating diseases like cancer and microbial infections. This article serves as a vital resource for researchers interested in the chemical diversity of steroids and their applications in drug discovery and development.

Keywords:

Subject: Biology and Life Sciences - Biochemistry and Molecular Biology

Introduction

Ketosteroids are a subclass of steroids that contain a ketone group (a carbonyl group, C=O) at one or more positions in the steroid skeleton. The steroid skeleton, also known as the sterane core, is a tetracyclic structure consisting of three six-membered rings (A, B, and C) and one five-membered ring (D) [1,2,3,4,5,6,7]. The positions at which the ketone group can be located, 1, 2, 3, 4, 6, 7, 11, 12, 15, 16, 17, and 20 refer to specific carbon atoms in the steroid skeleton. The presence of a ketone group at these positions can significantly alter the biological activity of the steroid molecule [7,8,9,10]. Ketosteroids can be found in a variety of natural sources, including: various parts of plants, such as leaves, roots, seeds, and bark, can contain ketosteroids. These compounds are often involved in the plant’s defense mechanisms against pests and diseases. Marine invertebrates, ketosteroids are commonly found in marine organisms such as soft corals, marine and freshwater sponges, starfish, and other invertebrates [1,2,3,11,12,13,14,15,16].

Ketosteroids are also present in animals, where they serve as hormones and signaling molecules. For example, cortisone and cortisol are keto-steroids that are involved in the stress response and metabolism regulation in mammals. Some ketosteroids are produced by fungi and other microorganisms as secondary metabolites [17,18,19,20,21].

Ketosteroids are of interest in various fields of research, including pharmacology, biochemistry, and ecology, due to their diverse biological activities and potential therapeutic applications. The biological activity of keto-steroids can depend significantly on the position of the ketone group within the steroid skeleton. The location of the ketone group can influence the molecule’s shape, electronic distribution, and ability to interact with specific biological targets, such as receptors, enzymes, and other proteins [22,23,24].

The keto group’s impact on the steroid molecule is significant because it alters how the steroid interacts with enzymes and receptors. These interactions can change the steroid’s solubility, its distribution within the body, its clearance rate, and its ability to enter target cells. In drug design, these properties are considered to maximize therapeutic effects and minimize unwanted side effects [25,26,27]. For example, the presence of a ketone group at the C-3 position (as in cortisone) or the C-11 position (as in cortisol) can greatly impact the anti-inflammatory and glucocorticoid activities of these steroids. Similarly, the presence of a ketone group at the C-17 position can influence the androgenic or estrogenic activity of a steroid. The specific configuration and substitution pattern of the steroid skeleton, including the presence and position of other functional groups, also contribute to the overall biological activity of the molecule. Therefore, even small changes in the structure of a keto-steroid can lead to significant differences in its biological effects.

This review focuses on ketosteroids, which are characterized by the presence of a ketone group at positions 1, 2, 3, 4, 6, 7, 11, 12, 15, 16, 17, and 20 in the steroid skeleton. These compounds are found in various natural sources, including plants, marine invertebrates, and are also produced by fungal endophytes and microorganisms. The review discusses questions related to their biological activity and the implications of the specific positioning of the ketone group within the steroid structure.

Figure 1. The structures of ketosteroids are discussed in this review. According to ChemNetBase (Dictionary of Natural Products) as of May 2024, the number of individual steroids (Σ = 100) containing a carbonyl group in various positions. By reviewing the scientific literature, the data presented by the Dictionary of Natural Products may be underestimated. This is apparently due to the fact that incomplete data were analyzed.

1-Ketosteroids

Steroids skeleton containing a carbonyl group at position 1 are found in nature in the amount of over 200 compounds, mainly in plants [28,29]. The carbonyl group at position 1 of steroids plays a crucial role in determining the chemical and biological properties of these compounds. The carbonyl group adds rigidity to the steroid structure, which can influence the overall shape and conformation of the molecule. This can have a significant impact on the interaction of the steroid with biological receptors and enzymes. The presence of a carbonyl group introduces a polar character to the steroid molecule, which can influence its solubility in water and other solvents. This can affect the distribution and transport of the steroid within biological systems. The carbonyl group is a reactive functional group that can undergo various chemical reactions, such as reduction, oxidation, and nucleophilic addition. These reactions can be utilized in the synthesis and modification of steroid compounds. The presence and position of the carbonyl group can have a significant impact on the biological activity of the steroid. The carbonyl group can engage in hydrogen bonding and other intermolecular interactions, which can influence the binding of the steroid to receptors, proteins, and other biological molecules. Overall, the carbonyl group at position 1 of steroids is an important structural and functional element that influences the chemical reactivity, physical properties, and biological activities of these compounds.

For example, withanolides and related steroids which has a carbonyl group at position 1, are acnistins, physalins, sativolides, spiranoid-δ-lactones, subtriflora-δ-lactones, trechonolides, withametelins, withajardins, withaphysalins, ring-D aromatic withanolides, and norbornane-type withanolides, which have been found in extracts of plants belonging to the families Datura, Dunalia, Hyoscyamus, Iochroma, Jaborosa, Larnax, Lycium, Solanum, Withania, and Witheringia [28,29,30,31]. As an example, we present steroids with different structures containing a carbonyl group in position 1 isolated from plants.

Steroids with a carbonyl group at position 1 of the steroid skeleton in marine invertebrates are found only in Coelenterata, Formosan soft coral Clavularia viridis and C. violacea. It appears that these steroids could be found in corals that feed on plant remains, marine mangrove plants, algae, or phytoplankton [32]. The following marine steroids, structurally akin to the steroids from the Physalis genus, have been identified. Yonarasterols A (1), B (2), C (3), D (4), E (5), and F (6, structures see in Figure 2), resembling witanolides, were extracted from the Okinawan soft coral Clavularia viridis in the Japan Sea [33]. Additionally, several marine steroids named stoloniferones A (7), B (8), C (9), and D (10) have been isolated from Clavularia viridis, as identified by Quoy and Gaimard in Okinawa, and steroids C and D demonstrated growth inhibitory effects on HeLa S3 cells and human diploid cells in vitro [34]. Moreover, cytotoxic steroids stoloniferone E-G (11-13) were obtained from the methylene chloride extract of the Formosan soft coral Clavularia viridis and C. violacea [35]. Notably, stoloniferone Q, D, J, S, yonarasterol C (14), F (15), and I (16) feature a carbonyl group at C-1 with a double bond between C-2 and C-3, except for stoloniferone S, which exhibits a double bond between C-3 and C-4. Additionally, stoloniferone Q includes an extra bond between C-4 and C-5 [32,33,34,35,36,37].

The genus Physalis (Solanaceae), which includes over 100 species primarily found in North and South America, produces cytotoxic peruvianoxide (17), C28 steroidal lactones, and physalins (18-27) [38]. Notably, the cytotoxic peruvianoxide (17) was detected in extracts from Physalis peruviana [39].

The plant Withania somnifera, commonly known as ashwagandha or winter cherry, contains a steroid (28) [40] and an unusual variant, compound (29), featuring a 3α,6α-epoxy bridge. This was found in an extract from the same plant [41]. Chlorinated withanolide Z (30) [42], arising from trans-diaxial cleavage of the 6,7-epoxide, and compound (31) with a unique 5α,7α-epoxy bridge resulting from rearrangement of the 5α-hydroxy-6α,7α-epoxide, were identified in the leaves and roots of Withania somnifera [43]. Additionally, two 14α,20-epoxywithanolides, including the diol coagulin M (32) and coagulin I (33), were isolated from W. coagulans [44,45].

Figure 3. 1-Ketosteroids derived from microorganisms and plants.

Several 14α-hydroxy withanolides have been reported from Physalis species, including phyperunolide A (34) [39] from P. peruviana and 15-acetyloxy withanolides from P. angulata, notably withangulatin I (35) [46] and physagulin M (36) featuring a free hydroxy group at C-23 [47]. A study on Mexican Physalis species revealed that physachenolide C (37) was isolated from the leaves, flowers, and stems of Physalis chenopodifolia [48]. Two withanolides with unmodified skeletons containing a free ketone at C-12 were reported from various plants, namely (-)-jaboromagellonine (38) from Jaborosa magellanica [49] and jaborosalactone 44 (39) from J. kurtzii [50]. A 12-oxygenated withanolide, daturalactone 7 (40), was isolated from Datura ferox collected in Argentina [51]. An intriguing example includes a C29 withanolide from the bark of Eucalyptus globulus (41) with an ethyl substituent at C-25 instead of the usual methyl group [52]. Daturacin (42), containing a 20,24 epoxide, was found in D. inoxia extract [53], and acnistins B (43), C (44), and D (45) were isolated from the leaves of Dunalia solanacea collected in Medellin, Colombia [54,55]. Withaphysalins K (46) and L (47) were isolated from Eriolarynx lorentzii (sub nom. Vassobia lorentzii) collected in Argentina [28].

The steroid Nic-1 (48) was obtained from Nicandra physalodes [30], and the minor component in S. origanifolia plants collected in Buenos Aires and Cordoba provinces, Argentina, was salpichrolide C (49) [56,57]. Salpichrolide H (50) was isolated from plants collected in Buenos Aires during the winter [58], and salpichrolide J (51) from plants collected in Salta province, Argentina, during the summer. Plants collected in Buenos Aires during the winter also contained two ergostane derivatives, salpichrolides E (52) and F (53), likely resulting from the degradation of the lactone side chain of salpichrolides A and C [59].

The 19-oxygenated trechonolide (54) was isolated from Jaborosa laciniata, with its 6,19-oxygen bridge being an unusual feature for a natural product [60]. Notably, synthetic steroids with this moiety exhibit significant biological properties as selective glucocorticoid receptor modulators [61], and jaborosalactone 15 (55) was found in plants collected in the summer [62]. Jaborosalactone 31 (56), isolated from J. rotacea, closely relates to the spiranoid withanolides isolated from J. odonelliana, J. runcinata, and J. araucana, where the C-12–C-23 bond remains intact, forming a dlactone between the C-26 carboxyl and the C-12 hydroxy group [63].

Subtrifloralactones D (57) and E (58) are similar to the classic withanolide structure but notably lack the C-18 [64]. The isolation of 13β-hydroxymethylsubtrifloralactone E (59) from Deprea subtriflora suggests an oxidative pathway leading to the loss of C-18, potentially resulting in a 16-formate group through the rearrangement of a 16,18-hemiketal [65]. Additionally, subtrifloralactones F (60) and G (61), which exhibit a trans fusion between rings C and D, resulting in an ixocarpalactone-type structure, were also detected in Deprea subtriflora [64].

Withanolides, specifically TH-6 (62A) and TH-12 (62B), are 17-methyl-18-nor-ergostanes that were isolated over 30 years ago by Shingu and co-workers [66] from the acid hydrolysate of a methanolic extract of Tubocapsicum anomalum. The researchers linked these compounds to a presumable precursor with a withanolide side chain that is thought to rearrange under acidic conditions.

Summarized on the biological activity of 1-ketosteroids is presented in Table 1, and details are described partially in the text or a full description of the activity is written in the original articles.

Figure 3. 1-Ketosteroids derived from microorganisms and plants.

2-Ketosteroids

2-Ketosteroids, also known as ketosteroids, are a group of steroid compounds that have a ketone group (C=O) at the second carbon atom in the steroid ring structure. This functional group distinguishes them from other steroids. These compounds are present in various biological systems and play important roles in metabolism and hormone regulation. 2-Ketosteroids can also be intermediate metabolites in the biosynthesis and metabolism of other steroids. For example, they can be precursors or breakdown products of hormones. 2-Ketosteroids are found in various tissues and organs, including the adrenal glands, gonads (ovaries and testes), and liver, depending on the specific function and type of steroid. They play crucial roles in maintaining homeostasis and regulating various physiological processes in the body [67,68,69].

3-Hydroxypregnane-2,16-dione (63) was isolated from ethanol extracts of the wood and bark of the Red cedar, Trichilia hirta [70]. The spirostane known as (25S)-3α-Hydroxy-5α-spirostane-2,12-dione, or nummularogenin (64), along with two other spirostanes (65 and 66), were discovered in the extract of the Ziziphus nummularia shrub, commonly referred to as wild jujube or jhahrberi in Hindi [71]. Monocarpine (67), a cycloartane derivative featuring an intriguing combination of oxygen functions in ring A and a unique C-17 side chain, was isolated from the trunk bark of Monocarpia marginalis [72], and monocarpinin (68) was detected in the same tree [73].

A series of 2-ketosteroids related to A-nor steroids have been identified in marine invertebrates and various plant species. Notably, crellasterones A (69) and B (70) were isolated from the sponge Crella incrustans, collected in New Caledonia [74]. These crellasterones structurally resemble the semi-synthetic steroid maltadiolone (71), which is medically used and exhibits calcium-binding activity comparable to cells not treated with calcium channel blockers [75]. This category also includes xidaosterol B (72), found in extracts from the South China Sea sponge Neopetrosia chaliniformis [76], and a compound from the brown alga Sargassum carpophylum (73), collected in the South China Sea [77]. Additionally, A-nor steroids (74-77) were detected in crude oil extracts, marine sediments, and other geological and environmental sources [67].

Viburnum dilatatum, known as linden viburnum, a deciduous shrub from the Adoxaceae family, is noted for producing clusters of red drupes when ripe. Introduced in the mid-Atlantic regions of the USA, from New York to Virginia, its berries, leaves, and stems are used in Traditional Chinese Medicine to treat snake bites, dysentery, and as an anti-helminthic. From this shrub, A-nor triterpenoids viburnols E (78) and G (79) have been isolated [78,79].

The fruits of Citrullus colocynthis contain a cucurbitane 3-nor-triterpenoid named norcolocynthenin B (80), with a unique 5/6/6/5-fused ring system, showing significant cytotoxic activity against human cancer cell lines HL-60 and PC-3 [80].

Dysoxylum hainanense, known for its twigs and leaves, produces triterpenoids such as dysoxyhainic acid A (81, structures see in Figure 4), with a novel 2-nor-1,3-cyclotirucallane skeleton, showing moderate antibacterial activity against Gram-positive bacteria [81].

Moreover, a phytochemical analysis of Citrullus colocynthis fruits revealed a variety of structurally diverse nonanorcucurbitane-type triterpenoids, including colocynins, among which colocynin A (82) displayed anti-acetylcholinesterase activity and notable cytotoxicity against various cancer cell lines [82,83].

In the study of Dysoxylum hainanense, a novel triterpenoid named dysoxyhainol (83) was identified from its twigs and leaves. This compound, with a modified ring A structure, exhibited moderate antibacterial activity against Gram-positive bacteria [81]. Additionally, malabanone B (84), featuring a unique tricyclo[4.3.1.01,6]decane unit, was isolated from the same plant parts [84].

Aphanamixis grandifolia stems produced aphanamgrandins E (85) and F (86), which are derivatives of 2,3-seco-tirucallane triterpenoids [85]. The rootwood of Aglaia sylvestris yielded dammarane-type triterpenoids, including silvaglin A (87), isosilvaglin A (89), and their 1H-β-epimers, silvaglin B (88) and isosilvaglin B (90), characterized by a ^Δ1(3)-bond [86]. Viburnum dilatatum leaves yielded dammarane triterpenoids viburnols E (91) and G (92) [87,88], and the cytotoxic steroid kiheisterone B (93) was discovered in a Maui sponge [89]. The minor steroid (93), isolated from the red alga Laurencia obtusa of the Lakshadweep islands, was identified through spectroscopic data and synthesis as 2α-oxa-2-oxo-5α-hydroxy-3,4-di-norcholestane, marking the first isolation of a ring A-dinorsteroid from a natural source. This compound, named 2α-oxa-2-oxo-5α-hydroxy-3,4-dinorcholestane (94), was also found in the Arabian Sea red alga Laurencia obtuse [90]. Additionally, three compounds (95, 96, and 97) were isolated from a Western Australian sponge, Spongia sp. [91].

Zeng and co-workers [92] reported the discovery of new compounds zimoclactone A (98) and zimoclactone B (99) from marine sponges. Furthermore, Parrish and co-workers isolated three new diterpenes: 18-nor-3,17-dihydroxy-spongia-3,13(16),14-trien-2-one (100), 18-nor-3,5,17-trihydroxyspongia-3,13(16),14-trien-2-one (101), and spongiapyridine (102) from an unidentified Spongia species collected in Sulawesi, Indonesia [93].

Summarized on the biological activity of 2-ketosteroids is presented in Table 2, and details are described partially in the text or a full description of the activity is written in the original articles.

Figure 4. 2-Ketosteroids derived from algae, plants, and sponges.

3-Ketosteroids

3. -Ketosteroids are interesting primarily because of their biological significance and their roles in various physiological processes. Many 3-ketosteroids are key hormones, including corticosteroids and sex hormones like testosterone and progesterone. These hormones play crucial roles in regulating metabolism, immune function, salt and water balance, development of sexual characteristics, and reproductive functions. Due to their hormonal activities, 3-ketosteroids are used in a variety of therapeutic applications. For example, corticosteroids are widely used to treat inflammation, allergies, and autoimmune diseases. Similarly, synthetic derivatives of sex hormones can be used in hormone replacement therapy, contraception, and treatment of hormone-sensitive cancers. 3-ketosteroids are involved in key biochemical pathways such as steroidogenesis, where they are intermediates in the synthesis of various other steroids. This makes them critical for maintaining the balance and production of hormones in the body [94,95,96,97].

In scientific research, 3-ketosteroids are studied for their role in metabolic pathways, their impact on various health conditions, and their potential as targets for new drugs. Understanding how these compounds interact with cellular receptors and enzymes can lead to the development of new treatments for a variety of diseases [94,98].

The 3-keto group in these steroids affects their chemical reactivity and interaction with biological molecules, influencing how they bind to receptors and other proteins. This structural aspect is crucial for their biological function and is a key area of study in biochemistry and pharmacology. Overall, the study of 3-ketosteroids blends aspects of biochemistry, medicine, and pharmacology, making them a fascinating and important area of scientific inquiry [98,99,100,101].

Wallenone (103, structures see in Figure 5), a C32 tirucallane-type triterpene, was isolated from the leaves of Gyrinops wala, a small tree from the Thymelaeaceae family grown in Ceylon [102]. More recently, this compound was also extracted from the ethyl acetate extract of the dried leaves of Esenbeckia stephani (Rutaceae) [103]. A neosteroid named 24ξ-methoxy-24,25-dimethyl-lanost-9(11)-en-3-one (104) was isolated from extracts of Neolitsea pulchella, a tree primarily found in the subtropical biome of Hong Kong, in the early 1970s [104,105]. Additionally, the triterpenoid 24,25-dimethyl-9(11),23-lanostadienol (105) was obtained from the stems of various Quercus species (Q. bambusaefolia, Q. championi, and Q. myrsinaefolia) [106].

An anticancer agent, t-Bu 7α,12α-dihydroxy-4,4,14α-trimethyl-3,11,15-trioxo-5α-chol-8-en-24-oate (106), known as t-butyl lucidenate B, was isolated from the fruiting bodies of the oriental fungus Ganoderma lucidum [107]. Cycloeucalenone (107) was isolated from an unidentified fungus collected in New Jersey [108]. Akihisa and co-workers [109] reported that the fungus Glomerella fusarioides transformed cycloartenol into cycloartane-3,24-dione (108), rare 4α,4β,14α-trimethyl-9β,19-cyclopregnane-3,20-dione (109), and 24,25-dihydroxy-cycloartan-3-one (110). An extract from Parthenium argentatum, commonly known as guayule, contained a cytotoxic steroid named argentatin A (111), which showed cytotoxic effects against human colon cancer cell lines and normal epidermal keratinocytes [110].

Unique steroids named malabanone A (112), which incorporate a unique tricyclo [4.3.1.01,6] decane unit, were isolated from the stem bark of Ailanthus malabarica. The biosynthesis of these steroids is suggested to originate from ailanthol, also found in this plant [111]. Three steroids with an incorporated cyclopropane unit at positions 14 and 18, named ailanthusins A (113), B (114), and D (115), were isolated from the CH₂Cl₂ extracts of the Thailand rainforest tree Ailanthus triphysa [112].

A CHCl₃-MeOH extract from the bark of Aglaia crassinervia collected in Indonesia led to the isolation of aglaiaglabretol A (116), found in the stems of Spathelia excelsa (Rutaceae), exhibiting larvicidal properties against the yellow fever mosquito, Aedes aegypti, with an LC₅₀ of 4.8 µg/mL [113]. A series of antitumor triterpene glucosides, named cumingianosides M (117), containing a 14,18-cycloapotirucallane-type skeleton, were isolated from a cytotoxic fraction of the leaves of Dysoxylum cumingianum, displaying significant cytotoxicity against leukemia and melanoma cell lines [114,115].

A cytotoxic steroid, aragusterol A (118), possessing potent antitumor activity, was isolated from an Okinawan sponge of the genus Xestospongia. The compound strongly inhibited cell proliferation in KB, HeLaS3, P388, and LoVo cells in vitro and demonstrated potent in vivo antitumor activity against P388 and L1210 in mice [116]. Additionally, 26,27-cyclosterols aragusterols B (119), C (120), and D (121) have been identified in the same Okinawan marine sponge [116,117]. A wide array of steroids, including aragusterol A (118) and another compound (122), were found in the marine sponge Petrosia (Strongylophora) sp. collected from the Similan Island, Thailand [118].

A limonoid named hortiolide D (123) was found in CH₂Cl₂ and MeOH extracts from the stem of Hortia oreadica [119], and a protolimonoid named capulin (124), featuring a four-membered ring in its side chain, was isolated from the stem barks of Capuronianthus mahafalensis, a species endemic to Madagascar [120].

Two unusual malabaricane-type triterpenes, (14S,17S,20S,24R)-25-hydroxy-14,17-cyclo-20,24-epoxy-malabarican-3-one (125) and (14S,17S,20S,24R)-20,24,25-trihydroxy-14,17-cyclo-malabarican-3-one (126), were isolated from the oleoresin of the wounded trunk of Ailanthus malabarica [121]. The steroid altrenogest, a progestin from the 19-nortestosterone group widely used in veterinary medicine to suppress or synchronize estrus in horses and pigs, produces two photoproducts (127 and 128) through photolysis experiments [122]. The steroid erectasteroid H (129) exhibited cytotoxic activity against P-388 (leukemia) and HT-29 cells [123], and a spirosteroid (130) was isolated from the Formosan soft coral Nephthea erecta [124,125].

Two steroids, theonellasterone (131) and conicasterone (132), featuring a keto group at C-3, were identified in marine sponges from the genus Theonella [126]. Additionally, two steroidal oximes (133 and 134) from the Cinachyrella sp. sponge were found to inhibit human placental aromatase competitively, suggesting their potential as inhibitors in hormone-dependent tumors [127]. Holland and colleagues described the synthesis of these compounds [128]. The cytotoxic kicheisterone A (135), distinguished by cis-fused rings A and B with carboxy groups at position 21 and furan fragments in the side chains, was isolated from an unidentified Hawaiian sponge of the Poecilosclerida sp. [129]. This steroid, along with kicheisterones C-E (136-138) which contain a chlorine atom and are part of a rare group of halogenated steroids, was also found in the sponge Strongylacidon sp. [130].

A series of 3-oxo-4,6,8(14)-triunsaturated steroids with cholestane (139 and 140), ergostane (141–143 and 145), and stigmastane skeletons (144 and 146–148) were discovered in the lipid extract of Dysidea herbacea [131]. Steroids 145 through 148 were isolated as C-24 epimeric mixtures. Compounds 139 through 148 represent the second instance of steroids from a marine source featuring a conjugated 3-oxo-4,6,8(14)-triene system; compound 140 had previously been isolated from Dyctionella incisa [132]. Cholest-4-ene-3,6-dione (149) and (24R)-24-ethylcholest-4-ene-3,6-dione (150) were isolated from the marine sponge Cinachyra tarentina [133]. Compound 149 was synthesized from cholesterol, while the structure of 150 was confirmed by synthesis from sitosterol, involving Jones oxidation to determine the R chirality at C-24.

The steroid mycalone (151), with a six-membered lactone side chain, was isolated from a Mycale species in southern Australia [134]. Ergosta-4,24(28)-dien-3-one (152) was identified in the subantarctic shallow-water sponge Geodia cydonium [135], and a similar compound, (25S)-26-Methyl-24-methylenecholest-4-en-3-one (153), was isolated from the marine fossil sponge Neosiphonia supertes [136].

Finally, a dimeric steroid, bistheonellasterone (154), likely biosynthesized via a Diels-Alder cycloaddition of theonellasterone, was discovered in the Okinawan marine sponge Theonella swinhoei [137].

A series of steroid hydroperoxides (155-158) isolated from the red alga Galaxaura marginata collected near the coasts of Taiwan demonstrated high cytotoxic activities against tumor cells P-388, KB, A-549, HT-29, with semi-inhibiting concentrations (IC₅₀) within the range of 0.2 μg/mL [138]. The steroidal 3,6-diketone 159, oxygenated at C(16), was isolated from the alga Jania rubens, showing high toxicity against some tumor cells (IC₅₀ = 0.5 μg/mL) [139]. Hydroperoxides (160 and 161) isolated from the brown alga Turbinaria conoides also exhibited cytotoxic properties [140].

Sterols and sterones were discovered in a sponge Stelletta sp., collected at a depth of 700 m in the deep Coral Sea, southeast of Noumea. These compounds, the first examples of stigmastane steroids with a Δ^24,25 from a marine origin, were elucidated as stigmasta-4,24(25)-dien-3-one (162), stigmasta-4,6,24(25)-trien-3-one (163), stigmasta-4,24(25)-diene-3,6-dione (164), 6β-hydroxystigmasta-4,24(25)-dien-3-one (165), stigmasta-5,24(25)-dien-3β-ol (166), and compound 167 [141].

Guggulsterones (168 and 169), phytosteroids found in the resin of the guggul plant, Commiphora mukul, exist as two stereoisomers, (E)-guggulsterone and (Z)-guggulsterone [142,143]. In humans, they act as antagonists of the farnesoid X receptor, initially thought to decrease cholesterol synthesis in the liver, though studies indicate no overall reduction in total cholesterol, with levels of low-density lipoprotein increasing in many cases [143,144,145,146,147].

An ethyl acetate extract from the gorgonian Leptogorgia sp., collected from the South China Sea, contained a dihydroxy-ketosteroid (170) [148]. From the gorgonian coral Euplexaura anastomosans, collected off the shore of Keomun Island, South Sea Korea, steroidal hemiacetals named anastomosacetals A (171) and D (172) were obtained. Another gorgonian species, Bebryce indica, collected off the coast of Sanya (Hainan, China), was found to contain a steroidal glycoside named bebrycoside (173) [150]. Additionally, bebrycoside (173) and related compounds such as 27-O-[β-D-arabino-pyranosyloxy]-20β,22α-dihydroxy-cholest-4-ene-3-one, named muricellasteroid D (174), and the rare steroid 22α-O-acetyl-2β-O-methylene-[4β-hydroxy-phenyl]-cholest-4-ene-3-one, named muricellasteroid E (175), were isolated from the EtOH/CH₂Cl₂ extracts of the South China Sea gorgonian coral Muricella flexuosa. Both compounds 174 and 175 demonstrated moderate cytotoxicity against A375, K562, and A549 cancer cell lines [151].

An unusual hemiketal steroid, 23-keto-cladiellin A (176), was obtained from the monohydroxylated sterol fraction of the soft coral Chromonephthea braziliensis [152]. From the soft coral Nephthea sp., a unique pentacyclic hemiacetal sterol named nephthoacetal (177) and its acetyl derivative (178) were isolated. Compound (177) exhibited significant inhibitory effects with an EC₅₀ value of 2.5 μg/mL, while maintaining low toxicity with an LC₅₀ greater than 25.0 μg/mL. The in vitro cytotoxic activity of both compounds (177 and 178) showed moderate effects with IC₅₀ values of 12 and 10 μg/mL, respectively [153].

Krempene A (179, structures in Figure 6), an unprecedented pregnane-type steroid with a highly unusual hexacyclic oxadithiino unit fused to the steroidal ring A, was isolated from the marine soft coral Cladiella krempfi [154]. Additionally, a rare steroidal hydroperoxide, 13,14-seco-22-norergosta-4,24(28)-dien-19-hydro-peroxide-3-one (180), has been found in the diethyl ether fraction of the Red Sea soft coral Litophyton arboretum [159]. Lastly, an unprecedented spinaceamine-bearing pregnane named scleronine (181) was produced by a Chinese soft coral Scleronephthya sp. [156].

Two steroids (182 and 183) along with pregna-1,4,20-trien-3-one (184) have been isolated from the Pacific octocoral Carijoa multiflora. Compound (182), featuring a spiropregnane-based steroidal skeleton, has demonstrated antibacterial activity [157]. Additional pregnane steroids (185 and 186), similar to compounds (183 and 184), were isolated from a gorgonian Carijoa sp. collected from the South China Sea. These compounds, particularly (184, 185, and 186), exhibited cytotoxicity against the human hepatoma cell line Bel-7402, with IC₅₀ values of 9.3, 11.0, and 18.6 µM, respectively [158]. The Hainan soft coral Scleronephthya gracillimum has released a pregnane analogue (187) [159], and two unique chloro-pregnane steroids (188 and 189) have been isolated from the eastern Pacific octocoral Carijoa multiflora [160].

An unusual steroid thioester, parathiosteroid A (190), was isolated from the 2-propanol extract of the soft coral Paragorgia sp. collected in Madagascar. This compound displayed cytotoxicity against a panel of three human tumor cell lines at the micromolar level [161]. The reef soft coral S. brassica, which was cultured in an aquarium, yielded four steroids with methyl ester groups: sinubrasones A (191), B (192), D (193), and C (194). Compounds 191 and 192 showed significant cytotoxicity, while compounds 193 and 194 demonstrated notable anti-inflammatory activities [162]. Additionally, the ethyl acetate extract of a reef soft coral S. brassica, cultured in a tank, produced two steroids, sinubrasones A (195) and B (196), both of which exhibited significant cytotoxicity [163].

The soft coral Umbellulifera petasites produces steroid (197), while petasiterone B (198), and 5α-pregna-20-en-3-one (199) have been found in the soft coral Alcyonium gracillimum [162,164,167].

Figure 6. 3-Ketosperoids derived from algae, marine invertebretes and plants.

Figure 6. 3-Ketosteroids derived from marine invertebretes and plants.

Unique highly oxygenated 13,17-secosteroids with a split D ring, named isogosterones A–D (200–203), were obtained from extracts of a Japanese octocoral of the genus Dendronephthya collected off the Izu Peninsula. These steroids have demonstrated the ability to inhibit the settlement of B. amphitrita cyprid larvae [166]. A polyhydroxygenated steroid, hipposterone M (204), showing cytotoxicity against human cytomegalovirus (HCMV), was derived from extracts of the Taiwanese octocoral Isis hippuris collected at Orchid Island [167]. Additionally, steroids (205–208), isolated from the crude extract of Alcyonium gracillimum, exhibited moderate cytotoxicity (IC₅₀ 22 µg/mL) and antiviral activity (IC₅₀ 8 µg/mL) against P388 and HSV-I (human α-herpesvirus), respectively [168,169].

A pregnane derivative, 4-hydroxymethyl-5β-pregnan-3, 20-dione (209), was isolated from the South China Sea gorgonian Subergorgia suberosa [170]. From the lipid extracts of the Formosan soft coral Paraminabea acronocephala, a marine withanolide named paraminabeolide D (210) was obtained [171]. Summarized on the biological activity of 3-ketosteroids is presented in Table 3, and details are described partially in the text or a full description of the activity is written in the original articles.

4-Ketosteroids

4-Ketosteroids are also a significant class of steroid compounds with a ketone group at the fourth carbon of the steroid backbone. While they are less commonly discussed compared to 3-ketosteroids, 4-ketosteroids also have important role. The presence of the ketone group at the fourth position affects the chemical behavior and biological interactions of these steroids. This ketone group can influence how the steroid interacts with various enzymes and receptors within the body. Some 4-ketosteroids are intermediates in the metabolism of more commonly known steroids. They can arise during the breakdown and transformation processes of hormones in the body. Understanding their metabolism helps in elucidating the pathways of steroid degradation and synthesis [172,173,174,175].

While 4-ketosteroids themselves may not be widely used therapeutically, understanding their structure and function can aid in the development of steroid-related treatments. They can serve as models or starting points for the synthesis of novel compounds with improved efficacy and reduced side effects. Although not as prominent as other steroids, some 4-ketosteroids may exhibit unique biological activities that could be of interest in hormone research or drug development. Exploring these activities might provide new insights into steroid hormone action and regulation [173,176].

An oxygenated steroid, named aspersteroid A (211, structures see in Figure 7), was isolated from the marine-derived fungus Aspergillus flavus collected from the Bohai Sea [177]. Solamaladine (212) was extracted from the green fruits of Solanum hypomalacophyllum [178]. Additionally, green berries of S. hypomalacophyllum provided the known alkaloid solaphyllidine (213, 16-acetoxy-3,23-dihydroxy-16,28-secosolanidan-4-one), its 16-deacetoxy analog (214), and the deacetoxy, 3-O-β-D-glucopyranoside derivative (215) [179]. A steroidal alkaloid named pachystermine A (216), extracted from Pachysandra terminalis, also known as Japanese pachysandra, exhibited an anti-ulcer effect [180].

Several 4-keto-withanolides and related steroids have been discovered in plants from the Solanaceae family. Specifically, 15-acetyloxy withanolide was isolated from P. angulata, along with withangulatin I (35) [46]. Compounds (217) and the secowithametelins 218 and 219, as well as withaperuvin M (220), were obtained from the leaves and flowers of Datura metel [181]. Withaphysalins K (221) and L (222) were isolated from Eriolarynx lorentzii (sub nom. Vassobia lorentzii) collected in Argentina [28], and perulactone G (223) was found in Physalis peruviana [182]. Withaperuvin E (224), characterized by a special D2-1,4-dione system in ring A, was detected in Physalis peruviana [183]. Withanolides (225) and (226), showing nitric oxide inhibitory effects and affinities with iNOS, were also detected in Physalis peruviana [184]. Additionally, 3,25,26-trihydroxyergost-24(28)-ene-1,4-dione (227) was obtained from the leaves of the genus Jaborosa [185]. Subtrifloralactone K (228), a C-18 oxygenated withanolide, was isolated from the active fractions of the chloroform-soluble extract of Deprea subtriflora [186].

Summarized on the biological activity of 4-ketosteroids is presented in Table 4, and details are described partially in the text or a full description of the activity is written in the original articles.

6-Ketosteroids

6-Ketosteroids are another interesting group within the steroid family, characterized by the presence of a ketone group at the sixth carbon of the steroid nucleus. Similar to other ketosteroids, 6-ketosteroids can be involved in specific metabolic pathways. They may serve as intermediates in the synthesis or breakdown of steroid hormones, although their presence and role in these pathways tend to be more specialized and less general than those of 3- or 4-ketosteroids. The specific activities of 6-ketosteroids can vary, but like other steroids, they might interact with certain receptors or enzymes, influencing various physiological processes. The exact functions and significance of these interactions can depend heavily on the particular structure and context of the 6-ketosteroid [187,188,189,190,191].

Due to their unique position of the ketone group, they may have distinct biochemical properties that could be exploited in drug development or in studies of steroid metabolism and function. The presence of a ketone group at the sixth position can significantly affect the steroid’s ability to bind to and activate or inhibit various receptors. Structural studies, such as X-ray crystallography or NMR spectroscopy, can help elucidate how these changes impact receptor interaction and function. While not as directly utilized in therapy as some other ketosteroids, understanding the properties of 6-ketosteroids could lead to the development of new drugs, particularly if these steroids exhibit unique interactions with biological molecules that can be modulated for therapeutic benefit [191,192,193]. In general, 6-ketosteroids are a more niche area of study within the broader field of steroid research. Their unique characteristics can provide valuable insights into steroid chemistry and biology, contributing to our overall understanding of steroid functions and their implications in health and disease.

Antibiotic WF 15604A (229, structures see Figure 8), a bioactive secondary metabolite that inhibits cholesterol synthesis, has been found in the leaves of Preussia minima collected in the Iberian Peninsula [194]. Two steroids, chiograsterone (230) and isochiograsterone (231), have been isolated from Chionographis japonica [195].

Plant hormones such as 3,24-diepicastasterone (232) were detected in the seeds of Phaseolus vulgaris. Homoteasterone (233) was isolated from the EtOAc-hexane extract of rice from Oryza sativa, radish Raphanus sativus, and “Remo” seeds. Furthermore, 25-methylcastasterone (234) and another compound (235) were isolated from a methanol extract of ryegrass Lolium perenne pollen [196].

Polyoxygenated meroterpenoids named aperterpene N (236) and O (237) were isolated from the marine algal-derived fungus Aspergillus terreus EN-539 [197]. Compound (236) displayed neuraminidase inhibitory activity, with an IC₅₀ value of 18.0 μM. Meroterpenoid terretonin D1 (238) was obtained from the marine sediment-derived fungus Aspergillus ustus KMM 4664 and from Aspergillus terreus EN-539, associated with the fresh gut of a Pacific oyster [198].

The 5α,9α-endoperoxide (239) was isolated from the fruiting bodies of Stropharia rugosoannulata and protected neuronal cells by attenuating endoplasmic reticulum stress caused by thapsigargin, an inhibitor of Ca2+-ATPase [199]. Additionally, two steroids containing an oxetane ring (240 and 241) have been isolated from the endophytic fungi Chaetomium sp. and Colletotrichum sp., respectively. Both compounds demonstrated activity in an AChE inhibitory assay [200,201].

A cytotoxic steroid (242) has been discovered in the filamentous fungus Talaromyces stipitatus, belonging to the family Trichocomaceae. It exhibited cytotoxic activity against Hep3B (IC₅₀ 4.75 µM), HepG2 (IC₅₀ 8.85 µM), and Huh-7 (IC₅₀ 13.78 µM) [202]. A 4-ketosteroid (243) was identified in several fungal species, including Fomes fomentarius [203], Grifola frondosa [204], and Phellinus linteus [205], showing activities such as β-hexosaminidase inhibition, HNE inhibitory, and NO production inhibition. Hericium erinaceus, commonly known as the lion’s mane mushroom, contained a steroid (244) that demonstrated inhibition of TNF-α secretion and NO production in lipopolysaccharide-induced RAW 264.7 cells [206].

Three ergosterols, ganocalidophins A–C (245‒247), were isolated from the fruiting bodies of Ganoderma sinense. These compounds exhibited inhibitory activities against NO production with IC₅₀ values of 17.7, 32.4, and 19.8 µM, respectively [207]. 4-Keto-ergosterol (248), produced by various fungi including Colletotrichum sp. [200], Ganoderma sinense [207], Pleurotus eryngii [208], Psathyrella candolleana [209], and Volvariella volvacea [210], demonstrated cytotoxic activity against HepG2 (IC₅₀ 5.90 µM), SGC-7901 (IC₅₀ 12.03 µM) [210], and minimal activity against A549, HL-60, MCF-7, SMMC-7721, SW480 (IC₅₀ > 40 µM) [209], RAW264.7 (IC₅₀ > 100 µM) [208]. This compound also inhibited NO production with varying efficacy (IC₅₀ 28.5 µM and 100 µM) [208].

Steroid (249), obtained from the fungus Volvariella volvacea, exhibited cytotoxic activity against HepG2 cells with an IC₅₀ of 20.27 µM [210]. Another steroid (250) was isolated from the rare poroid fungus Ganoderma resinaceum and showed inhibition of NO production with an IC₅₀ of 35.19 µM [211]. A 3,11-diol steroid (251), detected in the fungus Gliomastix sp. belonging to the family Bionectriaceae, displayed antiviral activity against the EV-71 virus with an IC₅₀ of 17.8 µM and cytotoxic activity against several cancer cell lines including HL-60 (IC₅₀ 1.75 µM), DU-145 (IC₅₀ 7.37 µM), HeLa (IC₅₀ 12.1 µM), and MOLT-4 (IC₅₀ 6.53 µM) [212].

Dankasterone A (252) and B (253) were isolated from a fungal strain of Gymnascella dankaliensis derived from the sponge Halichondria japonica [213]. Dankasterone A demonstrated significant cytotoxicity against tumor cells in culture. Phomopsterone B (254), produced by the endophytic fungus Phomopsis sp., exhibited anti-inflammatory activity and showed promising results in iNOS inhibitory and NO production inhibition assays [214]. Three C25 steroids, neocyclocitrinols E-G (255–257), were isolated from the endophytic fungus Chaetomium sp. M453 [200].

Makisterone A (258), a 28-carbon ecdysteroid distinguished from the common C27 molting hormones like ecdysone and 20-hydroxy-ecdysone by an additional methyl group at the C-24 position, was isolated and characterized from the leaves of Podocarpus macrophyllus [215]. The steroidal alkaloid petisidine (260) was isolated from the leaves of Petilium raddeanum [216]. Another alkaloid, korsevinine (261), was detected in the total ether-soluble alkaloids of Korolkowia sewerzowii [217]. A unique steroidal alkaloid with a 5β-hydroxyl group, ebeietinone (262), was isolated from the bulbs of Fritillaria ebeiensis var. purpurea [218], and petisidinine (263) was detected in the essential oil of Petilium raddeana [219].

Summarized on the biological activity of 6-ketosteroids is presented in Table 5, and details are described partially in the text or a full description of the activity is written in the original articles.

7-Ketosteroids

7-Ketosteroids represent another specialized class of steroid compounds characterized by the presence of a ketone group at the seventh carbon of the steroid skeleton. While not as prominently featured in basic biological processes as some other steroid classes, 7-ketosteroids are noteworthy. The ketone group at the seventh position can significantly influence the steroid’s chemical reactivity and interaction with biological molecules, such as enzymes and receptors. This unique placement may alter the way these steroids are metabolized compared to their counterparts with ketone groups at other positions. 7-ketosteroids can occur as natural metabolites in the body, particularly as products of steroid hormone metabolism. They might play roles in various physiological processes, although these roles are often less direct than those of primary hormones like estrogens, androgens, or corticosteroids [220,221,222,223].

One of the most well studied 7-ketosteroids is 7-keto-DHEA (7-ketodehydroepi-androsterone). This compound is known for its potential in enhancing metabolism and is researched for its use in weight loss and immune function. Unlike many other steroids, 7-keto-DHEA is not converted to steroid hormones such as testosterone or estrogen, which makes it a candidate for non-hormonal applications. Overall, while 7-ketosteroids are not as central to major physiological pathways as some other steroids, they offer interesting possibilities for health and wellness applications, particularly in the realm of non-hormonal interventions. Their unique chemical structure and effects continue to be a subject of research and discussion in the scientific community [224,225,226,227,228].

The compound 15α-hydroxy-(22E,24R)-ergosta-3,5,8(14),22-tetraen-7-one (264, structures see in Figure 9) was isolated from the endophytic fungus Penicillium sp. FJ-1 associated with Acanthus ilicifolius, commonly known as holly-leaved acanthus, sea holly, or holy mangrove. This compound demonstrated potent cytotoxicity against glioma cell lines, with IC₅₀ values of 3.2 µM for U251, 4.1 µM for BT-325, and 2.3 µM for SHG-44 [229].

The apolar extract of the marine sponge Theonella swinhoei revealed a family of polyhydroxy steroids, including conicasterol G (265) which was isolated [230]. The compound (22E,24R)-3β-hydroxyergosta-5,8,22-trien-7-one (266) was identified from the culture extracts of Aspergillus oryzae, an endophytic fungus isolated from the marine red alga Heterosiphonia japonica [231]. Another compound, (22E)-25carboxy-8β,14β-epoxy-4α,5α-dihydroxyergosta-2,22-dien-7-one (267), exhibited cytotoxic activity towards the A-549 cell line and was isolated from the marine-derived fungus Aspergillus flavus collected from the Bohai Sea [177].

Three steroids with a rearranged ring B, including eringiacetal B (268), were isolated from the fruiting bodies of Pleurotus eryngii [232]. Eringiacetal B (268) demonstrated an IC₅₀ of 13.0 µM and showed inhibitory effects on nitric oxide production, compared to 23.9 µM for the L-NMMA positive control.

Two sterols, gargalol B (269) and C (270), were isolated from the polypore fungus Grifola gargal from the family Meripilaceae. Both compounds showed potential in inhibiting osteoclast formation, which may be relevant for the prevention of osteoporosis [233].

A 5,6-epoxy steroid (271) was discovered in Hericium erinaceum, also known as the lion’s mane mushroom, and demonstrated cytotoxic activity against HGC-27 with an IC₅₀ of 29.34 µM [234]. This sterol was also found in the saprophytic and parasitic fungus Omphalia lapidescens, where it showed HNE inhibitory activity (IC₅₀ 75 µM) and inhibited TNF-α secretion by 37% at 10 µM [235]. A polyoxygenated ergosteroid (272) was detected in an extract of the macrofungus Omphalia lapidescens, displaying a structure-cytotoxicity relationship with an IC₅₀ of 23.41 µM against the human gastric cancer cell line HGC-27 [235]. Another epoxy sterol (273) was obtained from the fruiting bodies of the fungus Amauroderma subresinosum and demonstrated 20.9% inhibition of acetylcholinesterase at 100 µM [236].

In the family Tricholomataceae, the agaric fungus Tricholoma imbricatum contained two steroids (274 and 275), which exhibited cytotoxic activity against various cancer cell lines: A549 (IC₅₀ 12.4 µM), HL-60 (IC50 12.2 µM), K562 (IC50 13.8 µM), MCF-7 (IC50 17.8 µM), SMMC-7721 (IC₅₀ 27.6 µM), and SW480 (IC₅₀ 19.7 µM) [237]. Additionally, steroid (275) was found in the fungus Phomopsis sp. [238] and Chaetomium globosum [239] and demonstrated α-glucosidase inhibition (IC₅₀ > 100 µM). Steroid (276) from the fruiting bodies of Tricholoma imbricatum showed cytotoxicity against A549 (IC₅₀ 22.8 µM) and SMMC-7721 (IC50 19.5 µM) [237].

Two steroids (277 and 278) were discovered in the Ganoderma mushroom. Specifically, 277, isolated from Ganoderma philippii, exhibited acetylcholinesterase inhibition [240], while steroid (278), found in Ganoderma resinaceum, demonstrated inhibition of NO production [241].

The compound 22E-3β-hydroxy-5α,6α,8α,14α-diepoxy-ergosta-22-en-7-one (279) was isolated from the fungus Aspergillus awamori, which was obtained from soil surrounding the mangrove plant Acrostichum speciosum [242]. Compound 279 exhibited weak cytotoxic activity against A549 cancer cell lines. Two 7-keto-ergosterol derivatives, 3β,11α-dihydroxyergosta-8,24(28)-dien-7-one (280) and 3β-hydroxyergosta-8,24(28)-dien-7-one (281), were isolated from the fungus Aspergillus ochraceus EN-31 obtained from the marine brown alga Sargassum kjellmanianum [243].

The marine-derived fungus Rhizopus sp., isolated from the bryozoan Bugula sp. collected in Jiaozhou Bay, China, yielded several ergosterols: 3β-hydroxy-(22E,24R)-ergosta-5,8,22-trien-7,15-dione (282), 3β-hydroxy-(22E,24R)-ergosta-5,8,14,22-tetraen-7-one (283), 3β,15β-dihydroxy-(22E,24R)-ergosta-5,8(14),22-trien-7-one (284), and 3β-hydroxyl-(22E,24R)-ergosta-5,8(14),22-trien-7,15-dione (285) [244]. All isolated compounds demonstrated cytotoxic activity to varying degrees against four different cancer cell lines.

Incrustasterol B (286), derived from the Mediterranean sponge Dysidea incrustans, is distinguished from other polar sponge steroids by the presence of Δ⁸⁽⁹⁾-7,9-diketo fragments, which are uncommon for marine steroids [245].

Three 7-keto-phytoecdysteroids (287-289), cyclopentanoperhydrophenanthrene-ringed polyhydroxylated chemicals known for protecting plants from nematodes and insect pests, have been isolated from various plant extracts [246]. Two ecdysterone-type sterol glycosides, which also act as melanogenesis inhibitors, were isolated from different sources: pfaffiaglycosides E (287) from the roots of Pfaffia glomerata and brainesteroside C (288, 25-deoxycalonysterone-3-O-β-D-glucopyranoside) from the rhizomes of Brainea insignis [247]. A minor ecdysteroid named calonysterone (289) was detected in extracts of Cyanotis arachnoidea [248].

The steroidal sapogenin, pogosterol (290), isolated from the leaves of Vernonia pogosperma, was characterized for its structure and stereochemistry. Pogosterol exhibited weak cytotoxic activity against L-1210 cells in vitro, with an IC₅₀ of 1.7 µg/mL [250]. Additionally, an antibiotic metabolite, helvolic acid (291), was isolated from the rice sheath rot pathogen fungus Sarocladium oryzae [251].

Taccalonolides are a unique class of microtubule-stabilizing agents isolated from plants of the genus Tacca, demonstrating effectiveness against drug-resistant tumors in cellular and animal models [252]. Taccalonolides AD (292), I (293), J (294), and K (295) are 7-keto steroids that exhibit cytotoxic effects. Taccalonolide AD (292) was isolated from Tacca plantaginea, increasing cellular microtubule density and microtubule bundling in HeLa cells at 17 µM, with anti-proliferative actions exhibiting an IC₅₀ of 3.48 µM [253]. Taccalonolides I, J, and K, characterized by a shift of the ketone group from C6 to C7 on ring B, were detected in extracts of T. plantaginea, with taccalonolide K (295) also found in T. paxiana [254].

The methanol extract of the Mediterranean encrusting sponge Oscarella lobularis yielded small amounts of two polyoxygenated sterols (296 and 297) featuring a unique 5α,6α-epoxy-7-keto function [255]. The marine sponge Polymastia sobustia from the South China Sea contained 3β-hydroxystigmast-5-en-7-one (298) [256], and polysterol A (299) was obtained from a Japanese sponge, Epipolasis sp. [257]. A rare steroid with a cyclopropane ring at C-25 and C-26, named 7-oxopetrosterol, 26,27-cyclo-24,27-dimethyl-3β-hydroxycholest-5-en-7-one (300), was observed in the marine sponge Strongylophora corticata [258]. An oxygenated sterol (301), obtained from a collection of marine sponge Polymastia tenax from the Caribbean coast of Colombia, exhibited significant anti-proliferative activity toward A-549, HT-29, H-116, MS-1, and PC-3 tumor cells in the range of 0.5−10 μg/mL [259]. A specimen from the South China Sea of Geodia japonica yielded 26-methylergosta-5,24(28)-dien-3β-ol (302) [260].

Acetylenic sterols, gelliusterol B (303, 26,27-bisnorcholest-5-en-23-yn-3β-ol-7-one), gelliusterol C (304, cholest-5-en-23-yn-3β,7-one), and D (305, cholest-5-en-23-yn-3β,25-diol-7-one), were isolated from an unidentified species of sponge, Gellius sp. [261].

Summarized on the biological activity of 7-ketosteroids is presented in Table 6, and details are described partially in the text or a full description of the activity is written in the original articles.

11-Ketosteroids

11-Ketosteroids are notable for their biological activities and their roles in human physiology. These steroids, characterized by a ketone group at the eleventh carbon of the steroid nucleus, include important physiological compounds such as 11-keto-testosterone and 11-dehydrocorticosterone. 11-Ketosteroids are biologically active and play crucial roles in the body. For example, 11-keto-testosterone is a potent androgen in fish, although it has lesser activity in mammals. However, its presence and effects in various species suggest a significant evolutionary and functional role [262,263,264,265,266].

Corticosteroid 11-ketosteroids, like 11-dehydrocorticosterone, are involved in the body’s stress response and immune regulation. They help modulate inflammation and immune responses, acting through glucocorticoid receptors to exert their effects [267,268,269]. These steroids are part of the metabolism of more commonly known corticosteroids and androgens. They are metabolized by enzymes in the liver and other tissues, influencing both the production and degradation of steroid hormones. Levels of certain 11-ketosteroids can serve as biomarkers for diagnosing and monitoring diseases that involve steroid metabolism disorders or adrenal function anomalies.

In essence, 11-ketosteroids contribute to a variety of physiological processes, and their study helps in understanding both the endocrine system’s complexity and the potential for targeted therapeutic strategies in medicine [270,271,272].

An antifungal antibiotic, 18,22-cyclosterol, Mer-NF8054X (306), and its analog (307) have been isolated from Aspergillus sp. [273]. Additionally, Mer-NF8054X was isolated from a shaken culture of Aspergillus ustus and from the culture filtrate of Emericella heterothallica [274]. Three lanostanoid triterpenes, ganotropic acid (308), 3β,7β,15α,24-tetrahydroxy-11,23-dioxo-lanost-8-en-26-oic acid (309), and 3β,7β,15α,28-tetrahydroxy-11,23-dioxo-lanost-8,16-dien-26-oic acid (310, structures see in Figure 10), were isolated from the n-BuOH extract of the fruiting bodies of the mushroom Ganoderma tropicum. Ganotropic acid possessed a two-oxygenic five-membered ring system in the side chain of the lanostane skeleton [275]. Both compounds demonstrated cytotoxic activity against A549, HepG2, THP-1 (with an IC₅₀ > 80 µM), as well as IL-6 immune-suppressive activity (with an IC₅₀ of 21 µM) and TNF-secretion inhibition (with an IC₅₀ of 28 µM) [275].

A polyhydroxy steroid, zahramycin B (313), has been isolated from the polar fraction of the extract of the coral Sarcophyton trocheliophorum. This steroid showed high antibacterial activity against Staphylococcus aureus, Bacillus subtilis, and the fungus Pythium ultimum [276].

Furthermore, 3β,7β-dihydroxy-5α-cholestan-11-one (314) was found in a mixture of chloroform and methanol (1:1) extracts of the red alga Laurencia papillosa [277].

The male African catfish (Clarias gariepinus) secretes 11-ketotestosterone (315), a potent androgen, in addition to testosterone. Research indicates that 11-ketotestosterone stimulates spermatogenesis, unlike testosterone, which promotes the development of pituitary gonadotrophs [278]. Additionally, 11-ketotestosterone (315) has been extracted from postspawned male sockeye salmon, Oncorhynchus nerka [279].

Three 11-ketosteroids, namely incrustasterol A (316), (317), and (318), were identified in the Mediterranean sponge Dysidea incrustans [280] and Dysidea fragilis from the Venice lagoon [281]. From the soft coral Klyxum flaccidum, two bioactive steroids, klyflaccisteroid C (319) and D (320), were isolated [282]. Furthermore, a sulfated polyhydroxy steroid (321) was isolated from three species of brittle stars collected near Noumea (New Caledonia): Ophiocoma dentata, Ophiarthrum elegans, and Ophiarachna incrassata [283].

Asperflotone (322), an 8(14-->15)-abeo-ergostane derived from the sponge-associated fungus Aspergillus flocculosus 16D-1, exhibited cytotoxic effects against A549, HepG2, and THP-1 cell lines with an IC₅₀ exceeding 80 µM, along with notable IL-6 immune-suppressive activity (IC₅₀ 22 µM) [284]. Additionally, the same fungal genus yielded three steroids featuring identical side chains, including asperflosterol (323) [285], compound (324), and asperfloroid (325) [285,286], both asperflosterol (323) and asperfloroid (325) exhibited anti-inflammatory properties. From the same fungus, an ochratoxin-ergosteroid heterodimer, ochrasperfloroid (326), was isolated and shown to significantly inhibit IL-6 and nitric oxide (NO) production in LPS-stimulated cells [284].

Major cardenolide glycosides, affinosides La-Le (327-331), featuring oxygen functionalities at C-11 of the aglycone, were isolated from the leaves of Anodendron affine [288]. The unique steroid inertogenin (332), characterized by a rare 7,15-tetrahydrofuran group, was found in the leaves of Strophanthus amboensis, a deciduous shrub used medicinally in Southwest Africa [289]. Furthermore, the fusidic acid-related antibiotics, including 11-keto-fusidic acid (333) produced by Fusidium coccineum, effectively inhibit protein synthesis both in vivo and in vitro in prokaryotic and eukaryotic cells [290,291,292].

The sex hormone 1,3,20-trihydroxypregnan-11-one (334) was identified in the urine of a patient diagnosed with 17α-hydroxylase deficiency syndrome [293]. Similarly, β-cortolone (3α,17α,20β,21-tetrahydroxypregnane-11-one, 335), a consistent metabolite, was detected in the urine of 20 young and elderly individuals of both genders [294].

Steroidal alkaloids (336-342), characterized by a basic steroidal structure with a nitrogen atom integrated into the rings or side chains, represent a significant group of natural compounds [295]. Among these, the rare 11-keto Buxus alkaloids (336-338), a type of triterpenoid alkaloids derived from the cycloartenol skeleton with a modified C-20 side chain and nitrogen-containing groups at C-3 and/or C-20, have shown diverse biological effects [296,297,298]. These alkaloids are notable secondary metabolites found in various plant families, including Solanaceae, Liliaceae, Apocynaceae, and Buxaceae [295]. Notably, steroidal alkaloids (339-342) featuring a carbonyl group at position 11 were extracted from Veratrum album and V. taliense, exhibiting antihypertensive properties [299,300,301].

Summarized on the biological activity of 11-ketosteroids is presented in Table 7, and details are described partially in the text or a full description of the activity is written in the original articles.

12-Ketosteroids

12-Ketosteroids are indeed rare and interesting compounds, primarily found in plants and algae, as opposed to the more commonly studied animal-derived steroids. 12-ketosteroids are predominantly found in plants and algae. Their presence indicates specialized roles in the biochemistry of these organisms, potentially involved in plant and algal growth, development, or defense mechanisms against environmental stressors. Steroids in plants, including 12-ketosteroids, contribute to the chemical diversity found in the plant kingdom. These compounds can vary greatly in structure and function, reflecting the wide array of evolutionary adaptations plants have developed to thrive in diverse environments. In plants, steroids, including those with a ketone group at the 12th position, are thought to play roles in cell membrane integrity, signaling, and possibly as precursors to other important biochemicals. Their exact functions, however, can be quite specific to the species and the environmental context [302,303,304].

A halotolerant fungus, Aspergillus flocculosus PT05-1, was discovered in the sediment of the Putian saltern in Fujian Province, China, cultivated in a hypersaline medium. It produced (22R,23S)-epoxy-3β,11α,14β,16β-tetrahydroxyergosta-5,7-dien-12-one (343), which exhibited cytotoxic effects against HL-60 and BEL-7402 cells with IC₅₀ values between 12-18 μM, and demonstrated antimicrobial activity against Enterobacter aerogenes, Pseudomonas aeruginosa, and Candida albicans with MIC values ranging from 1.6-15 μM [305].

The chloroform/methanol extract of the red alga Laurencia papillosa, sourced from the Red Sea in Saudi Arabia, was found to contain a cholestane derivative: 3α,6α-dihydroxy-5β-cholestan-12-one (344) [306].

From the organic extract of Allium porrum, sapogenins named 12-keto-porrigenin ((25R)-5α-spirostan-3β,6β-diol-12-one, 345 and 346) were isolated and shown to possess antiproliferative activity against four tumor cell lines in vitro [307].

The toxic 12-keto-bufadienolide, daigremontianin (347), was isolated from the plant Kalanchoe daigremontiana, formerly known as Bryophyllum daigremontianum [308]. Additionally, two bufadienolide glycosides, orbicusides A (348) and C (349), were identified as toxic constituents in Cotyledon orbiculata var. orbiculata [309].

Bufadienolides and their more polar conjugates, bufotoxins, are present in toads from the genus Bufo. These compounds are found not only in their unconjugated forms but also as several C-3 conjugates [310]. Two bufodienolides, arenobufagin (3β,11α,14-trihydroxy-12-oxo-5β,14β-bufa-20,22-dienolide, 350), and a second compound (351) were isolated from the Central Asian green toad, Bufo viridis [311]. Arenobufagin, a primary bufadienolide from Bufo viridis toad venom, has been shown to inhibit growth in various cancer cell lines [312].

Research into the defensive mechanisms of fireflies, specifically Photinus pyralis, P. ignitus, and P.marginellus (Coleoptera: Lampyridae), resulted in the isolation of certain compounds (352-357) that make the fireflies distasteful to birds [313].

Additionally, microbial transformation of 20(S)-protopanaxatriol by cell suspension cultures of Aspergillus niger AS3.1858 produced two steroids (358 and 359), which exhibited anticancer activity against multiple cancer cell lines including Du-145, Hela, K562, K562/ADR, SH-SY5Y, HepG2, and MCF-7 [314].

Figure 11. 12-Ketosteroids derived from algae, plants, and fungi.

Hu and colleagues [315] identified a triterpenoid named kadcoccinone F (360) from the plant Kadsura coccinea. Additionally, a bioactive triterpenoid pigment, stellettin A (361), was detected in the marine sponge Stelletta tenuis [316], while the cytotoxic triterpenoid pigment stellettin B (362) was isolated from the marine sponge Jaspis stellifera [317]. Stellettin B demonstrated significant inhibitory effects on the growth of human glioblastoma cancer SF295 cells.

An unusual steroidal compound, (3α,5α),(8β,11β)-diepidioxy-ergost-22E-en-12-one (363), was isolated and characterized from the dried fruit bodies of Trametes orientalis [318].

Regarding bile acids, most naturally occurring varieties are part of the 5β-series, featuring hydroxyl groups in the A, B, and C rings of the steroid system, commonly located at positions C3, C6, C7, C12, and C23, and predominantly oriented in the α configuration. Typically, the A/B ring junction is cis, whereas both the B/C and C/D ring junctions are trans [319]. 12-Ketolithocholic acid (364) was first identified in cattle bile by Wieland and Kishi over 90 years ago [320] and has also been detected in the feces of some animal species [321]. Furthermore, 3α,7α-dihydroxy-12-keto-5β-cholanic acid (365) has been identified in human feces [322]. This acid and its esters are crucial intermediates in the synthesis of chenodeoxycholic acid from cholic acid. 3α-Hydroxy-12-keto-5β-cholanoic acid (366), 3α-hydroxy-7,12-diketo-5β-cholanoic acids (367), and 365 were found in the urine of male patients with liver cirrhosis [323].

A 9,19-cycloartane triterpene, cimigenol-12-one (368), was isolated from the aerial parts of Cimicifuga foetida [324], and anodendroxide E2 (369) was detected in the volatile oil from matured leaves of Calotropis procera [325]. Additionally, a steroidal sapogenin (370) and its oxidized analogue (371) were isolated from the roots of Cynanchum otophyllum, demonstrating cytotoxic activities [326]. An isosteroidal alkaloid, delavidine (372), was isolated from Fritillaria delavayi collected from Sichuan, China [327].

Ritterazines, a class of complex natural compounds, have been isolated from ascidians, commonly known as sea squirts [328]. These compounds were first discovered in the 1990s in the ascidian Ritterella tokioka [329]. Characterized by their unique and diverse structures, which include macrocyclic lactams and multiple fused rings, ritterazines have garnered attention for their potent biological activities, particularly their cytotoxic properties against various cancer cell lines. Notably, ritterazines U (373) and Z (374), which are 12-keto bis-steroidal pyrazine alkaloids produced by Ritterella tokioka, have demonstrated significant anticancer properties [328].

FABCephalostatins are a group of steroidal pyrazine alkaloids that were first isolated from the marine worm Cephalodiscus gilchristi [331,332]. They are known for their potent cytotoxicity and have been the subject of extensive research due to their potential as anticancer agents. The cephalostatins exhibit remarkable biological activity, with some compounds in the series showing nanomolar or even picomolar potency against various cancer cell lines. Their mechanism of action is believed to involve the inhibition of tubulin polymerization, which disrupts the formation of the mitotic spindle, leading to cell cycle arrest and apoptosis in cancer cells. The chemical structure of cephalostatins is characterized by a unique dimeric steroid framework, with two steroid units linked by a pyrazine bridge. This complex structure has made the total synthesis of cephalostatins a challenging and significant achievement in synthetic organic chemistry. Due to their potent biological activity and complex structure, cephalostatins continue to be a focus of research in the fields of natural products chemistry, medicinal chemistry, and cancer pharmacology [333]. Cephalostatins 1-4 (375-378), 14 (379) and 15 (380) containing unique dimeric 12-keto steroids were found, isolated and their biological activity was established [334,335].

12-Ketosteroids in plants and algae may exhibit unique biological activities, such as antifungal, antibacterial, or anti-inflammatory properties. The rarity and specific occurrence of 12-ketosteroids in plants and algae make them fascinating subjects for chemical ecology and natural product chemistry. Overall, while not as extensively studied as their animal-derived counterparts, 12-ketosteroids in plants and algae represent an intriguing area of natural product research, with potential implications for both ecological studies and biotechnological applications. Summarized on the biological activity of 12-ketosteroids is presented in Table 8, and details are described partially in the text or a full description of the activity is written in the original articles.

15-Ketosteroids

15-Ketosteroids are a class of steroids characterized by the presence of a ketone group at the 15th carbon atom of the steroid nucleus. These compounds are found across a diverse range of organisms, including fungi, sea sponges, and some plants, reflecting their broad biological importance and diversity. In fungi, 15-ketosteroids may play roles in their development, reproduction, and secondary metabolism. Fungi are known for their capability to produce a variety of bioactive secondary metabolites, and ketosteroids can be crucial components of these pathways.

In marine sponges, these steroids are part of a complex chemical arsenal used for defense against predators and microbial infection, as well as for communication. Sponges are known to house a rich array of chemical compounds that serve ecological functions, and steroids such as 15-ketosteroids contribute to these roles [336,337,338].

In plants, while less commonly reported, steroids including 15-ketosteroids can influence growth, development, and defense mechanisms. They are part of the broader group of plant steroids that regulate various physiological processes [339].

Additionally, the biochemical pathways leading to the synthesis of 15-ketosteroids involve modifications of standard steroidal structures, which can alter their biological activity significantly. These modifications can impact receptor binding and biological outcomes, influencing processes such as hormone signaling and cellular regulation. Research into 15-ketosteroids often focuses on their potential pharmacological applications, given their structural diversity and biological activity. These studies might look into anti-inflammatory, anti-cancer, or antimicrobial properties, which are common areas of interest in natural product drug discovery.

A 15-ketosteroid (381, structures see in Figure 12) discovered in the fruiting bodies of the fungus Amauroderma subresinosum exhibited cytotoxic activity against the HL-60 cell line with an IC₅₀ of 32.1 µM and demonstrated less potency (IC₅₀ > 40 µM) against SMMC-7721, A549, MCF-7, and SW480 cell lines [340]. This compound was also detected in the culture of the basidiomycete Polyporus ellisii [341]. Additionally, a cytotoxic steroid (382) isolated from extracts of the king trumpet mushroom, Pleurotus eryngii, showed anti-proliferative activity toward RAW264.7 cells with an IC₅₀ over 30 µM and inhibited NO production with an IC₅₀ of 13.2 µM [342].

The compound 5β,6β-epoxide (383) was found in Polyporus ellisii and a Phomopsis species, exhibiting antibacterial activity (MIC of 28.2 µM against Micrococcus tenuis) and cytotoxic activity against cancer cell lines HL-60, SMMC-7721, A549, MCF-7, and SW480 (IC50 > 40 µM) [17,342]. A similar steroid (384) detected in fungi Ganoderma resinaceum, Polyporus ellisii, and Phomopsis sp. also showed cytotoxic activity, particularly against HL-60 with an IC₅₀ of 18.8 µM and other mentioned cell lines with IC₅₀ values over 40 µM [342].

The fungus Penicillium purpurogenum, known as a steroid producer (385), has demonstrated cytotoxic activity against A549, HepG2, and MCF-7 cancer cell lines, with IC₅₀ values exceeding 100 µM [343]. Furthermore, a fungus derived from the Halichondria sponge, Gymnacella dankaliensis, was cultured resulting in the isolation of gymnasterone C (386) from the original malt extract medium [344,345].

Marine sponge Theonella swinhoei, sourced from various locations in the Solomon Islands (Malaita and Vangunu Is.), has produced conicasterol J (387) [230], and theonellasterol C (388) was also detected in the same sponge [346]. Contignasterol (389), a highly oxygenated steroid with an unusual 14β-configuration, was obtained from the Papua New Guinea sponge Petrosia contignata [347]. Additionally, two unique pentacyclic steroids (390 and 391) with a cis C/D ring junction were isolated from Xestospongia bergquistia and have been noted as powerful inhibitors of histamine release [348].

Marine sponges from the genus Oceanapia, which includes over 50 species found in tropical and subtropical seas, contain tamasterone sulfates (392) and (393), a C-14 epimeric pair of polyhydroxylated sterols [349,350]. Similarly, 15-keto-haliclostanone sulfate (394) has been isolated from a Haliclona sponge [351].

Three saponins, pandaroside K–M (395–397), were identified from the marine sponge Pandaros acanthifolium (Martinique Is., Caribbean) and exhibited antiprotozoal activity [352]. Over 50 years ago, 14α-artebufogenin (398) and 14β-artebufogenin (399) were isolated from traditional Chinese medicine known as Chan Su [353].

Two structurally unusual steroids, compounds 400 and 401, were metabolized by a marine strain of Gymnasella dankaliensis isolated from the sponge Halichondria japonica (Osaka Bay, Japan). These compounds exhibited significant and marginal growth inhibition against the lymphocytic leukemia P388 cell line with ED50 values of 0.9, and 2.5 µg/mL, respectively [344,345].

Three cycloartane triterpenoids, isodahurinol (402), 20,24-di-O-acetylisodahurinol-3-O-α-L-arabinopyranoside (403), and 24-O-acetylisodahurinol-3-O-α-L-arabinopyranoside (404) were isolated from the aerial parts of Cimicifuga foetida [324], and isodahurinol (402) was also detected in other Cimicifuga species [354]. Additionally, 15-oxo-cucurbitacin F (405) and 15-oxo-23,24-dihydrocucurbitacin F (406), isolated from Cowania mexicana, exhibited inhibitory activity against HIV-1 replication in H9 cells, with EC₅₀ values of 0.3 and 2.5 μg/mL, respectively, and therapeutic index values of 17.0 and 15.2, respectively [355].

A cycloartane triterpene glycoside, 16α-hydroxyl-7(8)-en-dahurinol-3-O-[4′-O-acetyl]-α-L-arabinopyranoside, named cimiheraclein F (407), was isolated from the aerial parts of Actaea heracleifolia collected from Yichun County, Heilongjiang Province, China [356]. Dahurinol (408, (24R)-24,25-dihydroxy-15-oxoacta-(16R,23R)-16,23-monoxol) and acerionol (409, 3-deoxy-8,9-didehydro-(24S)-24,25-dihydroxy-(3S,10S)-3,10-epoxy-15-oxo-9,10-secoacta-(16R,23R)-16,23-monoxol) were found in extracts of Actaea racemosa [357].

Additionally, several 15-keto pregnane glycosides, namely stemmosides E, F, G, and H (410-413), were isolated from Solenostemma argel. These compounds, characterized by a unique 14 proton configuration, with stemmosides E and F additionally featuring a rare enolic function at C-16 and stemmosides G-J displaying an unusual C-17 side chain, effectively reduced cell proliferation in a dose-dependent manner [358].

The sponge Melophlus sarasinorum, belonging to the family Geodiidae and subfamily Erylinae, commonly found in the Indo-West Pacific tropical region, contains glycosides known as sarasinosides [359]. Dai and colleagues [360] isolated a glycoside, sarasinoside L (414), from specimens harvested near Sulawesi, Indonesia, while Santalova and coworkers [361] isolated a similar triterpene glycoside named sarasinoside A5 (415). Both steroids feature a keto group at position 15. Additionally, other steroidal oligoglycosides, mycalosides F (416) and H (417), were isolated from the polar extract of the Caribbean sponge Mycale laxissima [362].

From the Korean marine sponge Clathria gombawuiensis, a series of polyoxygenated steroids (418 - 424) were isolated. The structures of gombasterols A–F (419–424) were elucidated through combined spectroscopic analyses. These compounds are characterized as highly oxygenated steroids with a 3β,4α,6α,7β-tetrahydroxy substitution pattern or an equivalent structure (7β-sodium O-sulfonato for 421) and a common structural motif of a C-15 keto group [363]. Summarized on the biological activity of 15-ketosteroids is presented in Table 9, and details are described partially in the text or a full description of the activity is written in the original articles.

16-Ketosteroids

16-Ketosteroids are another interesting class of steroid compounds, defined by the presence of a ketone group at the carbon-16 position in the steroid nucleus. These compounds are primarily known for their presence in various plant species but are also found in some marine organisms such as sea cucumbers and sponges.

In plants, 16-ketosteroids are typically found in the leaves, bark, roots, seeds, pollen, and fruits. Similar to other phytochemicals, ketosteroids can help protect plants from herbivores and pathogens. Their bitter taste or toxic properties can deter predators, while their antimicrobial properties can prevent fungal and bacterial infections. Steroids are crucial in plant growth and development, influencing cell division, elongation, and differentiation. The specific roles of 16-ketosteroids in these processes might be less well-defined but are likely important due to the widespread presence of related compounds in the plant kingdom. Plants produce certain steroids in response to environmental stresses such as drought, salinity, and extreme temperatures. These compounds can help the plant manage the stress by modulating biochemical pathways [364,365].

In marine organisms like sea cucumbers and sponges, the presence of 16-ketosteroids, though less common, suggests a potential role in similar biological functions such as defense against predators or infections. The rarity of these compounds in marine environments compared to plants might indicate specialized roles or specific ecological adaptations [15].

Pharmacologically, steroids including 16-ketosteroids are of interest for their potential anti-inflammatory, anticancer, and other bioactive properties. The modification at the 16th carbon could influence how these steroids interact with biological receptors, potentially leading to unique activities not seen in more common steroids [366].

Aglaia lawii, a species in the Meliaceae family, contains three 16-ketosteroids in its leaves: 3-epi-dyscusin C (425, structures see in Figure 13), 3-epi-lansisterone E (426), and (Z)-2α-hydroxyaglawone (427). These C-21 pregnane steroids feature a highly oxygenated ring A and have shown significant anti-inflammatory activities, with IC₅₀ values for NO inhibition ranging from 4.47 to 7.67 µM [367].

From the wood of the Costa Rican tree Trichilia hirta, two steroids, trichiliasterone A (3β-hydroxypregnan-2,16-dione, 428) and trichiliasterone B (2-hydroxyandrost-1,4-diene-3,16-dione, 429), were isolated. Both compounds inhibited the growth of the European corn borer, Ostrinia nubilalis, and the variegated cutworm, Peridroma saucia. Steroid 428 was also isolated from Trichilia americana [368].

The fruits of Artocarpus heterophyllus led to the isolation of a steroid named artoheterophoid (430), which exhibited remarkable inhibitory effects on NO production with an IC₅₀ value of 0.72 µM [369]. Additionally, three pregnanes (431-433) were isolated from the leaves of Aglaia grandis [370], and several pregnane-type steroids, including 2β,3β-dihydroxy-5α-pregn-17(20)-(Z)-en-16-one (434) and aglatomin A (435), were detected in the leaves of Aglaia tomentosa [371]. Lansisterone E (436) and 2β,3β,4β-trihydroxypregnan-16-one (437) were obtained from the branches of A. perviridis [372].

Ampelozizyphus amazonicus, a medicinal climbing shrub native to the Amazonian region, used traditionally to prevent malaria, contains aglycone structures of saponins in its crude extract, specifically 16-keto-tetrahydroxydammar-23-ene (438) and 16-keto-tetrahydroxy-dammar-24-methylene (439) [373].

Bacopa monnieri, known as brahmi in Ayurveda, is celebrated for enhancing intelligence, memory, and revitalizing sensory organs. Its nootropic activity has been extensively studied, with several researchers confirming that alcoholic/hydroalcoholic extracts of the whole plant exhibit varied activities. These extracts contain two steroids, bacoside A (440) and B (441), which contribute to its therapeutic properties [374].

Several 9,10-seco-9,19-cyclolanostane arabinosides, named podocarpasides A–D (442-445), F (447), and G (448), were isolated from the roots of Actaea podocarpa, a species closely related to black cohosh, a well-known dietary supplement. Specifically, podocarpaside C (444) displayed modest complement activity inhibition with an IC₅₀ value of 200 µM [375].

The structure of podocarpaside E (446), also from Actaea podocarpa, was revised to 3β,15α,25-trihydroxy-16,23-dioxo-6α,19α-epidioxy-9,10-seco-9,19-cyclolanost-5(10),9(11)-diene 3α-O-L-arabinopyranoside [375]. Another compound, podocarpaside (449), an arabinoside with a unique triterpene skeleton isolated from the same species, exhibited anticomplement activity [376].

A phytochemical study on the rhizomes of Cimicifuga foetida led to the isolation of two cycloartane triterpenoids (450 and 451), which are part of a seven-membered-ring variant of 9,10-seco-9,19-cycloartane triterpenoids. Additionally, compounds 452 and 453 were identified as 3-O-β-D-xylopyranosides [377]. Further, from the roots of Actaea podocarpa, three cycloartane-type triterpene arabinosides, podocarpasides H-J (454-456), were isolated, with podocarpaside I (455) showing moderate anticomplement activity with an IC₅₀ value of 250 µM [375].

A glycoside named acanthifolioside A (457), a minor component, was isolated from the marine sponge Pandarosa canthifolium. Acanthifoliosides are distinct for having a rare oxidation pattern at C-15 and C-16 on the D ring [352].

From the Far Eastern sea cucumber Psolus chitonoides, collected near Bering Island (Commander Islands) at depths of 100–150 m, triterpene pentasides named chitonoidosides A (458) and A1 (459), which contain one or two sulfate groups, were isolated [378]. Additionally, from the sea cucumber Actinopyga flammea, 16-keto-holothurinogenin (460) was obtained through acid hydrolysis of the crude extract [379].

Steroidal alkaloids, cortistatins C (461) and D (462), featuring a 9(10−19)-abeo-androstane and isoquinoline skeleton, were isolated from the marine sponge Corticium simplex. These compounds demonstrated high selectivity in inhibiting the proliferation of human umbilical vein endothelial cells (HUVEC) [380].

Two toxic triterpenoid alkaloids, cyclobuxophylline O (463) and cyclobuxophylline M (464), have been discovered in the box tree moth Cydalima perspectalis [381]. Additionally, cyclobuxophylline M (464) and cyclobuxophylline K (465) were isolated from Buxus sp. and Buxus sempervirens [382,383]. An interesting feature of these alkaloids is the increase in the number of methyl groups on the amino group located at the 3rd position. Another alkaloid, sempervirone (466), was isolated from the leaves of Buxus sempervirens [384].

Pregnane alkaloids such as terminamine S (467), 3β-methylamino-16-oxo-5,17(20)-cis-pregnadiene (468) [385], (Z)-salignone (469) [386], terminamine H (470) [387], 3β-methylamino-16-oxo-5,17(20)-trans-pregnadiene (471) [385], and (E)-salignone (472) [386] were isolated from the whole herb of Pachysandra terminalis [388].

A phytochemical study on the stem of Ecdysanthera rosea resulted in the isolation of C-21 pregnane glycosides ecdysosides A–D (473–476). Notably, compound 473 exhibited moderate antibacterial activity against Enterococcus faecalis and Providencia smartii [389]. Summarized on the biological activity of 16-ketosteroids is presented in Table 10, and details are described partially in the text or a full description of the activity is written in the original articles.

17-Ketosteroids

17-ketosteroids (17-KS) are metabolites derived primarily from the catabolism of androgens and, to a lesser extent, estrogens. These compounds are significant markers in the body, providing insights into adrenal and gonadal function. 17-KS are key byproducts found in the urine, originating from the metabolism of androgenic hormones like testosterone and dehydroepiandrosterone (DHEA). The presence and levels of these ketosteroids are indicators of androgenic activity in the body, reflecting the functioning of the adrenal cortex and gonads. The measurement of 17-KS in urine is a valuable diagnostic tool. It helps in assessing adrenal gland function and diagnosing disorders like adrenal hyperplasia, adrenal tumors, and conditions affecting the gonads. This is particularly useful in clinical settings to monitor and diagnose endocrine disorders [9,100,390,391].

Though 17-KS themselves are not hormonally active, their formation and excretion reflect the body’s metabolic pathways in breaking down sex hormones. Thus, they indirectly influence the regulatory mechanisms associated with hormonal balance, impacting physiological processes such as growth, reproduction, and stress responses. In research, the levels of 17-KS can be studied to understand variations in hormonal activity due to various diseases, lifestyle factors, or environmental influences. This research helps in developing treatments for hormonal imbalances and related health issues [392,393]. In non-human animals, the specific functions of 17-KS can vary, but generally, they serve as markers of similar hormonal and metabolic processes. For example, in veterinary medicine, measuring these ketosteroids can assist in diagnosing health conditions in domestic and wild animals, particularly those related to reproductive and adrenal functions [393].

17-Ketosteroids are vital as both metabolic intermediates and diagnostic markers across various species, playing a significant role in understanding and managing health issues related to hormone regulation and adrenal gland function [393,394,395,396,397].

Holarrhena pubescens, an Indian medicinal tree indigenous to the tropical Himalaya and Assam, is known for its stem bark, commercially referred to as kurchi. This bark has astringent, antidysenteric, anthelmintic, stomachic, febrifugal, and tonic properties. A unique compound, puboestrene [3-acetoxy-17-oxo-1,3,5(10)-estratriene] (474, structures see in Figure 14), has been isolated from the bark of Holarrhena pubescens [398].

Estra-1,3,5(10)-triene-3-ol-17-one (475), commonly known as estrone, is a naturally occurring estrane steroid produced in vivo from androstenedione and/or testosterone via estradiol. This estrogen demonstrates estrogenic activity, with variations depending on its structure, some of which may also exhibit anticancer properties [399,400,401]. Butenandt and Jacobi [402] isolated estrone (475) from seeds and pollen of Phoenix dactylifera, Punica granatus, Malus pumila, Hyphaene thebaica, Salix caprea, and Glossostemon bruguieri. In 1926, Dohrn and co-workers first detected estrone (475), equilin (476), and hippulin (477) as female sex hormonal steroids in plants [403]. This discovery was followed by further identifications in the 1930s by Butenandt and Jacobi [402] and Skarzynski [404]. Additionally, extracts from the bark of the main wooden rod of ketapang Terminalia catappa (Combretaceae) contained estrone (474), equilin (475), and equilin sulfate (478) [405].

6,8-Didehydroestrone (479) and estra-1,3,5(10),6,8-pentaen-3-ol-17-one, known as equilenin, were first isolated from the urine of pregnant mares in 1936 by Desmond Beall [406]. Later, equilenin sulfate (480) was also extracted from the urine of pregnant mares by Schachter and Marrian in 1938, and subsequently synthesized by Bachmann and Wilds in 1939 [407,408]. Two naphthalene-containing steroids (481 and 482) have been found in the bark of Terminalia catappa, although it’s speculated that these compounds are naphthalenic steroids produced by the tree itself [409]. Terminalia catappa and Terminalia mantaly (Combretaceae) are recognized medicinal plants used in Cameroon to treat various diseases.

In the lipophilic fractions of Loranthus micranthus, a medicinal plant known in eastern Nigeria as a species of the African mistletoe and commonly used in traditional medicine, two notable steroids were identified: 5α,16,16-dimethyl-androstan-17-one (483) and 6β-hydroxy-17-oxo-4,5-secoandrostan-4-oic acid (484) [410].

Additionally, 3β-Hydroxy-5α-androstan-17-one (epiandrosterone, 485), 5α-androstan-3,17-dione (486), and 3α-hydroxy-5α-androstan-17-one (androsterone, 487), have been identified in the solvent-soluble fraction of peat from Bolton Fell Moss (Cumbria, U.K.). The structures and δ¹³C values of these androstane derivatives suggest a diagenetic origin from sterols also present in the peat, providing the first evidence that cleavage of the C-17 side-chain can occur during early diagenesis, likely through microbial oxidation [411].

Comamonas testosteroni is recognized as a key model in the study of bacterial aerobic steroid degradation, capable of degrading cholic acid. Three major steroids (488-490) have been identified as byproducts of cholic acid degradation [412].

From the stem bark of Ailanthus malabarica, rare octanor- and nonanor-triterpenoids, malabanones A (491) and B (492), featuring a unique tricyclo[4.3.1.0.1,6]decane unit, were isolated [413]. Additionally, a strain of the fungus Fusarium oxysporum SC1301, isolated from soil samples, is known as a steroid producer (493) [414].

Pinus nigra, also known as the Austrian pine or black pine, is found across Southern Europe from the Iberian Peninsula to the eastern Mediterranean, the Anatolian peninsula of Turkey, Corsica, Cyprus, and the high mountains of Northwest Africa. Various steroid hormones have been detected in the pollen of this pine species. These include epiandrosterone (485), androsterone (3α-hydroxy-5α-androstan-17-one, 487), dehydroepiandrosterone (3β-hydroxyandrost-5-en-17-one, 493), 2α,3α-dihydroxy-5β-androstan-17-one (494), 11β-hydroxy-etiocholanolone (3α,11β-dihydroxy-5β-androstan-17-one, 495), 3α-hydroxy-5β-androstane-11,17-dione (496), and 3α-hydroxy-5α-androstane-11,17-dione (497) [415]. Additionally, androstane-3,17-dione (486) was identified in the sugar pine (Pinus lambertiana) [416].

Steroid modifications via selected wild and engineered microbial strains have become a crucial method for producing valuable steroid drugs and their precursors for the pharmaceutical industry. These microorganisms excel in sterol side chain degradation, oxyfunctionalization of the steroid core, and redox reactions at various positions of the steroid molecule. Over ten 17-ketosteroids (498-516) have been isolated and identified, demonstrating the diverse capabilities of these microorganisms [9,99,417,418,419,420,421].

Phytochemical studies on an ethanol-soluble extract of the roots of Buxus sempervirens of Turkish origin have led to the isolation of (+)-17-oxocycloprotobuxine (517) [422].

Urinary steroids, metabolites of steroid hormones excreted in urine, are pivotal in assessing an individual’s metabolic state, endocrine function, and overall health [423]. The measurement of these steroids plays a critical role in diagnosing and monitoring various endocrine disorders. For example, elevated levels of certain urinary steroids may indicate adrenal gland disorders such as Cushing’s syndrome or adrenal tumors [425].

Urinary steroid profiles are invaluable for understanding an individual’s metabolic processes. The ratios of specific steroids can reveal the activity of enzymes involved in steroid metabolism. These steroids are end products of steroid hormone metabolism, formed in the liver and other tissues through various chemical modifications before being excreted in the urine [426].

Common urinary steroids include metabolites derived from steroid hormones such as cortisol, testosterone, estrogen (475), and progesterone. Notable among these are etiocholanolone (485), androsterone (487), and a range of 17-ketosteroids (485, 487, 518-526) [427].

Summarized on the biological activity of 17-ketosteroids is presented in Table 11, and details are described partially in the text or a full description of the activity is written in the original articles.

20-Ketosteroids

20-Ketosteroids are a category of steroid hormones characterized by the presence of a ketone group at the 20th carbon of the steroid structure. These compounds include important hormones such as cortisone, which is a significant glucocorticoid. The most well-known 20-ketosteroid, cortisone, plays a crucial role in the body’s stress response. It is involved in regulating metabolism, immune response, and inflammatory processes. Cortisone is produced in the adrenal cortex, specifically in the zona fasciculata and zona reticularis [428,429,430,431].

As a glucocorticoid, cortisone helps in the regulation of glucose metabolism. It stimulates gluconeogenesis, the process by which the liver generates glucose from amino acids and other substrates, which is vital during periods of fasting or stress [432,433,434]. Cortisone and similar 20-ketosteroids have potent anti-inflammatory and immunosuppressive effects. They inhibit the activities of white blood cells and other components of the immune system, thus reducing inflammation and the immune response. This makes them useful in treating a variety of inflammatory and autoimmune conditions, such as asthma, allergies, and rheumatoid arthritis. Cortisone is also part of the body’s response to stress. It is released in response to ACTH (adrenocorticotropic hormone) from the pituitary gland, which is stimulated by physical, emotional, or chemical stressors [435]. Due to their powerful anti-inflammatory and immunosuppressive actions, synthetic derivatives of 20-ketosteroids (such as prednisone) are commonly used in medical treatments. These are designed to mimic the effects of naturally occurring cortisone but may be more potent or have longer-lasting effects [435,436].

Overall, 20-ketosteroids like cortisone are crucial for maintaining homeostasis in the body, especially in response to stress. They play significant roles in metabolism, immune regulation, and inflammation control, making them vital both as natural hormones and as pharmacological agents [437,438].

The gorgonian Menella spinifera, collected off the South China Sea, was found to contain 3β-hydroxy-5α-pregnane-20-one (527) [439]. Additionally, several pregnane steroids—3α-hydroxy-5β-pregnan-20-one (528), 3β-hydroxy-pregnan-5-en-20-one (529), 5β-pregnan-3,20-dione (530), 5α-pregnan-3,20-dione (531), pregnan-4-en-3,20-dione (532), and pregnan-1,4-dien-3,20-dione (533) - were isolated from another species of the gorgonian Menella, collected off Meishan Island, Sanya Bay, Hainan province, China [440]. A strain of the fungus Fusarium oxysporum SC1301, isolated from soil samples, is known to produce pregnenolone (534) [414]. Moreover, extracts of Rhodococcus sp. cells have been shown to produce two oxygenated pregnane steroids (535 and 536) [441]. Phytochemical analysis of the methanolic extract of Euonymus alatus twigs led to the isolation of a sterol identified as (3,16)-3,16-dihydroxypregn-5-en-20-one (537) [442]. The sponge Psammaplysilla purpurea contains 3β-hydroxy-5α-pregnan-20-one (528) and 3β-hydroxy-pregn-5-en-20-one (529) as minor constituents in its free sterol mixture [443].

Recent findings highlight that only a few insect taxa are known to produce steroids essential for insects, including several chrysomelids (Chrysomelidae), carrion beetles (Silphidae, Staphylinidae), lampyrid beetles (Lampyridae), and giant aquatic bedbugs (Belostomatidae) [444,445,446]. The prothoracic protective glands of dytiscids are noted for producing a remarkable array of known vertebrate steroid hormones along with new and unusual steroids (530, 531, 532, 537–544), found also in predaceous diving beetles and belostomatid bugs. Some of these molecules are believed to be synthesized from cholesterol acquired from their prey [445].

Brassinosteroid metabolites, known as plant hormones (545-547), have been detected in extracts of the flowering plant Ornithopus sativus from the family Fabaceae [447]. Several pregnane glycosides and their aglycones (548-550) were identified in the roots of Asclepias tuberosa [448]. Chemical investigations into the roots of Dysoxylum densiflorum identified two known steroids, (527 and 528) [449], and from the leaves of oleander (Nerium indicum), pregnane 3β,14-dihydroxy-5α,14β-pregnan-20-one (551) has been identified [450].

A bioactive steroid (552) was isolated from an alcohol extraction of Solanum nigrum, demonstrating significant cytotoxic activities against SW480 and Hep3B cells [451].

Steroidal alkaloids, which possess a basic steroidal skeleton with a nitrogen atom integrated into rings or side chains, showcase a broad range of biological activities. Some steroidal alkaloids, such as abiraterone acetate—a widely used treatment for prostate cancer—exemplify how these compounds can be developed into therapeutic drugs. The structural diversity of natural steroidal alkaloids presents a spectrum of biological activities, making them highly valuable to both natural product chemistry and medicinal chemistry communities [295]. Examples include two steroidal alkaloids, cyclobuxomicreinine (553) and cyclorolfeine (554), found in extracts of Buxus hildebrandtii [452], cyclobuxomicreinine (555) identified from Buxus species [453], and buxippine K (556) which would be isolated from the leaves of Buxus hyrcana [454]. An antiprotozoal nor-triterpene alkaloid, 16-α-hydroxybuxaminone (557), was isolated from Buxus sempervirens and Buxus sp. [455,456].

Several steroidal glycosides (558-565) were isolated from the aerial parts of Ceropegia fusca (Asclepiadaceae), a crassulacean acid metabolism plant endemic to the Canary Islands, traditionally used as a cicatrizant, vulnerary, and disinfectant. The dichloromethane extract exhibited significant cytostatic activity against HL-60, A-431, and SK-MEL-1 cells—models for human leukemic, epidermoid carcinoma, and melanoma cells respectively [457]. Summarized on the biological activity of 20-ketosteroids is presented in Table 12, and details are described partially in the text or a full description of the activity is written in the original articles.

Figure 15. 20-Ketosteroids derived from insects, and plants.

Miscellaneous Ketosteroids Derived from Natural Sources

A rearranged sterol with an unusual tetracycle core skeleton, penicillitone (566), was obtained from the culture of the fungus Penicillium purpurogenum SC0070. This compound demonstrated potent inhibitory effects on tumor cell growth and key pro-inflammatory cytokine production in macrophages [458]. The mushroom Stropharia rugosoannulata, known as saketsubatake in Japanese and wine-cap stropharia in English, produces an unusual steroid, strophasterol A (567), which exhibited an inhibitory effect on TG toxicity in a dose-dependent manner [459].

An unusual steroid-type compound, dankasterone A (568), is produced by the fungus Gymnascella dankaliensis, which was isolated from the Japanese sponge Halichondria japonica [344,345]. Citreoanthrasteroid A (569) was isolated from the mycelia of a hybrid strain, KO 0231, prepared by a cell fusion technique using Penicillium citreo-viride IFO 6200 and 4692 [460].

Ergosteroid, gloeophyllin J (570), has been isolated from the solid cultures of fungus Gloeophyllum abietinum. This compound represents the first ergosteroid featuring the cleavage of a C8−C14 bond [461]. Steroids (234R)-3β-hydroxy-24-methyl-4-methylene-8,14-secocholestane-8,14-dione (571) and swinhosterol A (572) were isolated from an Okinawan sponge Theonella swinhoei. An undescribed 9,11-secosteroid, cyclosecosteroid A (573), was isolated from the mangrove endophytic fungus Talaromyces sp. SCNU-F0041, and it showed moderate inhibitory activity against AChE, with an IC₅₀ value of 46 µM [462].

An oxygenated 4-exo-methylene sterol, 28-homoswinhoeisterol (574), was discovered in the marine sponge of Theonella swinhoei collected from the Bohol province in the Philippines [463].

The 9,11-secosteroids, pinnigorgiols A (575) and E (576) with a rare carbon skeleton, a tricyclo[5,2,1]decane ring, were isolated from a gorgonian coral identified as Pinnigorgia sp. These compounds displayed inhibitory effects on the generation of superoxide anions and the release of elastase by human neutrophils [464,465]. Two secosteroids, 3β,11-dihydroxy-5β,6β-epoxy-9,11-secocholestan-9-one (577) and 3β,11-dihydroxy-5β,6β-epoxy-9,11-secogorgostan-9-one (578), have been identified from extracts of the Taiwanese soft coral Cespitularia taeniata [466,467,468].

Steroid, 8αH-3β,11-dihydroxy-5α,6α-epoxy-24-methylene-9,11-secocholestan-9-one (579) was obtained from Sinularia granosa and S. crassa soft coral extracts [469]. Two unusual steroidal derivatives, erectsterates A (580) and B (581), epimers at C-10, were isolated from the South China Sea soft coral S. erecta. These compounds are characterized by a high degree of degradation in ring B and an ester linkage between the A and C/D rings, similar to the compounds chaxines B and D from the edible mushroom Agrocybe chaxingu [470]. Compound (581) displayed cytotoxic activity against several cancer cell lines including A549 (human adenocarcinoma), HT-29 (human colorectal adenocarcinoma), SNU-398 (hepatocellular carcinoma), and Capan-1 (human pancreatic ductal adenocarcinoma) [471].

A series of cytotoxic steroids called stereonsteroids B (582) and F (583) were isolated from the methylene chloride extract of the Formosan soft coral Stereonephthya crystalliana. This coral extract showed significant cytotoxicity against A549, HT-29, and P-388 cancer cells in vitro [472].

Several neotecleanin-type limonoids, walrobsin C (584), I (585), Q (586), R (587), and U (588), were detected in methanol (MeOH) extracts of the root barks of Walsura robusta [473].

Belamchinanes A–D (589-592), four triterpenoids with a novel skeleton, were isolated from the seeds of Belamcanda chinensis. These structures feature a unique 4/6/6/6/5 polycyclic system where a four-membered carbocyclic ring bridges the C-1 and C-11 positions of a classical triterpenoid framework [474].

Strophasterols E and F (594 and 595) were isolated from Pleurotus eryngii, showing interesting structural properties [342], and tricholumin A (595), an ergosterol derivative from Trichoderma asperellum, exhibited antimicrobial activity [475].

In marine pharmacology, stellettins Q (596) from Stelletta sp. is a D-nor steroid with a cyclopentane unit linked to different positions of side chains [476,477], and stelliferins L (597) and M (598) from Rhabdastrella cf. globostellata exhibited antimicrobial activity [478].

Two C-nor-D-homo-estrones (599 and 600) were discovered in the Solanum family [479]. These compounds underscore the diverse potential of C-nor steroids in various therapeutic applications.

C-nor derivatives such as 14-hydroxy-7-methoxy-11,16-diketo-apian-8-en-(22,6)-olide (601) and 7-methoxy-11,16-diketo-apian-8,14-dien-(22,6)-olide (602) have been identified in Salvia officinalis, along with three other complex apianane terpenoids (603, 604, and 605) [480,481].

An unusual steroid-like metabolite, asterogynin B (606), with potential antimalarial properties, was produced by an endophytic fungus from the small palm Asterogyne martiana [482].

From the aerial parts of Premna fulva, a plant used in Zhuang medicine, a unique metabolite, premnafulvol A (607), was isolated. This compound features a distinct 6/5/7/3-fused tetracyclic carbon skeleton [483]. Spiroseoflosterol (608), an unusual ergostane steroid, was isolated from Butyriboletus roseoflavus and demonstrated cytotoxicity against liver cancer cell lines [484].

Figure 16. Miscellaneous ketosteroids derived from different speices.

Additionally, two steroids, urceoloids A (609) and B (610), characterized by a rearranged carbon skeleton with a unique spiro[4.4]nona-3,6,8-triene system, were identified. Both compounds exhibited immune-suppressive activities [485]. Summarized on the biological activity of 20-ketosteroids is presented in Table 12, and details are described partially in the text or a full description of the activity is written in the original articles.

Conclusions

The comprehensive review of steroidal compounds isolated from diverse natural sources such as marine organisms, fungi, plants, and through biotechnological processes reveals a profound complexity and immense pharmacological potential within the realm of natural steroids. This exploration has not only broadened our understanding of steroid chemistry but also highlighted the pivotal role these compounds play in both ecological systems and potential therapeutic applications.

The isolated steroids, ranging from pregnane steroids and steroidal alkaloids to ketosteroids and novel triterpenoids, exhibit a wide array of biological activities. Notably, many of these compounds have shown significant cytotoxic activities against various cancer cell lines, indicating their potential as anticancer agents. For instance, compounds like erectsterates A and B and penicillitone have demonstrated potent effects in inhibiting tumor growth and pro-inflammatory cytokine production. Such findings suggest that these natural steroids could be utilized as lead compounds for the development of new anticancer drugs.

The diverse mechanisms through which these steroids exert their effects are particularly intriguing. Many of these compounds interact with cellular pathways, influencing processes such as cell proliferation, inflammation, and immune response. The ability of these steroids to modulate these pathways at various levels underscores their potential utility in designing drugs with specific targets. This is particularly evident in the case of steroidal alkaloids like abiraterone acetate, which has been successfully developed into a therapeutic drug for prostate cancer by specifically inhibiting critical enzymes involved in steroid metabolism.

From an ecological perspective, the roles these steroids play in their native environments, such as defense mechanisms in marine sponges or regulatory functions in plant systems, provide insight into their natural functions and evolutionary significance. Understanding these roles not only enriches our ecological knowledge but also assists in bioprospecting, where ecological traits guide the search for pharmacologically active compounds.

Looking forward, the challenge lies in harnessing the full potential of these natural steroids. The complexity of their structures often makes synthesis challenging, and while microbial biotransformation offers a promising avenue, scaling these processes for industrial production requires further innovation. Additionally, the bioactivity of these compounds must be evaluated in more complex biological models to fully understand their potential adverse effects and therapeutic windows.

In conclusion, the study of natural steroids not only continues to push the boundaries of natural product chemistry but also offers promising leads for novel drug development. By advancing our understanding of their mechanisms, optimizing their synthesis, and investigating their ecological roles, we can better leverage the therapeutic potential of these diverse and potent molecules.

Funding

This work did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The author declares that he has no known competing financial interests or personal relationships that could affect the work described in this article.

References

Dembitsky, V.M. Bioactive steroids bearing oxirane ring. Biomedicines 2023, 11, 2237. [Google Scholar] [CrossRef] [PubMed]
Dembitsky, V.M. Fascinating furanosteroids and their pharmacological profile. Molecules 2023, 28, 5669. [Google Scholar] [CrossRef] [PubMed]
Dembitsky, V.M. Steroids bearing heteroatom as potential drugs for medicine. Biomedicines 2023, 11, 2698. [Google Scholar] [CrossRef] [PubMed]
Lieberman, S.; Dobriner, K. Biochemistry of steroids. Ann. Rev. Biochem. 1951, 20, 227–264. [Google Scholar] [CrossRef] [PubMed]
Penning, T.M.; Wangtrakuldee, P.; Auchus, R.J. Structural and functional biology of aldo-keto reductase steroid-transforming enzymes. Endocrin. Rev. 2019, 40, 447–475. [Google Scholar] [CrossRef] [PubMed]
Schänzer, W. Metabolism of anabolic androgenic steroids. Clin. Chem. 1996, 42, 1001–1020. [Google Scholar] [CrossRef] [PubMed]
Rohman, A.; Dijkstra, B.W. Application of microbial 3-ketosteroid Δ1-dehydrogenases in biotechnology. Biotech. Advan. 2021, 49, 107751. [Google Scholar] [CrossRef] [PubMed]
Biellmann, J.B. Enantiomeric steroids: Synthesis, physical, and biological properties. Chem. Rev. 2003, 103, 2019–2034. [Google Scholar] [CrossRef] [PubMed]
Mason, H.L.; Engstrom, W.W. The 17-ketosteroids: their origin, determination and significance. Physiol. Rev. 1950, 30, 321–374. [Google Scholar] [CrossRef] [PubMed]
Djerassi, C. Recent advances in the mass spectrometry of steroids. Mass Spect. Nat. Prod. 1978, 30, 171–184. [Google Scholar]
Dembitsky, V.M. Bioactive diepoxy metabolites and highly oxygenated triterpenoids from marine and plant-derived bacteria and fungi. Microbiol. Res. 2023, 15, 66–90. [Google Scholar] [CrossRef]
D’Auria, M.V.; Minale, L.; Riccio, R. Polyoxygenated steroids of marine origin. Chem. Rev. 1993, 93, 1839–1895. [Google Scholar] [CrossRef]
Dembitsky, V.M. In silico prediction of steroids and triterpenoids as potential regulators of lipid metabolism. Marine Drugs 2021, 19, 650. [Google Scholar] [CrossRef] [PubMed]
Dembitsky, V.M.; Gloriozova, T.A.; Poroikov, V.V. Antitumor profile of carbon-bridged steroids (CBS) and triterpenoids. Marine Drugs 2021, 19, 324. [Google Scholar] [CrossRef] [PubMed]
Stonik, V.A. Marine polar steroids. Russ. Chem. Rev. 2001, 70, 673–715. [Google Scholar] [CrossRef]
Vriet, C.; Russinova, E.; Reuzeau, C. Boosting crop yields with plant steroids. Plant Cell 2012, 24, 842–857. [Google Scholar] [CrossRef] [PubMed]
Zhabinskii, V.N.; Drasar, P.; Khripach, V.A. Structure and biological activity of ergostane-type steroids from fungi. Molecules 2022, 27, 2103. [Google Scholar] [CrossRef]
Middleditch, B.S.; Vouros, P.; Brooks, C.J.W. Mass spectrometry in the analysis of steroid drugs and their metabolites : electron- impact-induced fragmentation of ring D. J. Pharm. Pliarm. 1973, 25, 143–149. [Google Scholar] [CrossRef]
Miller, W.L. Steroidogenic Enzymes. Flück, C.E.; Miller, W.L. (Eds). Disorders of the Human Adrenal Cortex. Endocr Dev. Basel, Karger, 2008, Vol. 13, pp. 1–18.
Donova, M.V.; Egorova, O.V.; Nikolayeva, V.M. Steroid 17(3-reduction by microorganisms—a review. Process Biochem. 2005, 40, 2253–2262. [Google Scholar] [CrossRef]
Andrew, R.; Homer, N.Z.M. Mass spectrometry: Future opportunities for profiling and imaging steroids and steroid metabolites. Curr. Opinion Endocr. Metab. Res. 2020, 15, 71–78. [Google Scholar] [CrossRef]
Penning, T.M. The aldo-keto reductases (AKRs): Overview. Chem. Biol. Interact. 2015, 234, 236–246. [Google Scholar] [CrossRef] [PubMed]
Penning, T.M.; Wangtrakuldee, P.; Auchus, R.J. Structural and functional biology of aldo-keto reductase steroid-transforming enzymes. Endocrine Rev. 2019, 40, 447–475. [Google Scholar] [CrossRef]
Mannervik, B.; Ismail, A.; Lindström, H.; Sjödin, B.; Ing, N.H. Glutathione transferases as efficient ketosteroid isomerases. Front. Mol. Biosci. 2021, 8, 765970. [Google Scholar] [CrossRef] [PubMed]
Mirsalami, S.M.; Mirsalami, M.; Ghodousian, A. Techniques for immobilizing enzymes to create durable and effective biocatalysts. Result. Chem. 2024, 7, 101486. [Google Scholar] [CrossRef]
Talalay, P. Enzymatic mechanisms in steroid metabolism. Physiol. Rev. 1957, 37, 362–389. [Google Scholar] [CrossRef]
Duax, W.L.; Griffin, J.F.; Ghosh, D. The fascinating complexities of steroid-binding enzymes. Curr. Opinion Struct. Biol. 1996, 6, 813–823. [Google Scholar] [CrossRef] [PubMed]
Misico, R.I.; Gil, R.R.; Oberti, J.C.; Veleiro, A.S.; Burton, G. Withanolides from Vassobia lorentzii. J. Nat. Prod. 2000, 63, 1329. [Google Scholar] [CrossRef] [PubMed]
Chen, L.X.; He, H.; Qiu, F. Natural withanolides: an overview. Nat. Prod. Rep. 2011, 28, 705–740. [Google Scholar] [CrossRef] [PubMed]
Glotter, E. Withanolides and related ergostane-type steroids. Nat. Prod. Rep. 1991, 8, 415–40. [Google Scholar] [CrossRef]
Xu, Q.Q.; Wang, K.W. Natural bioactive new withanolides. Mini Rev. Med. Chem. 2020, 20, 1101–1117. [Google Scholar] [CrossRef]
Ermolenko, E.V.; Imbs, A.B.; Gloriozova, T.A.; Poroikov, V.V.; Sikorskaya, T.V.; Dembitsky, V.M. Chemical diversity of soft coral steroids and their pharmacological activities. Mar. Drugs 2020, 18, 613. [Google Scholar] [CrossRef]
Iwashima, M.; Nara, K.; Iguchi, K. New marine steroids, yonarasterols, isolated from the okinawan soft coral, Clavularia viridis. Steroids. 2000, 65, 130–137. [Google Scholar] [CrossRef]
Watanabe, K.; Iwashima, M.; Iguchi, K. New bioactive marine steroids from the Okinawan soft coral Clavularia viridis. Steroids 1996, 61, 439–446. [Google Scholar] [CrossRef]
Duh, C.Y.; El-Gamal, A.A.H.; Chu, C.J.; Wang, S.K.; Dai, C.F. New cytotoxic constituents from the formosan soft corals Clavularia viridis and Clavularia violacea. J. Nat. Prod. 2002, 65, 1535–1539. [Google Scholar] [CrossRef]
Kobayashi, M.; Lee, N.K.; Son, B.W.; Yanag, K.; Kyogoku, Y.; Kitagawa, I. Stoloniferone-a,-b,-c, and-d, four new cytotoxic steroids from the okinawan soft coral Clavularia viridis. Tetrahedron Lett. 1984, 25, 5925–5928. [Google Scholar] [CrossRef]
Iwashima, M.; Nara, K.; Nakamichi, Y.; Iguchi, K. Three new chlorinated marine steroids, yonarasterols G, H and I, isolated from the Okinawan soft coral, Clavularia viridis. Steroids 2001, 66, 25–32. [Google Scholar] [CrossRef]
Zhang, W.N.; Tong, W.Y. Chemical constituents and biological activities of plants from the genus Physalis. Chem. Biodiver. 2016, 13, 48–65. [Google Scholar] [CrossRef]
Lan, Y.H.; Chang, F.R.; Pan, M.J.; Wu, C.C.; Wu, S.J. New cytotoxic withanolides from Physalis peruviana. Food Chem. 2009, 116, 462–469. [Google Scholar] [CrossRef]
Jayaprakasam, B.; Nair, M.G. Cyclooxygenase-2 enzyme inhibitory withanolides from Withania somnifera leaves. Tetrahedron 2003, 59, 841. [Google Scholar] [CrossRef]
Zhao, J.; Nakamura, N.; Hattori, M.; Kuboyama, T.; Tohda, C.; Komatsu, K. Withanolide derivatives from the roots of Withania somnifera and their neurite outgrowth activities. Chem. Pharm. Bull. 2002, 50, 760. [Google Scholar] [CrossRef]
Pramanick, S.; Roy, A.; Ghosh, S.; Majumder, H.K.; Mukhopadhyay, S. Withanolide Z, a new chlorinated withanolide from Withania somnifera. Planta Med. 2008, 74, 1745. [Google Scholar] [CrossRef] [PubMed]
Misra, L.; Mishra, P.; Pandey, A.; Sangwan, R.S.; Sangwan, N.S.; Tuli, R. Withanolides from Withania somnifera roots. Phytochemistry 2008, 69, 1000. [Google Scholar] [CrossRef]
Atta-ur-Rahman; Choudhary, M.I.; Yousaf, M.; Gul, W.; Qureshi, S. New withanolides from Withania coagulans. Chem. Pharm. Bull. 1998, 46, 1853. [Google Scholar] [CrossRef]
Atta-ur-Rahman; Yousaf, M.; Gul, W.; Qureshi, S.; Choudhary, M.I.; Voelter, W.; Hoff, A.; Jens, F.; Naz, A. Five new withanolides from Withania coagulans. Heterocycles 1998, 48,, 1801. [Google Scholar] [CrossRef]
Lee, S.-W.; Pan, M.-H.; Chen, C.-M.; Chen, Z.-T. Withangulatin I, a new cytotoxic withanolide from Physalis angulata. Chem. Pharm. Bull. 2008, 56, 234. [Google Scholar] [CrossRef] [PubMed]
Abe, F.; Nagafuji, S.; Okawa, M.; Kinjo, J. Trypanocidal constituents in plants 6. Minor. Withanolides from the aerial parts of Physalis angulata. Chem. Pharm. Bull. 2006, 54, 1226. [Google Scholar]
Maldonado, E.; Torres, F.R.; Martınez, M.; Perez-Castorena, A.L. 18-Acetoxywithanolides from Physalis chenopodifolia. Planta Med. 2004, 70, 59. [Google Scholar]
Carcamo, C.; Fajardo, V. (-)-Jaboromagellonine: New withanolide from seeds of Jaborosa magellanica. Heterocycles 1993, 36, 1771. [Google Scholar]
Ramacciotti, N.S.; Nicotra, V.E. Withanolides from Jaborosa kurtzii. J. Nat. Prod. 2007, 70, 1513. [Google Scholar] [CrossRef]
Veleiro, A.S.; Cirigliano, A.M.; Oberti, J.C.; Burton, G. 7-Hydroxywithanolides from Datura ferox. J. Nat. Prod. 1999, 62, 1010. [Google Scholar] [CrossRef]
Vankar, P.S.; Srivastava, J.; Molcanov, K.; Kojic-Prodic, B. Withanolide A series steroidal lactones from Eucalyptus globulus Bark. Phytochemistry Lett. 2009, 2, 67. [Google Scholar] [CrossRef]
Siddiqui, B.S.; Arfeen, S.; Begum, S.; Sattar, F.A. Daturacin, a new withanolide from Datura innoxia. Nat. Prod. Res. 2006, 19, 619. [Google Scholar] [CrossRef]
Luis, J.G.; Echeverri, F.; Garcıa, F.; Rojas, M. The Structure of Acnistin B and the immunosuppressive effects of acnistins A, B, and E. Planta Med. 1994, 60, 348. [Google Scholar] [CrossRef]
Luis, J.G.; Echeverri, F.; Gonzalez, A.G. Acnistins C and D, Withanolides from Dunalia solanacea. Phytochemistry 1994, 36, 1297. [Google Scholar] [CrossRef]
Veleiro, A.S.; Burton, G.; Bonetto, G.M.; Gil, R.R.; Oberti, J.C. New withanolides from Salpichroa origanifolia. J. Nat. Prod. 1994, 57, 1741. [Google Scholar] [CrossRef]
Tettamanzi, M.C.; Veleiro, A.S.; Oberti, J.C.; Burton, G. New hydroxylated withanolides from Salpichroa origanifolia. J. Nat. Prod. 1998, 61, 338. [Google Scholar] [CrossRef]
Tettamanzi, M.C.; Veleiro, A.S.; de la Fuente, J.R.; Burton, G. Withanolides from Salpichroa origanifolia. J. Nat. Prod. 2001, 64, 783. [Google Scholar] [CrossRef]
Tettamanzi, M.C.; Veleiro, A.S.; Oberti, J.C.; Burton, G. Ring D aromatic ergostane derivatives from Salpichroa origanifolia. Phytochemistry 1996, 43, 461. [Google Scholar] [CrossRef]
Cirigliano, A.M.; Veleiro, A.S.; Misico, R.I.; Tettamanzi, M.C.; Oberti, J.C.; Burton, G. Withanolides from Jaborosa laciniata. J. Nat. Prod. 2007, 70, 1644. [Google Scholar] [CrossRef]
Pecci, A.; Alvarez, L.D.; Veleiro, A.S.; Ceballos, N.R.; Lantos, C.P.; Burton, G. New lead compounds in the search for pure antiglucocorticoids and the dissociation of antiglucocorticoid effects. J. Steroid Biochem. Mol. Biol. 2009, 113, 155. [Google Scholar] [CrossRef]
Cirigliano, A.M.; Veleiro, A.S.; Oberti, J.C.; Burton, G. Spiranoid withanolides from Jaborosa odonelliana. J. Nat. Prod. 2002, 65, 1049. [Google Scholar] [CrossRef] [PubMed]
Nicotra, V.E.; Ramacciotti, N.S.; Gil, R.R.; Oberti, J.C.; Feresin, G.E.; Guerrero, C.A.; Baggio, R.F.; Garland, M.T.; Burton, G. Phytotoxic withanolides from Jaborosa rotacea. J. Nat. Prod. 2006, 69, 783. [Google Scholar] [CrossRef] [PubMed]
Su, B.-N.; Park, E.J.; Nikolic, D.; Santarsiero, B.D.; Mesecar, A.D.; Vigo, J.S.; Graham, J.G.; Cabieses, F.; van Breemen, R.B.; Fong, H.H.S.; Farnsworth, N.R.; Pezzuto, J.M.; Kinghorn, A.D. Activity-guided isolation of novel norwithanolides from Deprea subtriflora with potential cancer chemopreventive activity. J. Org. Chem. 2003, 68, 2350. [Google Scholar] [CrossRef] [PubMed]
Su, B.-N.; Park, E.J.; Nikolic, D.; Vigo, J.S.; Graham, J.G.; Cabieses, F.; Van Breemen, R.B.; Fong, H.H.S.; Farnsworth, N.R.; Pezzuto, J.M.; Kinghorn, A.D. Isolation and characterization of miscellaneous secondary metabolites of Deprea subtriflora. J. Nat. Prod. 2003, 66, 1089. [Google Scholar] [CrossRef] [PubMed]
Shingu, K.; Marubayashi, N.; Ueda, I.; Yahara, S.; Nohara, T. Two new ergostane derivatives from Tubocapsicum anomalum (Solanaceae). Chem. Pharm. Bull. 1990, 38, 1107. [Google Scholar] [CrossRef]
Dembitsky, V.M. Naturally occurring nor-steroids and their design and pharmaceutical application. Preprints 2024, 2024041079. [Google Scholar] [CrossRef]
Nagarajan, M.; Waszkuc, T.W.; Sun, J. Simultaneous determination of E- and Z-guggulsterones in dietary supplements containing Commiphora mukul extract (Guggulipid) by liquid chromatography. J. AOAC Int. 2001, 84, 24–28. [Google Scholar] [CrossRef]
Wajchenberg, B.L.; Gelman, A.; Melo, E.H.; Pereira, V.G. Adrenocortical function. II. Determination of urinary 17, 21-dihydroxy-2-ketosteroids in some clinical conditions. Interpretation in relation to the metabolic pattern of cortisol. Rev. Paul. Med. 1961, 58, 217–226. [Google Scholar]
Chauret, D.C.; Durst, T.; Arnason, J.T.; Sanchez-Vindas, P.; San Roman, L.; Poveda, L. Novel steroids from Trichilia hirta as identified by nanoprobe 2D-NMR spectroscopy. Tetrahedron Lett. 1996, 37, 7875–7878. [Google Scholar] [CrossRef]
Srivastava, S.K. Nummularogenin, a New Spirostane from Zizyphus nummularia. J. Nat. Prod. 1984, 47, 781–783. [Google Scholar] [CrossRef]
Mahmood, K.; Pais, M.; Fontaine, C.; Ali, H.M.; Hamid, A.; Hadi, A.; David, B.; Guittet, E. Monocarpin, a new cycloartane from Monocarpia marginalis. Tetrahedron Lett. 1992, 33, 3761–3764. [Google Scholar] [CrossRef]
Lim, S.-H.; K.; Komiyama, M.K.; Kam, T.-S. A Cycloartane incorporating a fused tetrahydrofuran ring and a cytotoxic lactam from Monocarpia marginalis. J. Nat. Prod. 2008, 71, 1104–1106. [Google Scholar]
Ragini, K.; Piggott, A.M.; Karuso, P. Crellasterones A and B: A-Norsterol derivatives from the New Caledonian sponge Crella incrustans. Mar. Drugs 2017, 15, 177. [Google Scholar] [CrossRef]
Gutierrez, G.; Serrar, M.; Hadid, Z. Steroid derivatives and use thereof as medicaments. Patent WO2005014614A1, 17 02 2005. [Google Scholar]
Chen, B.; Gu, Y.C.; de Voogd, N.J.; Wang, C.Y.; Guo, Y.W. Xidaosterols A and B, two new steroids with unusual α-keto-enol functionality from the South China Sea sponge Neopetrosia chaliniformis. Nat. Prod. Res. 2022, 36, 1941–1947. [Google Scholar] [CrossRef]
Tang, H.F.; Yi, Y.H.; Yao, X.S.; Xu, Q.; Zhang, S.; Lin, H. A novel steroid for Sargassum carpophyllum. Zhongguo Haiyang Yaowu 2003, 22, 28–30. [Google Scholar]
Machida, K.; Kikuchi, M. Viburnols: Six novel triterpenoids from Viburnum dilatatum. Tetrahedron Lett. 1997, 38, 571–574. [Google Scholar] [CrossRef]
Wang, X.Y.; Shi, H.M.; Li, X.-B. Chemical constituents of plants from the genus Viburnum. Chem. Biodiver. 2010, 7, 567–593. [Google Scholar]
Liu, Y.; Zhang, L.; Xue, J.; Wang, K.; Hua, H.; Yuan, T. Norcolocynthenins A and B, two cucurbitane 3-nor-Triterpenoids from Citrullus colocynthis and their cytotoxicity. Bioorg. Chem. 2020, 101, 104045. [Google Scholar] [CrossRef]
He, X.F.; Wang, X.N.; Yin, S.; Dong, L.; Yu, J.M. Ring A modified novel triterpenoids from Dysoxylum hainanense. Eur. J. Org. Chem. 2009, 4818–4824. [Google Scholar] [CrossRef]
Lv, H.W.; Wang, Q.L.; Li, S.W.; Zhu, M.D.; Zhou, Z.B. Cucurbitane-type triterpenoids from the fruits of Citrullus colocynthis. Fitoterapia 2023, 165, 105405. [Google Scholar] [CrossRef]
Kapoor, M.; Kaur, N.; Sharma, C.; Kaur, G.; Kaur, R.; Batra, K.; Rani, J. Citrullus colocynthis an important plant in Indian traditional system of medicine. Pharmacog. Rev. 2020, 14, 22–27. [Google Scholar] [CrossRef]
Hitotsuyanagi, Y.; Ozeki, A.; Choo, C.Y.; Chan, K.L.; Itokawa, H.; Takeya, K. Malabanones A and B, novel nortriterpenoids from Ailanthus malabarica DC. Tetrahedron 2001, 57, 7477–7480. [Google Scholar] [CrossRef]
Zeng, Q.; Guan, B.; Qin, J.J.; Wang, C.H.; Cheng, X.R.; Ren, J. 2,3-Seco- and 3,4-seco-tirucallane triterpenoid derivatives from the stems of Aphanamixis grandifolia Blume. Phytochemistry 2012, 80, 148–155. [Google Scholar] [CrossRef] [PubMed]
Promdang, S.; Vajrodaya, S.; Pannell, C.M.; Hofer, O.; Mereiter, K.; Greger, H. Silvaglins and related 2, 3-secodammarane derivatives–unusual types of triterpenes from Aglaia silvestris. Phytochemistry 2008, 69, 2696. [Google Scholar]
Machida, K.; Kikuchi, M. Studies on the constituents of Viburnum species. XVII. New dammarane-type triterpenoids from Viburnum dilatatum THUNB. Chem. Pharm. Bull. 1997, 45, 1589. [Google Scholar] [CrossRef]
Machida, K.; Kikuchi, M. Viburnols: Novel triterpenoids with a rearranged dammarane skeleton from Viburnum dilatatum. Tetrahedron Lett. 1996, 37, 4157. [Google Scholar] [CrossRef]
Carney, J.R.; Yoshida, W.Y.; Scheuer, P.J. Kiheisterones, new cytotoxic steroids from a Maui sponge. J. Org. Chem. 1992, 57, 6637–6640. [Google Scholar] [CrossRef]
Kobayashi, M.; Murata, O.; Rao, N.; Chavakula, R.; Sarma, N.S. Marine sterols. 23. 2a-oxa-2-oxo-5α-hydroxy-3,4-dinorcholestane from the Arabian sea red alga Laurencia obtusa. Tetrahedron Lett. 1992, 33, 519–520. [Google Scholar] [CrossRef]
Searle, P.A.; Molinski, T.F. Scalemic 12-hydroxyambliofuran and 12-acetoxy-ambliofuran, five tetracyclic furanoditerpenes and a furanosesterterpene from Spongia sp. Tetrahedron 1994, 50, 9893–9908. [Google Scholar] [CrossRef]
Zeng, L.M.; Guan, Z.; Su, J.Y.; Feng, X.L.; Cai, J.W. Two new spongian diterpene lactones. Acta Chim. Sin. 2001, 59, 1675–1679. [Google Scholar]
Parrish, S.M.; Yoshida, W.Y.; Kondratyuk, T.P.; Park, E.-J.; Pezzuto, J.M.; Kelly, M.; Williams, P.G. Spongiapyridine and related spongians isolated from an Indonesian Spongia sp. J. Nat. Prod. 2014, 77, 1644–1649. [Google Scholar] [CrossRef]
Zhang, B.; Zhou, D.F.; Li, M.J. Progress of 3-ketosteroid Δ1-dehydrogenases for steroid production. Syst Microbiol. Biomanuf. 2024, 4, 631–660. [Google Scholar] [CrossRef]
Chen, M.; Trevor, M. Penning. 5β-Reduced steroids and human Δ4-3-ketosteroid 5β-reductase (AKR1D1). Steroids 2014, 83, 17–26. [Google Scholar] [CrossRef] [PubMed]
Batzold, F.H.; Benson, A.M.; Covey, D.F.; Robinson, C.H.; Talalay, P. The Δ5-3-ketosteroid isomerase reaction: catalytic mechanism, specificity and inhibition. Adv. Enzyme Regul. 1976, 14, 243–267. [Google Scholar] [CrossRef] [PubMed]
Mason, I.J. The 3β-hydroxysteroid dehydrogenase gene family of enzymes. Trends Endocrin. Metabol. 1993, 4, P199–P203. [Google Scholar] [CrossRef] [PubMed]
Abaffy, T.; Lu, H.Y.; Matsunami, H. Sex steroid hormone synthesis, metabolism, and the effects on the mammalian olfactory system. Cell Tissue Res. 2023, 391, 19–42. [Google Scholar] [CrossRef]
El Menoufy, H.A.; Elkhateeb, W.A.; Daba, G.M. Biotransformation of Steroids: History, Current Status, and Future Prospects. In Fungi Bioactive Metabolites; Deshmukh, S.K., Takahashi, J.A., Saxena, S., Eds.; Springer: Singapore, 2024. [Google Scholar]
Rosenfield, R.L. Normal and premature adrenarche. Endocr. Rev. 2021, 42, 783–814. [Google Scholar] [CrossRef]
Melcangi, R.C.; Cioffi, L.; Diviccaro, S.; Traish, A.M. Synthesis and actions of 5a-reduced metabolites of testosterone in the nervous system. Androg. Clinical Res. Therapeut. 2021, 2, 173–188. [Google Scholar] [CrossRef]
Schun, Y.; Cordell, G.A.; Cox, P.J.; Howie, R.A. Studies on Thymelaeaceae. Part 4. Wallenone, a C32 triterpenoid from the leaves of Gyrinops walla. Phytochemistry 1986, 25, 753–755. [Google Scholar] [CrossRef]
Rios, M.Y.; Aguilar-Guadarrama, A.B. Terpenes and a new bishomotriterpene from Esenbeckia stephani. Biochem. Syst. Ecol. 2002, 30, 1006–1008. [Google Scholar] [CrossRef]
Hui, W.H.; Luk, K.; Arthur, H.R.; Loo, S.N. Structure of three C32 triterpenoids from Neolitsea pulchella. J. Chem. Soc. 1971, 16C, 2826–2829. [Google Scholar] [CrossRef]
Chan, W.S.; Hui, W.H. Further C32 triterpenoids from Neolitsea pulchella. J. Chem. Soc., Perkin Trans 1 1973, 5, 490–492. [Google Scholar] [CrossRef]
Hui, W.H.; Li, M.M. Six new triterpenoids and other triterpenoids and steroids from three Quercus species of Hong Kong. J. Chem. Soc., Perkin Trans 1 1977, 8, 897–904. [Google Scholar] [CrossRef]
Lee, I.; Kim, H.; Youn, U. Effect of lanostane triterpenes from the fruiting bodies of Ganoderma lucidum on adipocyte differentiation in 3T3-L1 cells. Planta Med. 2010, 76, 1558–1563. [Google Scholar] [CrossRef]
Ondeyka, J.G.; Jayasuriya, H.; Herath, K.B.; Guan, Z.; Schulman, M. Steroidal and triterpenoidal fungal metabolites as ligands of liver X receptors. J. Antibiot. 2005, 58, 559–565. [Google Scholar] [CrossRef]
Akihisa, T.; Watanabe, K.; Yoneima, K.; Suzuki, T.; Kimura, Y. Biotransformation of cycloartane-type triterpenes by the fungus Glomerella fusarioides. J. Nat. Prod. 2006, 69, 604–607. [Google Scholar] [CrossRef]
Tavarez-Santamaría, Z.T.; Jacobo-Herrera, N.J.; Rocha-Zavaleta, L.; Zentella-Dehesa, A.; del Carmen Couder-García, B.; Martínez-Vázquez, M. A higher frequency administration of the nontoxic cycloartane-type triterpene argentatin A improved its anti-tumor activity. Molecules 2020, 25, 1780. [Google Scholar] [CrossRef]
Hitotsuyanagi, Y.; Ozeki, A.; Choo, C.Y.; Chan, K.L.; Itokawa, H.; Takeya, K. Malabanones A and B, novel nortriterpenoids from Ailanthus malabarica DC. Tetrahedron 2001, 57, 7477–7480. [Google Scholar] [CrossRef]
Thongnest, S.; Boonsombat, J.; Prawat, H.; Mahidol, C.; Ruchirawat, S. Ailanthusins A-G and nor-lupane triterpenoids from Ailanthus triphysa. Phytochemistry 2017, 134, 98–105. [Google Scholar] [CrossRef]
de Freitas, A.C.; da Paz Lima, M.; Ferreira, A.G.; Tadei, W.P.; da Silva Pinto, A.C. Constituintes quimicos do caule de Spathelia excelsa (Rutaceae) e atividade frente a Aedes aegypti. Quim. Nova 2009, 32, 2068–2072. [Google Scholar] [CrossRef]
Kashiwada, Y.; Fujioka, T.; Chang, J.J.; Chen, I.S.; Mihashi, K.; Lee, K.H. Anti-tumor agents. 136. Cumingianosides A-F, potent antileukemic new triterpene glucosides, and cumindysosides A and B, trisnor- and tetranortriterpene glucosides with a 14,18-cycloapoeuphane-type skeleton from Dysoxylum cumingianum. J. Org. Chem. 1992, 57, 6946–6953. [Google Scholar] [CrossRef]
Fujioka, T.; Sakurai, A.; Mihashi, K.; Kashiwada, Y.; Chen, I.S.; Lee, K.H. Antitumor agents. 168. Dysoxylum cumingianum. IV. The structures of cumingianosides G-O, new triterpene glucosides with a 14,18-cycloapotirucallane-type skeleton from Dysoxylum cumingianum, and their cytotoxicity against human cancer cell lines. Chem. Pharm. Bull. (Tokyo) 1997, 45, 68–74. [Google Scholar] [CrossRef]
Iguchi, K.; Fujita, M.; Nagaoka, H.; Mitome, H.; Yamada, Y. Aragusterol A: A potent antitumor marine steroid from the okinawan sponge of the genus, Xestospongia. Tetrahedron Lett. 1993, 34, 6277–6280. [Google Scholar] [CrossRef]
Iguchi, K.; Shimura, H.; Taira, S.; Yokoo, C.; Matsumoto, K.; Yamada, Y. Aragusterol B and D, new 26,27-cyclosterols from the Okinawan marine sponge of the genus Xestospongia. J. Org. Chem. 1994, 59, 7499–7502. [Google Scholar] [CrossRef]
Pailee, P.; Mahidol, C.; Ruchirawat, S.; Prachyawarakorn, V. Sterols from Thai marine sponge Petrosia (Strongylophora) sp. and their cytotoxicity. Mar. Drugs 2017, 15, 54. [Google Scholar] [CrossRef]
Severino, V.G.P.; de Freitas, S.D.L.; Braga, P.A.C.; Forim, M.R.; da Silva, M.F.G.F.; Fernandes, J.B.; Vieira, P.C.; Venâncio, T. New limonoids from Hortia oreadica and unexpected coumarin from H. superba using chromatography over cleaning sephadex with sodium hypochlorite. Molecules 2014, 19, 12031–12047. [Google Scholar] [CrossRef]
Fossen, T.; Rasoanaivo, P.; Manjovelo, C.S.; Raharinjato, H.F.; Sviatlana Yahorava, S.; Yahorau, A.; Wikberg, J.E.S. A new protolimonoid from Capuronianthus mahafalensis. Fitoterapia 2012, 83, 901–906. [Google Scholar] [CrossRef]
Achanta, P.S.; Gattu, R.K.; Belvotagi, A.R.V.; Akkinepally, R.R.; Rao, A.; Achanta, V.N. New malabaricane triterpenes from the oleoresin of Ailanthus malabarica. Fitoterapia 2015, 100, 166–173. [Google Scholar] [CrossRef]
Wammer, K.H.; Anderson, K.C.; Erickson, P.R.; Kliegman, S.; Moffatt, M.E.; Berg, S.M.; Heitzman, J.A. Environmental photochemistry of altrenogest: Photoisomerization to a bioactive product with increased environmental persistence via reversible photohydration. Environ. Sci. Technol. 2016, 50, 7480–7488. [Google Scholar] [CrossRef]
Cheng, S.-Y.; Dai, C.-F.; Duh, C.-Y. New 4-methylated and 19-oxygenated steroids from the Formosan soft coral Nephthea erecta. Steroids 2007, 72, 653–659. [Google Scholar] [CrossRef]
Amir, F.; Koay, Y.C.; Yam, W.S. Chemical constituents and biological properties of the marine soft coral Nephthea: A review (Part 1). Tropical J. Pharm. Res. 2012, 11, 485–498. [Google Scholar]
Cheng, S.-Y.; Wen, Z.-H.; Wang, S.-K.; Chiang, M.Y.; El Gamal, A.A.H.; Dai, C.-F.; Duh, C.-Y. Revision of the absolute configuration at C(23) of lanostanoids and isolation of secondary metabolites from Formosan soft coral Nephthea erecta. Chem. Biodiver. 2009, 6, 86–95. [Google Scholar] [CrossRef] [PubMed]
Festa, C.; De Marino, S.; Zampella, A.; Fiorucci, S. Theonella: A treasure trove of structurally unique and biologically active sterols. Mar. Drugs 2023, 21, 291. [Google Scholar] [CrossRef] [PubMed]
Rodriguez, J.; Nunez, L.; Peixinho, S.; Jimenez, C. Isolation and synthesis of the first natural 6-hydroximino 4-en-3-one-steroids from the sponges Cinachyrella spp. Tetrahedron Lett. 1997, 38, 1833. [Google Scholar] [CrossRef]
Holland, H.L.; Kumaresan, S.; Tan, L.; Njar, V.C.O. Synthesis of 6-hydroximino-3-oxo steroids, a new class of aromatase inhibitor. J. Chem. Soc., Perkin Trans. 1 1992, 4, 585. [Google Scholar] [CrossRef]
Makarieva, T.N.; Bondarenko, I.A.; Dmitrenok, A.S.; Boguslavsky, V.M.; Stonik, V.A.; Chernih, V.I.; Efremova, S.M. Natural products from Lake Baikal organisms, I. Baikalosterol, a novel steroid with an unusual side chain, and other metabolites from the sponge Baicalospongia bacilifera. J. Nat. Prod. 1991, 54, 953. [Google Scholar] [CrossRef]
Carney, J.R.; Scheuer, P.J.; Kelly-Borges, M. Three unprecedented chloro steroids from the Maui sponge Strongylacidon sp.: kiheisterones C, D, and E. J. Org. Chem. 1993, 58, 3460. [Google Scholar] [CrossRef]
Kobayashi, M.; Krishna, M.M.; Ishida, K.; Anjaneyulu, V. Marine sterols. XXII. Occurrence of 3-oxo-4,6,8(14)-triunsaturated steroids in the sponge Dysidea herbacea. Chem. Pharm. Bull. 1992, 40, 72–74. [Google Scholar] [CrossRef]
Ciminiello, P.; Fattorusso, E.; Magno, S.; Mangoni, A. A novel conjugated ketosteroid from the marine sponge Dictyonella incisa. J. Nat. Prod. 1989, 52, 1331–133. [Google Scholar] [CrossRef]
Aiello, A.; Fattorusso, E.; Magno, S.; Menna, M. Steroids of the marine sponge Cinachyra tarentina: isolation of cholest-4-ene-3,6-dione and (24R)-24-ethylcholest-4-ene-3,6-dione. J. Nat. Prod. 1991, 54, 281–285. [Google Scholar] [CrossRef]
Rochfort, S.J.; Gable, R.W.; Capon, R.J. Mycalone: a new steroidal lactone from a Southern Australian marine sponge. Mycale sp. Aust. J. Chem. 1996, 49, 715–718. [Google Scholar] [CrossRef]
Guella, G.; Mancini, I.; Pietra, F. Isolation of ergosta-4,24(28)-dien-3-one from both astrophorida demosponges and subantarctic hexactinellides. Comp. Biochem. Phys. 1988, 90B, 113–115. [Google Scholar] [CrossRef]
Oger, J.M.; Richomme, P.; Bruneton, J.; Guinaudeau, H.; Sevenet, T.; Debitus, C. Steroids from Neosiphonia supertes, a marine fossil sponge. J. Nat. Prod. 1991, 54, 273–275. [Google Scholar] [CrossRef]
Kobayashi, M.; Kawazoe, K.; Katori, T.; Kitagawa, I. Marine natural products. XXX. Two new 3-keto-4-methylene steroids, Theonellasterone and Conicasterone, and a Diels-alder type dimeric steroid Bistheonellasterone, from the Okinawan marine sponge Theonella swinhoei. Chem. Pharm. Bull. 1992, 40, 1773–1778. [Google Scholar] [CrossRef]
Sheu, J.-H.; Huang, S.-Y.; Wang, G.-H.; Duh, C.-Y. Study on cytotoxic oxygenated desmosterols isolated from the red alga Galaxaura marginata. J. Nat. Prod. 1997, 60, 900. [Google Scholar] [CrossRef] [PubMed]
Ktari, L.; Blond, A.; Guyot, M. 16β-Hydroxy-5α-cholestane-3, 6-dione, a novel cytotoxic oxysterol from the red alga Jania rubens. Bioorg. Med. Chem. Lett. 2000, 10, 2563. [Google Scholar] [CrossRef] [PubMed]
Sheu, J.-H.; Wang, G.H.; Sung, P.-J.; Duh, C.-Y. New cytotoxic oxygenated fucosterols from the brown alga Turbinaria conoides. J. Nat. Prod. 1999, 62, 224. [Google Scholar] [CrossRef] [PubMed]
Guerriero, A.; Debitus, C.; Pietra, F. On the first marine stigmastane sterols and sterones having a 24,25-double bond. Isolation from the sponge Stelletta sp. of deep Coral sea. Helv. Chim. Acta 1991, 5, 487–94. [Google Scholar] [CrossRef]
Garang, Z.; Feng, Q.; Luo, R.; La, M.; Zhang, J.; Wu, L. Commiphora mukul (Hook. ex Stocks) Engl. Historical records, application rules, phytochemistry, pharmacology, clinical research, and adverse reaction. J. Ethnopharm. 2023, 317, 116717. [Google Scholar] [CrossRef]
Rani, R.; Mishra, S. Phytochemistry of guggul (Commiphora wightii). Asian J. Res. Chem. 2013, 6, 413–424. [Google Scholar]
Szapary, P.O.; Wolfe, M.L.; Bloedon, L.T.; Cucchiara, A.J.; Dermarderosian, A.H.; Cirigliano, M.D.; Rader, D.J. Guggulipid ineffective for lowering cholesterol. JAMA 2003, 290, 765–772. [Google Scholar] [CrossRef] [PubMed]
Sahni, S.; Hepfinger, C.A.; Sauer, K.A. Guggulipid use in hyperlipidemia. Am. J. Health-Syst. Pharm. 2005, 62, 1690–1692. [Google Scholar] [CrossRef]
Kciuk, M.; Mujwar, S.; Rani, I.; Munjal, K.; Gielecińska, A.; Kontek, R.; Shah, K. Computational bioprospecting guggulsterone against ADP ribose phosphatase of SARS-CoV-2. Molecules 2022, 27, 8287. [Google Scholar] [CrossRef]
Burris, T.P. The hypolipidemic natural product guggulsterone is a promiscuous steroid receptor ligand. Mol. Pharmacol. 2004, 67, 948–954. [Google Scholar] [CrossRef] [PubMed]
Kapustina, I.I.; Makarieva, T.N.; Guzii, A.G.; Kalinovsky, A.I.; Popov, R.S.; Dyshlovoy, S.A.; Grebnev, B.B.; von Amsberg, G.; Stonik, V.A. Leptogorgins A–C, humulane sesquiterpenoids from the Vietnamese gorgonian Leptogorgia sp. Mar. Drugs 2020, 18, 310. [Google Scholar] [CrossRef] [PubMed]
Seo, Y.; Rho, J.-R.; Cho, K.W.; Shin, J. Isolation of new steroidal hemiacetals from the gorgonian Euplexaura anastomosans. J. Nat. Prod. 1996, 59, 1196–1199. [Google Scholar] [CrossRef]
Yang, J.; Qi, S.-H.; Zhang, S.; Xiao, Z.-H.; Li, Q.-X. Bebrycoside, a new steroidal glycoside from the Chinese gorgonian coral Bebryce indica. Pharmazie 2007, 62, 154–155. [Google Scholar] [CrossRef] [PubMed]
Wang, P.; Qi, S.H.; Liu, K.S.; Huang, L.S.; He, F.; Wang, Y.F. Steroids from the South China sea gorgonian coral Muricella Flexuosa. Z. Naturforsch. 2011, 66, 635–640. [Google Scholar] [CrossRef]
Fleury, B.G.; Lages, B.G.; Barbosa, J.P.; Kaiser, C.R.; Pinto, A.C. New hemiketal steroid from the introduced soft coral Chromonephthea braziliensis is a chemical defense against predatory fishes. J. Chem. Ecol. 2008, 34, 987–993. [Google Scholar] [CrossRef]
Zhang, J.; Li, L.-C.; Wang, K.-L.; Liao, X.-J.; Deng, Z.; Xu, S.-H. Pentacyclic hemiacetal sterol with antifouling and cytotoxic activities from the soft coral Nephthea sp. , Bioorg. Med. Chem. Lett. 2013, 23, 1079–1082. [Google Scholar] [CrossRef]
Huang, X.; Deng, Z.; Zhu, X.; van Ofwegen, L.; Proksch, P.; Lin, W. Krempenes A–D: A series of unprecedented pregnane-type steroids from the marine soft coral Cladiella krempfi. Helv. Chim. Acta 2006, 89, 2020–2026. [Google Scholar] [CrossRef]
Ghandourah, M.A.; Alarif, W.M.; Abdel-Lateff, A.; Al-Lihaibi, S.S.; Ayyad, S.-E.N.; Basaif, S.A.; Badria, F.A. Two new terpenoidal derivatives: A himachalene-type sesquiterpene and 13,14-secosteroid from the soft coral Litophyton arboretum. Med. Chem. Res. 2015, 24, 4070–4077. [Google Scholar] [CrossRef]
Cheng, W.; Liu, Z.; Yu, Y.; van Ofwegen, L.; Proksch, P.; Yu, S.; Lin, W. An unusual spinaceamine-bearing pregnane from a soft coral Scleronephthya sp. inhibits the migration of tumor cells. Bioorg. Med. Chem. Lett. 2017, 27, 2736–2741. [Google Scholar] [CrossRef]
Díaz-Marrero, A.R.; Porras, G.; Aragón, Z.; de la Rosa, J.M.; Dorta, E.; Cueto, M.; D’Croz, L.; Maté, J.; Darias, J. Carijodienone from the octocoral Carijoa multiflora. A spiropregnane-based steroid. J. Nat. Prod. 2011, 74, 292–295. [Google Scholar] [CrossRef]
Zhao, H.Y.; Shao, C.L.; Li, Z.Y.; Han, L. Bioactive pregnane steroids from a South China Sea Gorgonian Carijoa sp. Molecules 2013, 18, 3458–3466. [Google Scholar] [CrossRef]
Dorta, E.; Diaz-Marrero, A.R.; Cueto, M.; D’Croz, L.; Maté, J.L.; San-Martín, A.; Darías, J. Two unique chloro-pregnane steroids have been isolated from the eastern Pacific octocoral Carijoa Multiflora. Tetrahedron Lett. 2004, 45, 915–917. [Google Scholar] [CrossRef]
Han, L.; Wang, C.Y.; Huang, H.; Shao, C.L.; Liu, Q.A.; Qi, J.; Sun, X.P.; Zhai, P.; Gu, Y.C. A new pregnane analogue from Hainan soft coral Scleronephthya gracillimum Kukenthal. Biochem. Syst. Ecol. 2010, 38, 243–246. [Google Scholar] [CrossRef]
Poza, J.; Fernández, R.; Reyes, F.; Reyes, F.; Jiménez, C.; Jiménez, C. Isolation, biological significance, synthesis, and cytotoxic evaluation of new natural parathiosteroids A-C and analogues from the soft coral Paragorgia sp. J. Org. Chem. 2008, 73, 7978–7984. [Google Scholar] [CrossRef]
Huang, C.Y.; Chang, C.W.; Sheu, J.H. Bioactive steroids from the Formosan soft coral Umbellulifera petasites. Mar. Drugs 2016, 14, 180. [Google Scholar] [CrossRef]
Xiao, J.; Gao, M.; Fei, B.; Huang, G.; Diao, Q. Nature-derived anticancer steroids outside cardica glycosides. Fitoterapia 2020, 147, 104757. [Google Scholar] [CrossRef]
Seo, Y.; Jung, J.H.; Rho, J.R.; Shin, J. Isolation of novel bioactive steroids from the soft coral Alcyonium gracillimum. Tetrahedron 1995, 51, 2497–2506. [Google Scholar] [CrossRef]
Gunatilaka, A.A.L.; Gopichand, Y.; Schmitz, F.J.; Djerassi, C. Minor and trace sterols in marine invertebrates. Isolation and structure elucidation of nine new 5α,8α-epidioxy sterols from four marine organisms. J. Org. Chem. 1981, 46, 3860–3866. [Google Scholar] [CrossRef]
Tomono, Y.; Hirota, H.; Fusetani, N. Isogosterones A-D, antifouling 13,17-secosteroids from an octocoral Dendronephthya sp. J. Org. Chem. 1999, 64, 2272–2275. [Google Scholar] [CrossRef]
Chen, W.H.; Wang, S.K.; Duh, C.Y. Polyhydroxylated steroids from the bamboo coral Isis Hippuris. Tetrahedron 2002, 58, 6259–6266. [Google Scholar] [CrossRef] [PubMed]
Abdel-Lateff, A.; Alarif, W.M.; Alburae, N.A.; Algandaby, M.M. Alcyonium octocorals: Potential source of diverse. Bioactive terpenoids. Molecules 2019, 24, 1370. [Google Scholar] [CrossRef] [PubMed]
Häder, D.-P. Natural bioactive compounds technological advancements. In Bioreactive substances from coral reefs and gorgonians; Sinha, R.P., Häder, D.-P., Eds.; Academic Press, 2021; pp. 381–391. [Google Scholar]
Chen, X.Q.; Xing, N.; Yang, B.; Zhou, X.; Gao, C.; Liu, Y. Two novel sesquiterpenes and a new pregnane derivative from the South China Sea Gorgonian Subergorgia suberosa. Rec. Nat. Prod. 2020, 14, 57–64. [Google Scholar] [CrossRef]
Chao, C.H.; Chou, K.J.; Wen, Z.H.; Wang, G.H.; Wu, Y.C.; Dai, C.F.; Sheu, J.H. Paraminabeolides A-F, cytotoxic and anti-inflammatory marine withanolides from the Soft Coral Paraminabea acronocephala. J. Nat. Prod. 2011, 74, 1132–1141. [Google Scholar] [CrossRef] [PubMed]
Cao, J.; Wang, Y.; Wang, S.; Shen, Y.; Li, W.; Wei, Z.; Li, S.; Lin, Q.; Chang, Y. Expression of key steroidogenic enzymes in human placenta and associated adverse pregnancy outcomes. Maternal. Fetal. Med. 2023, 5, 163–172. [Google Scholar] [CrossRef]
Chatterton, R.T. Functions of dehydroepiandrosterone in relation to breast cancer. Steroids 2022, 179, 108970. [Google Scholar] [CrossRef]
Simard, J.; Ricketts, M.L.; Gingras, S.; Soucy, P.; Feltus, F.A.; Melner, M.H. Molecular biology of the 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase gene family. Endocrine Rev. 2005, 26, 525–582. [Google Scholar]
Tsutsui, K. Biosynthesis, mode of action and functional significance of neurosteroids in the developing Purkinje cell. J. Steroid Biochem. Mol. Biol. 2006, 102, 187–194. [Google Scholar] [CrossRef]
Acién, P.; Acién, M. Disorders of sex development: Classification, review, and impact on fertility. J. Clin. Med. 2020, 9, 3555. [Google Scholar] [CrossRef] [PubMed]
Yang, M.Y.; Yanga, J.K.; Yang, J.K.; Hua, L.D.; Zhua, H.J.; Caoa, F. New oxygenated steroid from the marine-derived fungus Aspergillus flavus. Nat. Prod. Commun. 2018, 13, 949–951. [Google Scholar] [CrossRef]
Schakirov, R.; Yunusov, M.S. Steroidal alkaloids. Nat. Prod. Rep. 1990, 7, 557–564. [Google Scholar] [CrossRef]
Harrison, D.M. Steroidal alkaloids. Nat. Prod. Rep. 1986, 3, 443–449. [Google Scholar] [CrossRef]
Watanabe, H.; Watanabe, K.; Shimadzu, M.; Kikuchi, T.; Liu, Z. Anti-ulcer effect of steroidal alkaloids extracted from Pachysandra terminalis. Planta Med. 1986, 52, 56–58. [Google Scholar] [CrossRef]
Pan, Y.; Wang, X.; Hu, X. Cytotoxic withanolides from the flowers of Datura metel. J. Nat. Prod. 2007, 70, 1127. [Google Scholar] [CrossRef] [PubMed]
Fang, S.-T.; Liu, J.-K.; Li, B. Ten new withanolides from Physalis peruviana. Steroids 2012, 77, 36. [Google Scholar] [CrossRef]
Bagchi, A.; Neogi, P.; Sahai, M. Withaperuvin E and nicandrin B, withanolides from Pysalis peruviana and Nicandra physaloides. Phytochemistry 1984, 23, 853–855. [Google Scholar] [CrossRef]
Dong, B.; An, L.; Yang, X.; Zhang, X.; Zhang, J.; Tuerhong, M.; Jin, D.Q.; Ohizumi, Y.; Lee, D. Withanolides from Physalis peruviana showing nitric oxide inhibitory effects and affinities with iNOS. Bioorg. Chem. 2019, 87, 585–593. [Google Scholar] [CrossRef]
Misico, R.I.; Nicotra, V.E.; Oberti, J.C.; Barboza, G.; Gil, R.R.; Burton, G. Withanolides and related steroids. In Progress in the Chemistry of Organic Natural Products Vol. 94; Kinghorn, A., Falk, H., Kobayashi, J., Eds.; Springer: Vienna, 2011. [Google Scholar] [CrossRef]
Su, B.N.; Park, E.J.; Nikolic, D.; Vigo, J.S.; Graham, J.G. Isolation and characterization of miscellaneous secondary metabolites of Deprea subtriflora. J. Nat. Prod. 2003, 66, 1089–1093. [Google Scholar] [CrossRef] [PubMed]
Kovganko, N.V.; Kashkan, Z.N. An investigation of pathways to the synthesis of 2β,3β,5β-tri-hydroxy-6-ketosteroids. Chem. Nat. Compd. 1993, 29, 637–641. [Google Scholar] [CrossRef]
Le Bizec, B.; Antignac, J.P.; Monteau, F.; Andre, F. Ecdysteroids: one potential new anabolic family in breeding animals. Anal. Chim. Acta 2002, 473, 89–97. [Google Scholar] [CrossRef]
Kovganko, N.V.; Sokolov, S.N. Synthesis of 2α,3α-dihydroxy-Δ4,7-6-ketosteroids, structural analogs of diaulusteroids A and B. Chem. Nat. Comp. 2001, 37, 455–461. [Google Scholar] [CrossRef]
Kovganko, N.V.; Kashkan, Z.N. Reactivity of hydroxy and keto groups on C-6 and C-17 of 3α,5α-cycloandrostanes. Chem. Nat. Comp. 2001, 37, 47–51. [Google Scholar] [CrossRef]
Kovganko, N.V.; Sokolov, S.N. Novel synthesis of 5-hydroxy-5α-cholesta-2,7-dien-6-one and its criegee hydroxylation. Chem. Nat. Comp. 2000, 36, 590–594. [Google Scholar] [CrossRef]
Bastaev, U.A.; Abubakirov, N.K. Phytoecdysteroids ofRhaponticum carthamoides. Chem Nat Compd 1987, 23, 565–568. [Google Scholar] [CrossRef]
Odinokov, V.N. Synthesis of natural ecdysteroids and structural analogs by chemical transformations of available phytoecdysteroids. Russ. Chem. Bull. 2012, 61, 1391–1398. [Google Scholar] [CrossRef]
Shady, N.H.; Zayed, A.; Alaaeldin, R.; Hisham, M. Plant and endophyte-derived anti-hyperlipidemics: A comprehensive review with in silico studies. South African J. Bot. 2023, 163, 105–120. [Google Scholar] [CrossRef]
Sauer, G.; Shimaoka, A.; Takeda, K. Components of Chionographis japonica Maxim. IV. Structures of chiograsterone and isochiograsterone, two new sterols from Chionographis japonica Maxim. J. Chem. Soc. Perkin 1. 1970, 7, 910–914. [Google Scholar] [CrossRef]
Thomas, T.H. Brassinosteroids. In: A new class of plant hormones. Khripach, V.A.; Zhabinskii, V.N.; de Groot, A.E. Plant Growth Regulation 1999, 28, 73–74. [Google Scholar]
Li, H.L.; Li, X.M.; Li, X.; Yang, S.Q.; Wang, B.G. Structure, absolute configuration and biological evaluation of polyoxygenated meroterpenoids from the marine algal-derived Aspergillus terreus EN-539. Phytochemistry Lett. 2019, 32, 138–142. [Google Scholar] [CrossRef]
Wu, C.J.; Cui, X.; Xiong, B.; Yang, M.S.; Zhang, Y.X.; Liu, X.M. Terretonin D1, a new meroterpenoid from marine-derived Aspergillus terreus ML-44. Nat. Prod. Res. 2019, 33, 2262–2265. [Google Scholar] [CrossRef] [PubMed]
Wu, J.; Fushimi, K.; Tokuyama, S.; Ohno, M.; Miwa, T.; Koyama, T.; Yazawa, K.; Nagai, K.; Matsumoto, T.; Hirai, H. Functional-food constituents in the fruiting bodies of Stropharia rugosoannulata. Biosci. Biotechnol. Biochem. 2011, 75, 1631–1634. [Google Scholar] [CrossRef] [PubMed]
Yu, F.-X.; Li, Z.; Chen, Y.; Yang, Y.-H.; Li, G.-H.; Zhao, P.-J. Four new steroids from the endophytic fungus Chaetomium sp. M453 derived of Chinese herbal medicine Huperzia serrata. Fitoterapia 2017, 117, 41–46. [Google Scholar] [PubMed]
Lei, H.-M.; Ma, N.; Wang, T.; Zhao, P.-J. Metabolites from the endophytic fungus Colletotrichum sp. F168. Nat. Prod. Res. 2021, 35, 1077–1083. [Google Scholar] [CrossRef]
Zhang, M.; Deng, Y.; Liu, F.; Zheng, M.; Liang, Y.; Sun, W.; Li, Q.; Li, X.N.; Qi, C.; Liu, J.; et al. Five undescribed steroids from Talaromyces stipitatus and their cytotoxic activities against hepatoma cell lines. Phytochemistry 2021, 189, 112816. [Google Scholar] [CrossRef] [PubMed]
Kawai, J.; Higuchi, Y.; Hirota, M.; Hirasawa, N.; Mori, K. Ergosterol and its derivatives from Grifola frondosa inhibit antigeninduced degranulation of RBL-2H3 cells by suppressing the aggregation of high affinity IgE receptors. Biosci. Biotechnol. Biochem. 2018, 82, 1803–1811. [Google Scholar] [CrossRef] [PubMed]
Lee, I.-S.; Bae, K.; Yoo, J.K.; Ryoo, I.-J.; Kim, B.Y.; Ahn, J.S.; Yoo, I.-D. Inhibition of human neutrophil elastase by ergosterol derivatives from the mycelium of Phellinus linteus. J. Antibiot. 2012, 65, 437–440. [Google Scholar] [CrossRef]
Zang, Y.; Xiong, J.; Zhai, W.-Z.; Cao, L.; Zhang, S.-P.; Tang, Y.; Wang, J.; Su, J.-J.; Yang, G.-X.; Zhao, Y. Fomentarols A-D, sterols from the polypore macrofungus Fomes fomentarius. Phytochemistry 2013, 92, 137–145. [Google Scholar] [CrossRef]
Li, W.; Zhou, W.; Cha, J.Y.; Kwon, S.U.; Baek, K.-H.; Shim, S.H.; Lee, Y.M.; Kim, Y.H. Sterols from Hericium erinaceum and their inhibition of TNF-α and NO production in lipopolysaccharide-induced RAW 264.7 cells. Phytochemistry 2015, 115, 231–238. [Google Scholar] [CrossRef] [PubMed]
Mei, R.-Q.; Zuo, F.-J.; Duan, X.-Y.; Wang, Y.-N.; Li, J.-R.; Qian, C.-Z.; Xiao, J.-P. Ergosterols from Ganoderma sinense and their anti-inflammatory activities by inhibiting NO production. Phytochem. Lett. 2019, 32, 177–180. [Google Scholar] [CrossRef]
Kikuchi, T.; Masumoto, Y.; In, Y.; Tomoo, K.; Yamada, T.; Tanaka, R. Eringiacetal A, 5,6-seco-(5S,6R,7R,9S)-5,6:5,7:6,9-triepoxyergosta-8(14),22-diene-3β,7β-diol, an unusual ergostane sterol from the fruiting bodies of Pleurotus eryngii. Eur. J. Org. Chem. 2015, 215, 4645–4649. [Google Scholar] [CrossRef]
Liu, Y.P.; Pu, C.J.; Wang, M.; He, J.; Li, Z.H.; Feng, T.; Xie, J.; Liu, J.K. Cytotoxic ergosterols from cultures of the basidiomycete Psathyrella candolleana. Fitoterapia 2019, 138, 104289. [Google Scholar] [CrossRef]
Chen, P.; Qin, H.-J.; Li, Y.-W.; Ma, G.-X.; Yang, J.-S.; Wang, Q. Study on chemical constituents of an edible mushroom Volvariella volvacea and their antitumor activity in vitro. Nat. Prod. Res. 2020, 34, 1417–1422. [Google Scholar] [CrossRef] [PubMed]
Shi, Q.; Huang, Y.; Su, H.; Gao, Y.; Peng, X.; Zhou, L.; Li, X.; Qiu, M. C28 steroids from the fruiting bodies of Ganoderma resinaceum with potential anti-inflammatory activity. Phytochemistry 2019, 168, 112109. [Google Scholar] [CrossRef] [PubMed]
He, W.-J.; Zhou, X.-J.; Qin, X.-C.; Mai, Y.-X.; Lin, X.-P.; Liao, S.-R.; Yang, B.; Zhang, T.; Tu, Z.-C.; Wang, J.-F. Quinone/hydroquinone meroterpenoids with antitubercular and cytotoxic activities produced by the sponge-derived fungus Gliomastix sp. ZSDS1-F7. Nat. Prod. Res. 2017, 31, 604–609. [Google Scholar] [CrossRef] [PubMed]
Amagata, T.; Doi, M.; Tohgo, M.; Minoura, K.; Numata, A. Dankasterone, a new class of cytotoxic steroid produced by a Gymnascella species from a marine sponge. Chem. Commun. 1999, 22, 1321–1322. [Google Scholar] [CrossRef]
Hu, Z.; Wu, Y.; Xie, S.; Sun, W.; Guo, Y. Phomopsterones A and B, two functionalized ergostane-type steroids from the endophytic fungus Phomopsis sp. TJ507A. Org. Lett. 2017, 19, 258–261. [Google Scholar] [CrossRef]
Imai, S.; Fujioka, S.; Murata, E.; Saskawa, Y.; Nakanishi, K. Isolation of four new phytoecdysones, makisterone A, B, C, D, and the structure of makisterone A, A C28 steroid. Tetrahedron Lett. 1968, 25, 3887. [Google Scholar] [CrossRef]
Nabiev, A.; Nakhatov, I.; Shakirov, R.; Yunusov, S.Yu. Alkaloids of Petilium raddeanum. III. Structure of petisidine. Chem. Nat. Compd. 1982, 18, 502–503. [Google Scholar] [CrossRef]
Nuriddinov, R.N.; Yunusov, S.Y. The structure and configuration of korsevinine. Chem. Nat. Compd. 1969, 5, 519–520. [Google Scholar] [CrossRef]
Li, P.; Yukie, K.; Koh, K.; Motoo, S.; Xu, G.-J.; Chen, Y.-P.; Hsu, H.-Y. A steroidal alkaloid from Fritillaria ebeiensis. Phytochemistry 1992, 31, 2190–2191. [Google Scholar]
Nakhatov, I.; Nabiev, A.; Shakirov, R.; Yunusov, S.Yu. Alkaloids of Petilium raddeana. III. Structure of petisidinine. Chem. Nat. Compd. 1983, 19, 710–712. [Google Scholar] [CrossRef]
Garbuz, N.I.; Yankovskaya, G.S.; Kashkan, Z.N. Circular dichroism of steroids with a lactone ring B. Brassinosteroids and compounds related to them. Chem. Nat. Compd. 1992, 28, 63–68. [Google Scholar] [CrossRef]
Rubin, M.B.; Glover, D.; Parker, R.G. Specificity in photochemical cycloadditions. Tetrahedron Lett. 1964, 5, 1075–1079. [Google Scholar] [CrossRef]
Goncharova, N.M.; Grinenko, G.S. Homogeneous catalytic hydrogenation of Δ1-double bonds in steroidal dienones. Pharm. Chem. J. 1980, 14, 245–246. [Google Scholar] [CrossRef]
Kamernitskii, A.V.; Reshetova, I.G.; Chernoburova, E.I. New advances in the field of synthesis of natural polyhydroxysteroids. Chem. Nat. Compd. 1988, 24, 1–22. [Google Scholar] [CrossRef]
El Kihel, L. Oxidative metabolism of dehydroepiandrosterone (DHEA) and biologically active oxygenated metabolites of DHEA and epiandrosterone (EpiA) – Recent reports. Steroids 2012, 77, 10–26. [Google Scholar] [CrossRef]
Jeyaprakash, N.; Maeder, S.; Janka, H. A systematic review of the impact of 7-keto-DHEA on body weight. Arch. Gynecol. Obstet. 2023, 308, 777–785. [Google Scholar] [CrossRef]
Prough, R.A.; Clark, B.J.; Klinge, C.M. Novel mechanisms for DHEA action. J. Mol. Endocrinol. 2016, 56, R139–R155. [Google Scholar] [CrossRef] [PubMed]
Lardy, H.; Marwah, A.; Marwah, P. C19-5-ene steroids in nature. Vitamins Hormones 2005, 71, 263–299. [Google Scholar]
Naelitz, B.D.; Sharifi, N. Through the looking-glass: Reevaluating DHEA metabolism Through HSD3B1 Genetics. Trends Endocrinol. Metab. 2020, 31, 680–690. [Google Scholar] [CrossRef]
Liu, J.F.; Chen, W-J.; Xin, B.-R.; Lu, J. Metabolites of the Endophytic Fungus Penicillium sp. FJ-1 of Acanthus ilicifolius. Nat. Prod. Commun. 2014, 9, 799–801. [Google Scholar] [CrossRef] [PubMed]
De Marino, S.; Ummarino, R.; D’Auria, M.V.; Chini, M.G. 4-Methylenesterols from Theonella swinhoei sponge are natural pregnane-X-receptor agonists and farnesoid-X-receptor antagonists that modulate innate immunity. Steroids 2012, 77, 484–495. [Google Scholar] [CrossRef]
Qiao, F.; Jia, N.Y.; Liua, X.H.; Li, F.; Xue, Q.Z. Asporyergosterol, a new steroid from an algicolous Isolate of Aspergillus oryzae. Nat. Prod. Commun. 2010, 5, 1575–1578. [Google Scholar] [CrossRef] [PubMed]
Kikuchi, T.; Horii, Y.; Maekawa, Y.; Masumoto, Y.; In, Y.; Tomoo, K.; Sato, H.; Yamano, A.; Yamada, T.; Tanaka, R. Pleurocins A and B: Unusual 11(9→7)-abeo-ergostanes and eringiacetal B: A 13,14-seco-13,14-epoxyergostane from fruiting bodies of Pleurotus eryngii and their inhibitory effects on nitric oxide production. J. Org. Chem. 2017, 82, 10611–10616. [Google Scholar] [CrossRef]
Wu, J.; Choi, J.H.; Yoshida, M.; Hirai, H.; Harada, E. Osteoclast-forming suppressing compounds, gargalols A, B, and C, from the edible mushroom Grifola gargal. Tetrahedron 2011, 67, 6576–6581. [Google Scholar] [CrossRef]
Li, W.; Zhou, W.; Cha, J.Y.; Kwon, S.U.; Baek, K.-H.; Shim, S.H.; Lee, Y.M.; Kim, Y.H. Sterols from Hericium erinaceum and their inhibition of TNF-α and NO production in lipopolysaccharide-induced RAW 264.7 cells. Phytochemistry 2015, 115, 231–238. [Google Scholar] [CrossRef]
Wang, Y.; Dai, O.; Peng, C.; Su, H.G.; Miao, L.L.; Liu, L.S.; Xiong, L. Polyoxygenated ergosteroids from the macrofungus Omphalia lapidescens and the structure-cytotoxicity relationship in a human gastric cancer cell line. Phytochem. Lett. 2018, 25, 99–104. [Google Scholar] [CrossRef]
Wang, Q.; Wang, Y.G.; Ma, Q.Y.; Huang, S.Z.; Kong, F.D.; Zhou, L.M.; Dai, H.F.; Zhao, Y.X. Chemical constituents from the fruiting bodies of Amauroderma subresinosum. J. Asian Nat. Prod. Res. 2016, 18, 1030–1035. [Google Scholar] [CrossRef]
Zhang, F.L.; Yang, H.X.; Wu, X.; Li, J.Y.; Wang, S.Q.; He, J.; Li, Z.H.; Feng, T.; Liu, J.K. Chemical constituents and their cytotoxicities from mushroom Tricholoma imbricatum. Phytochemistry 2020, 177, 112431. [Google Scholar] [CrossRef] [PubMed]
Zhu, X.-C.; Huang, G.-L.; Mei, R.-Q.; Wang, B.; Sun, X.-P.; Luo, Y.-P.; Xu, J.; Zheng, C.-J. One new α,β-unsaturated 7-ketone sterol from the mangrove-derived fungus Phomopsis sp. MGF222. Nat. Prod. Res. 2020, 35, 3970–3976. [Google Scholar] [CrossRef] [PubMed]
Zhang, C.-Y.; Ji, X.; Gui, X.; Huang, B.-K. Chemical constituents from an endophytic fungus Chaetomium globosum Z1. Nat. Prod.Commun. 2013, 8, 1217–1218. [Google Scholar] [CrossRef]
Yang, S.; Ma, Q.Y.; Kong, F.D.; Xie, Q.Y.; Huang, S.Z.; Zhou, L.M.; Dai, H.F.; Yu, Z.F.; Zhao, Y.X. Two new compounds from the fruiting bodies of Ganoderma philippii. J. Asian Nat. Prod. Res. 2018, 20, 249–254. [Google Scholar] [CrossRef]
Shi, Q.; Huang, Y.; Su, H.; Gao, Y.; Peng, X.; Zhou, L.; Li, X.; Qiu, M. C28 steroids from the fruiting bodies of Ganoderma resinaceum with potential anti-inflammatory activity. Phytochemistry 2019, 168, 112109. [Google Scholar] [CrossRef] [PubMed]
Gao, H.; Hong, K.; Chen, G.-D.; Wang, C.-X.; Tang, J.-S.; Yu, Y.; Jiang, M.-M.; Li, M.-M.; Wang, N.-L.; Yao, X.-S. New oxidized sterols from Aspergillus awamori and the endo-boat conformation adopted by the cyclohexene oxide system. Magn. Reson. Chem. 2010, 48, 38–43. [Google Scholar] [CrossRef]
Cui, C.-M.; Li, X.-M.; Meng, L.; Li, C.-S.; Huang, C.-G.; Wang, B.-G. 7-Nor-ergosterolide, a pentalactone-containing norsteroid and related steroids from the marine-derived endophytic Aspegillus ochraceus EN-31. J. Nat. Prod. 2010, 73, 1780–1784. [Google Scholar] [CrossRef]
Wang, F.; Fang, Y.; Zhang, M.; Lin, A.; Zhu, A.; Gu, Q.; Zhu, W. Six new ergosterols from the marine-derived fungus Rhizopus sp. Steroids 2008, 73, 19–26. [Google Scholar] [CrossRef]
Casapullo, A.; Minale, L.; Zollo, F.; Roussakis, C. New cytotoxic polyoxygenated steroids from the sponge Dysidea incrustans. Tetrahedron Lett. 1995, 36, 2669. [Google Scholar] [CrossRef]
Das, N.; Mishra, S.K.; Bishaye, A.; Alid, E.S.; Bishaye, A. The phytochemical, biological, and medicinal attributes of phytoecdysteroids: An updated review. Acta Pharmaceutica Sinica B 2021, 11, 1740–1766. [Google Scholar] [CrossRef] [PubMed]
Nakamura, S.; Chen, G.; Nakashima, S.; Matsuda, H.; Pei, Y.; Yoshikawa, M. Brazilian natural medicines. IV. New noroleananetype triterpene and ecdysterone-type sterol glycosides and melanogenesis inhibitors from the roots of Pfaffia glomerata. Chem Pharm Bull (Tokyo) 2010, 58, 690e5. [Google Scholar] [CrossRef] [PubMed]
Wu, P.; Xie, H.; Tao, W.; Miao, S.; Wei, X. Phytoecdysteroids from the rhizomes of Brainea insignis. Phytochemistry 2010, 71, 975e81. [Google Scholar] [CrossRef] [PubMed]
Issaadi, H.M.; Tsai, Y.C.; Chang, F.R.; Hunyadi, A. Centrifugal partition chromatography in the isolation of minor ecdysteroids from Cyanotis arachnoidea. J Chromatogr B Analyt Technol Biomed Life Sci 2017, 1054, 44e9. [Google Scholar] [CrossRef] [PubMed]
Mungarulire, J.; Munabu, R.M.; Ikekawa, N. A novel steroidal sapogenin, pogosterol from vernonia pogosperma. Chemical and Pharmaceutical Bulletin 1993, 41, 411–413. [Google Scholar] [CrossRef]
Tschen, J.S.M.; Chen, L.L.; Hsieh, S.T.; Wu, T.S. Isolation and phytotoxic effects of helvolic acid from plant pathogenic fungus Sarocladium oryzae. Bot. Bull. Acad. Sin. 1997, 38, 251–256. [Google Scholar]
Chen, X.; Winstead, A.; Yu, H.; Peng, J. Taccalonolides: A Novel Class of Microtubule-Stabilizing Anticancer Agents. Cancers 2021, 13, 920. [Google Scholar] [CrossRef] [PubMed]
Li, J.; Risinger, A.L.; Peng, J.; Chen, Z.; Hu, L.; Mooberry, S.L. Potent Taccalonolides, AF and AJ, Inform Significant Structure–Activity Relationships and Tubulin as the Binding Site of These Microtubule Stabilizers. J. Am. Chem. Soc. 2011, 133, 19064–19067. [Google Scholar] [CrossRef]
Chen, Z.-L.; Shen, J.-H.; Gao, Y.-S.; Wichtl, M. Five Taccalonolides from Tacca plantaginea. Planta Med. 1997, 63, 40–43. [Google Scholar] [CrossRef]
Aiello, A.; Fattorusso, E.; Magno, S.; Mayol, L.; Menna, M. Isolation of two novel 5α, 6α-epoxy-7-ketosterols from the encrusting demospongia Oscarella lobularis. J. Nаt. Prod. 1990, 53, 487. [Google Scholar] [CrossRef]
Xu, S.H.; Zeng, L.M. The Identification of Two New Sterols from Marine Organism. Chinese Chem Lett. 2000, 6, 531. [Google Scholar]
Umeyama, A.; Adachi, K.; Ito, S.; Arihara, S. New 24-Isopropylcholesterol and 24-Isopropenylcholesterol Sulfate from the Marine Sponge Epipolasis Species. J. Nat. Prod. 2000, 63, 1175. [Google Scholar] [CrossRef] [PubMed]
Umeyama, A.; Ito, S.; Yoshigaki, A.; Arihara, S. Two New 26,27-Cyclosterols from the Marine Sponge Strongylophora corticata. J. Nat. Prod. 2000, 63, 1540. [Google Scholar] [CrossRef] [PubMed]
Santafé, G.; Paz, V.; Rodríguez, J.; Jiménez, C. Novel Cytotoxic Oxygenated C29 Sterols from the Colombian Marine Sponge Polymastia tenax. J. Nat. Prod. 2002, 65, 1161. [Google Scholar] [CrossRef]
Zhang, W.H.; Chen, C.T. Isomalabaricane-Type Nortriterpenoids and Other Constituents of the Marine Sponge Geodia japonica. J. Nat. Prod. 2001, 64, 12, 1489–1492. [Google Scholar] [CrossRef]
Gallimore, W.A.; Kelly, M.; Scheuer, P.J. Gelliusterols A−D, New Acetylenic Sterols from a Sponge, Gellius Species. J. Nat. Prod. 2001, 64, 6, 741–744. [Google Scholar] [CrossRef]
STÁRKA, L.; DUŠKOVÁ, M.; VÍTKŮ, J. 11-Keto-testosterone and Other Androgens of Adrenal Origin. Physiol Res. 2020, 69, S187–S192. [Google Scholar] [CrossRef]
Kobayashi, Y.; Nagahama, Y.; Nakamura, M. Diversity and Plasticity of Sex Determination and Differentiation in Fishes. Sex Dev 2012, 7, 115–125. [Google Scholar] [CrossRef]
Dai, C.; Dehm, S.M.; Sharifi, N. Targeting the Androgen Signaling Axis in Prostate Cancer. J. Clinical Oncology 2023, 41, 4267–4278. [Google Scholar] [CrossRef]
Moisan, M.P. Sexual dimorphism in glucocorticoid stress response. Int. J. Mol. Sci. 2021, 22, 3139. [Google Scholar] [CrossRef]
Kupczyk, D.; Studzińska, R.; Kołodziejska, R.; Baumgart, S.; Modrzejewska, M.; Woźniak, A. 11β-Hydroxysteroid Dehydrogenase Type 1 as a Potential Treatment Target in Cardiovascular Diseases. J. Clin. Med. 2022, 11, 6190. [Google Scholar] [PubMed]
Wepler, M.; Preuss, J.M.; Merz, T.; et al. Impact of downstream effects of glucocorticoid receptor dysfunction on organ function in critical illness-associated systemic inflammation. 2020, 8, 37. [Google Scholar] [CrossRef] [PubMed]
de Kloet, E.R. Coping with the multifaceted and multifunctional role of cortisol in the brain. Neuroscience Applied 2024, 3, 104047. [Google Scholar] [CrossRef]
Deploey, N.; Van Moortel, L.; Rogatsky, I.; Peelman, F.; De Bosscher, K. The Biologist’s Guide to the Glucocorticoid Receptor’s Structure. Cells 2023, 12, 1636. [Google Scholar] [CrossRef] [PubMed]
Turcu, A.F.; Nanba, A.T.; Auchus, R.J. The Rise, Fall, and Resurrection of 11-Oxygenated Androgens in Human Physiology and Disease. Horm. Res. Paediatr. 2018, 89, 284–291. [Google Scholar]
Michael, A.E.; Lisa, M. Thurston1,2 and Michael T. Rae. Glucocorticoid metabolism and reproduction: a tale of two enzymes Reproduction. 2003, 126, 425–441. [Google Scholar] [PubMed]
Marciniak, B.; Patro-Malysza, J.; Poniedzialek-Czajkowska, E.; Kimber-Trojnar, Z.; Leszczynska-Gorzelak, B.; Oleszczuk, J. Glucocorticoids in Pregnancy. Current Pharmaceutical Biotechnology 2011, 12, 750–757. [Google Scholar] [CrossRef]
Sakai, K.; Chiba, H.; Kaneto, R.; Sakamoto, M. Mer-NF8054A and X, novel antifungal steroids, isolated from Aspergillus sp. The Journal of Antibiotics 1994, 47, 591–594. [Google Scholar] [CrossRef] [PubMed]
Mizuno, R.; KAWAHARA, N.; NOZAWA, K. Sterochemistry of an 18, 22-Cyclosterol, Mer-NF8054X, from Emericella heterothallica and Aspergillus ustus. Chemical and Pharmaceutical Bulletin 1995, 43, 9–11. [Google Scholar] [CrossRef]
Zhang, S.S.; Wang, Y.-G.; Ma, Q.-Y.; Huang, S.-Z.; Hu, L.-L. Three New Lanostanoids from the Mushroom Ganoderma tropicum. Molecules 2015, 20, 3281–3289. [Google Scholar] [CrossRef]
Shaabana, M.; Ghanic, M.A.; Shaabana, K.A. Zahramycins A-B, Two New Steroids from the Coral Sarcophyton trocheliophorum. Z. Naturforsch. 2013, 68b, 939–945. [Google Scholar] [CrossRef]
Al-lihaibia, S.S.; Ayyad, S.-E.N.; Al-wessaby, E.; Alarif, W.M. 3b,7b-Dihydroxy-5a-cholestan-11-one: A new oxidation pattern of cholestane skeleton from Laurencia papillosa. Biochemical Systematics and Ecology 2010, 38, 861–863. [Google Scholar] [CrossRef]
Cavaco, J.E.B.; Bogerd, J.; Goos, H.; Schulz, R.W. Testosterone Inhibits 11-Ketotestosterone-Induced Spermatogenesis in African Catfish (Clarias gariepinus). Biol. Reproduct. 2001, 65, 1807–1812. [Google Scholar] [CrossRef] [PubMed]
Idler, D.R.; Schmidt, P.J.; Ronald, A.P. Isolation and identification of 11- ketotestosterone in Salmon plasma. Can. J. Biochem. Physiol. 1960, 38, 28–37. [Google Scholar] [CrossRef]
Izzo, I.; De Riccardis, F.; Massa, A.; Sodano, G. Synthesis of incrustasterols, two cytotoxic polyoxygenated sponge steroids. Tetrahedron Lett. 1996, 37, 4775. [Google Scholar] [CrossRef]
Aiello, A.; Fattorusso, E.; Menna, M.; Carnuccio, R.; Iuvone, T. New cytotoxic steroids from the marine sponge Dysidea fragilis coming from the lagoon of Venice Steroids. 1995, 60, 666. [Google Scholar] [CrossRef]
Tsai, C.-R.; Huang, C.-Y.; Chen, B.-W.; Tsai, Y.-Y.; Shih, S.-P.; Hwang, T.-L.; Dai, C.-F.; Wang, S.-Y.; Sheu, J.-H. New bioactive steroids from the soft coral Klyxum flaccidum. RSC Adv. 2015, 5, 12546–12554. [Google Scholar] [CrossRef]
D’Auria, V.; Riccio, R.; Minale, L.; La Barre, S.; Pusseta, J. Novel Marine Steroid Sulfates from Pacific Ophiuroids. J. Org. Chem. 1987, 52, 3947–3952. [Google Scholar] [CrossRef]
Gu, B.-B.; Jiao, F.-R.; Wu, W.; Liu, L.; Jiao, W.-H.; Sun, F.; Wang, S.-P.; Yang, F.; Lin, H.-W. Ochrasperfloroid, an ochratoxinergosteroid heterodimer with inhibition of IL-6 and NO production from Aspergillus flocculosus 16D-1. RSC Adv. 2019a, 9, 7251–7256. [Google Scholar] [CrossRef]
Gu, B.-B.; Wu, W.; Jiao, F.-R.; Jiao, W.-h.; Li, L.; Sun, F.; Wang, S.-P.; Yang, F.; Lin, H.-W. Aspersecosteroids A and B, two 11(9->10)-abeo-5,10-secosteroids with a dioxatetraheterocyclic ring system from Aspergillus flocculosus 16D-1. Org. Lett. 2018a, 20, 7957–7960. [Google Scholar] [CrossRef]
Gu, B.B.; Wu, W.; Jiao, F.R.; Jiao, W.H.; Li, L.; Sun, F.; Wang, S.P.; Yang, F.; Lin, H.W. Asperflotone, an 8(14->15)-abeo-ergostane from the sponge-derived fungus Aspergillus flocculosus 16D-1. J. Org. Chem. 2019b, 84, 300–306. [Google Scholar] [CrossRef]
Tao, H.; Li, Y.; Lin, X.; Zhou, X.; Dong, J.; Liu, Y.; Yang, B. A new pentacyclic ergosteroid from fungus Aspergillus sp. ScSiO41211 derived of mangrove sediment sample. Nat. Prod. Commun. 2018b, 13, 1629–1631. [Google Scholar]
Abe, F.; Yamauchi, T. Affinosides La-Le, Major Cardenolide Glycosides from the Leaves of Anodendron affine (Anodendron. VII). Chem. Pharm. Bull. 1985, 33, 3662–3669. [Google Scholar] [CrossRef]
Renkonen, O.; Schindler, O.; Reichstein, T. Die Konstitution von Sinogenin. Glykoside und Aglykone. 181. Mitteilung. Croatica Chem. Acta 1957, 29, 239–245. [Google Scholar]
Larsen, K.L.; Andersen, S.B.; Mørkbak, A.L. Inclusion complexes of fusidic acid and three structurally related compounds with cyclodextrins. J Incl Phenom Macrocycl Chem 2007, 57, 185–190. [Google Scholar] [CrossRef]
Godtfredsen, W.O.; von Daehne, W.; Tybring, L.; Vangedal, S. Fusidic Acid Derivatives. I. Relationship between structure and antibacterial activity. J. Med. Chem. 1966, 9, 15–22. [Google Scholar]
Von Daehne, W.; Godtfredsen, W.O.; Rasmussen, P.R. Structure-Activity Relationships in Fusidic Acid-Type Antibiotics. Advances in Applied Microbiology 1979, 25, 95–146. [Google Scholar]
Honour, J.W.; Tourniaire, J.; Biglieri, E.G.; Shackleton, C.H.L. Urinary steroid excretion in 17α-hydroxylase deficiency. J. Steroid Biochem. 1978, 9, 495–505. [Google Scholar] [CrossRef] [PubMed]
Romanoff, L.P.; PARENT, C.; RODRIGUEZ, R.; PINCUS, G. Urinary excretion of β-cortolone (3α, 17α, 20β, 21-tetrahydroxypregnane-11-one) in young and elderly men and women. J. Clin. Endocrinol. Metabol. 1959, 19, 819–826. [Google Scholar] [CrossRef]
Xiang, M.L.; Hu, B.Y.; Qi, Z.H.; Wang, X.N.; Xie, T.Z.; Wang, Z.J.; Ma, D.Y.; Zeng, Q.; Luo, X.-D. Chemistry and bioactivities of natural steroidal alkaloids. Nat. Prod. Bioprosp. 2022, 12, 23. [Google Scholar] [CrossRef]
Khuong-Huu, F.; Herlem, D.; Simes, J.J. Steroid alkaloids. LXXXI. The Buxacae family (12th communication). Study of the Wolff-Kishner reduction of the 9 beta, 19 cyclo 11-keto system, and of N-3-isobutyryl cycloxobuxine-F, and of N-3-isobutyryl cycloxobuxidine-F. Bull. Soc. Chim. de France 1969, 1, 258–262. [Google Scholar]
Kurakina, I.O.; Proskurnina, N.F.; Kibal’chich, P.N. Alkaloids of Buxus balearica. I. Chem Nat Compd. 1969, 5, 20–21. [Google Scholar] [CrossRef]
Yan, Y.-X.; Sun, Y.; Li, Z.-R.; Zhou, L.; Qiu, M.-H. Chemistry and Biological Activities of Buxus alkaloids. Curr. Bioact. Comp. 2011, 7, 47–64. [Google Scholar] [CrossRef]
Atta-ur-Rahman; Ali, R.A.; Ashraf, M.; Choudhary, M.I.; Sener, B.; Turkoz, S. Steroidal alkaloids from Veratrum album. Phytochemistry 1996, 43, 907–11. [Google Scholar] [CrossRef]
Atta-ur-Rahman; Ali, R.A.; Gilani, A.; Chou, M.I.; Hary, D.; Aftab, K.; Sener, B.; Turkoz, S. Isolation of antihypertensive alkaloids from the rhizomes of Veratrum album. Planta Med. 1993, 59, 569–71. [Google Scholar] [PubMed]
Yun, S.; Chen, J.X.; Lin, Z.; Jia, S.; Yan, L.; Qiu, M.H. Three new pregnane alkaloids from Veratrum taliense. Helv Chim Acta. 2012, 95, 1114–1120. [Google Scholar]
Vulfson, N.S.; Zaikin, V.G. The Determination of the Position of Double Bond in Unsaturated Steroids by Mass Spectrometry. Russ. Chem. Rev. 1973, 42, 625. [Google Scholar] [CrossRef]
Szpilfogel, S.A.; Zeelen, F.J. Steroid research at Organon in the golden 1950s and the following years. Steroids 1996, 61, 483–491. [Google Scholar] [CrossRef]
Pattenden, G.; Gonzalez, M.A.; McCulloch, S.; Woodhead, S.J. A total synthesis of estrone based on a novel cascade of radical cyclizations. Proceed. Nat. Acad. Sci. USA 2004, 101, 12024–12029. [Google Scholar] [CrossRef]
Zheng, J.; Wang, Y.; Wang, J.; Liu, P.; Li, J.; Zhu, W. Antimicrobial ergosteroids and pyrrole derivatives from halotolerant Aspergillus flocculosus PT05-1 cultured in a hypersaline medium. Extremophiles 2013, 17, 963–71. [Google Scholar] [CrossRef]
Alarif, W.M.; Al-Lihaibi, S.S.; Abdel-Lateff, A.; Ayyad, S.-E.N. New Antifungal Cholestane and Aldehyde Derivatives from the Red Alga Laurencia papillosa. Nat. Prod. Commun. 2011, 6, 1821–1824. [Google Scholar] [CrossRef] [PubMed]
Carotenuto, A.; Fattorusso, E.; Lanzotti, V.; Magno, S.; Carnuccio, R.; D’Acquisto, F. 12-Keto-porrigenin and the unique 2,3-seco-porrigenin, new antiproliferative sapogenins from Allium porrum. Tetrahedron 1997, 53, 3401–3406. [Google Scholar] [CrossRef]
Wagner, H.; Fischer, M.; Lotter, H. Isolation and structure determination of daigremontianin, a novel bufadienolide from Kalanchoe daigremontiana. Planta Med. 1985, 169. [Google Scholar]
Steyn, P.S.; van Heerden, F.R.; Vleggaar, R.; Anderson, L.A.P. Bufadienolide glycosides of the Crassulaceae. Structure and stereochemistry of orbicusides A—C, novel toxic metabolites of Cotyledon orbiculata. J. Chem. Soc., Perkin Trans. 1 1986, 1633–1636. [Google Scholar] [CrossRef]
Steyn, P.S.; van Heerden, F.R. Bufadienolides of plant and animal origin. Nat Prod Rep. 1998, 15, 397–413. [Google Scholar] [CrossRef] [PubMed]
Tashmukhamedov, M.S.; Mirzaakhmedov, S.Y.; Ibragimov, B.T.; et al. Arenobufagin and gamabufotalin from the venom of the Central Asian green toad Bufo viridis. Introduction, structural—functional features. Chem Nat Compd 1995, 31, 214–220. [Google Scholar] [CrossRef]
Dong, Q.; Turdu, G.; Aisa, H.A.; Yili, A. Arenobufagin, isolated from Bufo viridis toad venom, inhibits A549 cells proliferation by inducing apoptosis and G2/M cell cycle arrest. Toxicon 2024, 240, 107641. [Google Scholar] [CrossRef] [PubMed]
Eisner, T.; Wiemer, D.F.; Haynes, L.W.; Meinwald, J. Lucibufagins: Defensive steroids from the fireflies Photinus ignitus and P. marginellus (Coleoptera: Lampyridae). Proceed. Nat. Acad. Sci. 1978, 75, 905–908. [Google Scholar]
Chen, G.; Song, Y.; Ge, H.; Ren, J.; Yang, X.; Li, J. Biotransformation of 20(S)-protopanaxatriol by Aspergillus niger and the cytotoxicity of the resulting metabolites. Phytochemistry Letters 2015, 11, 111–115. [Google Scholar] [CrossRef]
Hu, Z.X.; Shi, Y.M.; Wang, W.G.; et al. KadcoccinonesA–F, new biogenetically related lanostane-type triterpenoids with diverse skeletons from Kadsura coccinea. Organic Letters 2015, 17, 4616–4619. [Google Scholar] [CrossRef]
Su, J.Y.; Meng, Y.H.; Zeng, L.M.; Fu, X.; Schmitz, F.J. Stellettin A, a New Triterpenoid Pigment from the Marine Sponge Stelletta tenuis. J. Nat. Prod. 1994, 57, 1450–1451. [Google Scholar] [CrossRef] [PubMed]
Tang, S.A.; Zhou, Q.; Guo, W.Z.; Qiu, Y.; Wang, R.; Jin, M. In Vitro Antitumor Activity of Stellettin B, a Triterpene from Marine Sponge Jaspis stellifera, on Human Glioblastoma Cancer SF295 Cells. Mar. Drugs 2014, 12, 4200–4213. [Google Scholar] [CrossRef] [PubMed]
Chen, H.L.; Chiang, H.C. Constituents of Fruit Bodies of Tramete orientalis. Journal of the Chinese Chemical Society 1995, 42, 97–10. [Google Scholar] [CrossRef]
Kuhajda, K.; Kandrac, J.; Kevresan, S.; Mikov, M.; Fawcett, J.P. Structure and origin ofbile acids: An overview. Eur. J. Drug Metabol. Pharmacokin. 2006, 31, 135–143. [Google Scholar] [CrossRef] [PubMed]
Sobotka, H.; Bloch, E. The Steroids. Ann. Rev. Biochem. 1943, 12, 45–80. [Google Scholar] [CrossRef]
Kuroda, M.; Arata, H. PYTHCHOLICLACTONEAND, 3, 12-DIHYDROXY-7-ETOCHOLANICACIDFROMTHEBILEOFBOIE (Python reticulatus). J. Biochem. 1952, 39, 225. [Google Scholar]
Eneroth, P.; Gordon, B.; Sjovall, J. Characterization of trisubstituted cholanoic acids in human feces. J. Lipid Res. 1966, 7, 524. [Google Scholar] [CrossRef] [PubMed]
Amuro, Y.; Endo, T.; Higashino, K.; Uchida, K.; Yamamura, Y. Urinary and fecal keto bile acids in liver cirrhosis. Clinica Chimica Acta 1981, 114, 137–147. [Google Scholar]
Nian, Y.; Zhang, X.M.; Li, Y.; Wang, Y.Y.; Chen, J.-C.; Lua, Lu; Zhou, L. Cycloartane triterpenoids from the aerial parts of Cimicifuga foetida Linnaeus. Phytochemistry 2011, 72, 1473–1481. [Google Scholar]
Ajiboso, S.O. Determination of chemical composition of volatile oil obtained from Calotropis procera leaf through GC-MS analysis. Int. J. Recent Res. Phys. Chem. Sci. 2023, 10, 20–26. [Google Scholar]
Shimizu, Y.; Mitsuhashi, H. Studies on the components of asclepiadaceae plants—XXII: Structures of cynanchogenin and sarcostin. Tetrahedron 1968, 24, 4143–4157. [Google Scholar] [CrossRef]
Cao, X.W.; Chen, S.B.; Li, J.; Xiao, P.G.; Chen, S.L. Steroidal alkaloids from the bulbs of Fritillaria delavayi Franch. (Liliaceae). Biochemical Systematics and Ecology 2008, 36, 665–668. [Google Scholar]
Fukuzawa, S.; Matsunaga, S.; Fusetani, N. Isolation of 13 New Ritterazines from the Tunicate Ritterella tokioka and Chemical Transformation of Ritterazine B1. J. Org. Chem. 1997, 62, 4484–4491. [Google Scholar] [CrossRef] [PubMed]
Nishikawa, T. An Atrial Membrane in the Colonial Ascidian, Ritterella tokioka (Urochordata: Ascidiacea) from Sagami Bay. Zoological Science 2005, 22, 363–366. [Google Scholar] [CrossRef] [PubMed]
Moser, B.R. Review of Cytotoxic Cephalostatins and Ritterazines: Isolation and Synthesis. J. Nat. Prod. 2008, 71, 487–491. [Google Scholar] [CrossRef] [PubMed]
Dilly, P.N. The habitat and behaviour of Cephalodiscus gracilis (Pterobranchia, Hemichordata) from Bermuda. J. Zool., Lond. (A) 1985, 207, 223–239. [Google Scholar] [CrossRef]
Pettit, G.R.; Xu, J.-P.; Williams, M.D.; Christie, N.D.; Doubek, D.L.; Schmidt, J.M.; Boyd, M.R. Isolation and Structure of Cephalostatins 10 and 11. J. Nat. Prod. 1994, 57, 52–63. [Google Scholar] [CrossRef] [PubMed]
Iglesias-Arteaga, M.A.; Morzycki, J.W. Cephalostatins and Ritterazines The Alkaloids. Chemistry and Biology 2013, 72, 153–279. [Google Scholar] [PubMed]
Pettit, G.R.; Inoue, M.; Kamano, Y.; Herald, D.L.; Arm, C. Antineoplastic agents. 147. Isolation and structure of the powerful cell growth inhibitor cephalostatin 1. J. Am. Chem. Soc. 1988, 110, 2006–2007. [Google Scholar]
Mansour, N. Chemo- and regioselective hydroboration of Δ14,15 in certain cephalostatin analogue. Chinese Chemical Letters 2008, 19, 1391–1394. [Google Scholar]
D’Auria, M.V.; Minale, L.; Riccio, R. Polyoxygenated steroids of marine origin. Chem. Rev. 1993, 93, 1839–1895. [Google Scholar] [CrossRef]
Aiello, A.; Fattorusso, E.; Menna, M. Steroids from sponges: Recent reports. Steroids 1999, 64, 687–714. [Google Scholar] [CrossRef] [PubMed]
Hong, L.L.; Ding, Y.F.; Zhang, W.; et al. Chemical and biological diversity of new natural products from marine sponges: a review (2009–2018). Mar Life Sci Technol. 2022, 4, 356–372. [Google Scholar] [CrossRef] [PubMed]
Sedlaczek, L.; Smith, L.L. Biotransformations of steroids. Critical reviews in biotechnology 1988, 7, 187–236. [Google Scholar] [CrossRef] [PubMed]
Wang, Q.; Wang, Y.G.; Ma, Q.Y.; Huang, S.Z.; Kong, F.D.; Zhou, L.M.; Dai, H.F.; Zhao, Y.X. Chemical constituents from the fruiting bodies of Amauroderma subresinosum. J. Asian Nat. Prod. Res. 2016, 18, 1030–1035. [Google Scholar] [CrossRef] [PubMed]
Wang, S.; Zhang, L.; Liu, L.-Y.; Dong, Z.-J.; Li, Z.-H.; Liu, J.-K. Six novel steroids from culture of basidiomycete Polyporus ellisii. Nat. Prod. Bioprospect. 2012, 2, 240–244. [Google Scholar] [CrossRef]
Kikuchi, T.; Isobe, M.; Uno, S.; In, Y.; Zhang, J.; Yamada, T. Strophasterols E and F: Rearranged ergostane-type sterols from Pleurotus eryngii. Bioorg. Chem. 2019, 89, 103011. [Google Scholar] [CrossRef] [PubMed]
Xue, J.; Wu, P.; Xu, L.; Wei, X. Penicillitone, a potent in vitro anti-inflammatory and cytotoxic rearranged sterol with an unusual tetracycle core produced by Penicillium purpurogenum. Org. Lett. 2014, 16, 1518–1521. [Google Scholar] [CrossRef] [PubMed]
Amagata, T.; Tanaka, M.; Yamada, T.; Doi, M.; Minoura, K.; Ohishi, H.; Yamori, T.; Numata, A. Variation in cytostatic constituents of a sponge-derived Gymnascella dankaliensis by manipulating the carbon source. J. Nat. Prod. 2007, 70, 1731–1740. [Google Scholar] [CrossRef] [PubMed]
Amagata, T.; Doi, M.; Tohgo, M.; Minoura, K.; Numata, A. Dankasterone, a new class of cytotoxic steroid produced by a Gymnascella species from a marine sponge. Chem. Commun. 1999, 1321–1322. [Google Scholar] [CrossRef]
De Marino, S.; Ummarino, R.; D’Auria, M.V.; Chini, M.G.; Bifulco, G.; Renga, B.; D’Amore, C.; Fiorucci, S.; Debitus, C.; Zampella, A. Theonellasterols and Conicasterols from Theonella swinhoei Novel Marine Natural Ligands for Human Nuclear Receptors. J. Med. Chem. 2011, 54, 3065–3075. [Google Scholar] [CrossRef]
Burgoyne, D.L.; Andersen, R.J.; Allen, T.M. J. Org. Chem. 1992, 57, 525. [CrossRef]
Shoji, N.; Umeyama, A.; Shin, K.; Takeda, K.; Arihara, S.; Kobayashi, J.; Takei, M. Two unique pentacyclic steroids with cis C/D ring junction from Xestospongia bergquistia Fromont, powerful inhibitors of histamine release. J. Org. Chem. 1992, 57, 2996–2997. [Google Scholar] [CrossRef]
Singh, K.S.; Tilvi, S. Chemical Diversity and Bioactivity of Marine Sponges of the Genus Oceanapia: A Review. Mini-Reviews in Organic Chemistry 2022, 19, 66–73. [Google Scholar] [CrossRef]
Fu, X.; Ferreira, M.L.G.; Schmitz, F.J.; Kelly, M. J. Org. Chem. 1999, 64, 6706. [CrossRef] [PubMed]
Sperry, S.; Crews, P. Haliclostanone sulfate and halistanol sulfate from an Indo-Pacific Haliclona sponge. J. Nat. Prod. 1997, 60, 29–32. [Google Scholar] [CrossRef] [PubMed]
Regaladoa, E.L.; Jimenez-Romero, C.; Genta-Jouve, G.; Tasdemir, D. Acanthifoliosides, minor steroidal saponins from the Caribbean sponge Pandaros acanthifolium. Tetrahedron 2011, 67, 1011–1018. [Google Scholar] [CrossRef]
Kamano, Y.; Kumon, S.; Arai, T.; Komatsu, M. Bufadienolides. VIII. Epimerization of 14α-and 14β-Artebufogenin. Chem. Pharm. Bull. 1973, 21, 1960. [Google Scholar] [CrossRef]
Kusano, G.; Murakami, Y.; Sakurai, N.; Takemoto, T. Studies on the constituents of Cimicifuga spp:, X.I. Isolation and stereostructures of dahurinol, dehydroxydahurinol, isodahurinol and 25-O-methylisodahurinol. Yakugaku Zasshi 1976, 96, 82–85. [Google Scholar] [CrossRef] [PubMed]
Konoshima, T.; Kashiwada, Y.; Takasaki, M.; Kozuka, M.; Yasuda, I. Cucurbitacin F derivatives, anti-HIV principles from cowania Mexicana. Bioorg. Med. Chem. Lett. 1994, 4, 1323–1326. [Google Scholar] [CrossRef]
Shi, Q.Q.; Wang, W.-H.; Lu, J.; Li, D.-S.; Zhou, L.; Qiu, M.-H. New Cytotoxic Cycloartane Triterpenes from the Aerial Parts of Actaea heracleifolia (syn. Cimicifuga heracleifolia). Planta Med 2019, 85, 154–159. [Google Scholar]
Qiu, F.; Imai, A.; McAlpine, J.B.; Lankin, D.C.; Burton, I. Dereplication, Residual Complexity and Rational Naming – the Case of the Actaea Triterpenes. J Nat Prod. 2012, 75, 432–443. [Google Scholar] [CrossRef]
Plaza, A.; Perrone, A.; Balestrieri, M.L.; Felice, F.; Balestrieri, C.; Hamed, A.I. New unusual pregnane glycosides with antiproliferative activity from Solenostemma argel. Steroids 2005, 70, 594–603. [Google Scholar] [CrossRef] [PubMed]
Ivanchina, N.V.; Kalinin, V.I. Triterpene and Steroid Glycosides from Marine Sponges (Porifera, Demospongiae): Structures, Taxonomical Distribution, Biological Activities. Molecules 2023, 28, 2503. [Google Scholar] [CrossRef] [PubMed]
Dai, H.-F.; Edrada, R.A.; Ebel, R.; Nimtz, M.; Wray, V.; Proksch, P. Norlanostane triterpenoidal saponins from the marine sponge Melophlus sarassinorum. J. Nat. Prod. 2005, 68, 1231–1237. [Google Scholar] [CrossRef] [PubMed]
Santalova, E.A.; Denisenko, V.A.; Dmitrenok, P.S.; Berdyshev, D.V.; Stonik, V.A. Two new sarasinosides from the sponge Melophlus sarasinorum. Nat. Prod. Commun. 2006, 1, 265–271. [Google Scholar] [CrossRef]
Antonov, A.S.; Afiyatullov, S.S.; Kalinovsky, A.I.; Ponomarenko, L.P. Mycalosides B−I, Eight New Spermostatic Steroid Oligoglycosides from the Sponge Mycale laxissima. J. Nat. Prod. 2003, 66, 1082–1088. [Google Scholar] [CrossRef]
Woo, J.K.; Ha, T.K.Q.; Oh, D.C.; Oh, W.K.; Oh, K.B.; Shin, J. Polyoxygenated Steroids from the Sponge Clathria gombawuiensis. J. Nat. Prod. 2017, 80, 3224–3233. [Google Scholar] [CrossRef]
Vriet, C.; Russinova, E.; Reuzeaua, C. Boosting Crop Yields with Plant Steroids. Plant Cell. 2012, 24, 842–857. [Google Scholar] [CrossRef]
Bartwal, A.; Mall, R.; Lohani, P.; et al. Role of Secondary Metabolites and Brassinosteroids in Plant Defense Against Environmental Stresses. J Plant Growth Regul 2013, 32, 216–232. [Google Scholar] [CrossRef]
Ervina, M.; Poerwono, H.; Widyowati, R.; Matsunami, K. Biotechnology Reports. Biotechnology Reports 2020, 25, e00437. [Google Scholar]
Li, J.F.; Ji, K.L.; Sun, P.; Cai, Q.; Zheng, X.L.; Xiao, Y.D. Structurally diverse steroids with nitric oxide inhibitory activities from Aglaia lawii leaves. Phytochemistry 2021, 183, 112651. [Google Scholar] [CrossRef]
Hantos, S.M. The syntheses of trichiliasterone A and B isolated from Trichilia hirta and the preparation of derivatives of the antimalarial agent gedunin. Thesis, University of Ottawa, Canada, 1998. [Google Scholar]
Liu, Y.Y.; Wang, T.; Yang, R.-X.; Tang, H.-X.; Qiang, L.; Liu, Y.-P. Anti-inflammatory steroids from the fruits of Artocarpus heterophyllus. Nat. Prod. Res. 2021, 35, 3071–3077. [Google Scholar] [CrossRef] [PubMed]
Inada, A.; Murata, H.; Inatomi, Y.; Nakanishi, T.; Darnaedi, D. Pregnanes and triterpenoid hydroperoxides from the leaves of Aglaia grandis Phprochemrsry. 1997, 45, 1225–1228. [Google Scholar]
Mohamad, K.; Sevenet, T.; Dumontet, V.; Pais, M.; Tri, M.V.; Hadi, H.; Awang, K.; Martin, M.T. Dammarane triterpenes and pregnane steroids from Aglaia lawii and A. tomentosa. Phytochemistry 1999, 51, 1031–1037. [Google Scholar] [CrossRef]
Yang, S.M.; Fu, W.W.; Wang, D.X.; Tan, C.H.; Zhu, D.Y. Two new pregnane from Aglaia perviridis Hiern, J. Asian Nat. Prod. Res. 2008, 10, 459–462. [Google Scholar] [CrossRef] [PubMed]
de Souza Figueiredoa, F.; Celanob, R.; de Sousa Silvac, D.; das Neves Costaa, F. Countercurrent chromatography separation of saponins by skeleton type from Ampelozizyphus amazonicus for off-line ultra-high-performance liquid chromatography/high resolution accurate mass spectrometry analysis and characterization. Journal of Chromatography A 2017, 1481, 92–100. [Google Scholar] [CrossRef] [PubMed]
Deepak, M.; Amit, A. The need for establishing identities of ′bacoside A and B′, the putative major bioactive saponins of Indian medicinal plant Bacopa monnieri. Phytomedicine 2004, 11, 264–268. [Google Scholar] [CrossRef]
Ali, Z.; Khana, I.A.; Fronczek, F.R. Revision of the structure of podocarpaside E, from Actaea podocarpa. Acta Cryst. 2007a, E63, o2101–o2103. [Google Scholar]
Ali, Z.; Khan, S.I.; Ferreira, D.; Khan, I.A. Podocarpaside, a Triterpenoid Possessing a New Backbone from Actaea podocarpa. Org. Lett. 2006, 24, 5529–5532. [Google Scholar] [CrossRef]
Chen, J.Y.; Li, P.-L.; Tang, X.-L.; Wang, S.-J.; Jiang, Y.-T. Cycloartane Triterpenoids and Their Glycosides from the Rhizomes of Cimicifuga foetida. J. Nat. Prod. 2014, 77, 1997–2005. [Google Scholar] [CrossRef]
Silchenko, A.S.; Kalinovsky, A.I.; Avilov, S.A.; Andrijaschenko, P.V.; Popov, R.S. Unusual Structures and Cytotoxicities of Chitonoidosides A, A1, B, C, D, and E, Six Triterpene Glycosides from the Far Eastern Sea Cucumber Psolus chitonoides. Mar. Drugs 2021, 19, 449. [Google Scholar] [CrossRef] [PubMed]
Bhatnagar, S.; Dudouet, B.; Ahond, A.; Poupat, C.; Thoison, O.; Clastres, A.; Laurent, D.; Potier, P. Invertébrés marins du lagon néocalédonien. IV: Saponines et sapogénines d’une holothurie, Actinopyga flammea. Bull. Soc. Chim. Fr. 1985, 1, 124–129. [Google Scholar]
Aoki, S.; Watanabe, Y.; Sanagawa, M.; Setiawan, A.; Kotoku, N.; Kobayashi, M. Cortistatins A, B, C, and D, Anti-angiogenic Steroidal Alkaloids, from the Marine Sponge Corticium simplex. J. Am. Chem. Soc. 2006, 128, 3148–3149. [Google Scholar] [CrossRef]
Leuthardt, F.L.G.; Glauser, G.; Baur, B. Composition of alkaloids in different box tree varieties and their uptake by the box tree moth Cydalima perspectalis. Chemoecology 2013, 23, 203–212. [Google Scholar] [CrossRef]
Desai, M.C.; Joginder Singh, H.P.S. Chawla, Sukh Dev. Higher isoprenoids—XI1: Partial syntheses from cycloartenol, cyclolaudenol—part 3: cyclobuxophyllinine-m, cyclobuxophylline-k and buxanine-m. Tetrahedron 1981, 37, 2935–2940. [Google Scholar] [CrossRef]
Ata, A.; Samina Naz, M.; Choudhary, I.; Atta-ur-Rahman. New Triterpenoidal Alkaloids from Buxus sempervirens. Z. Naturforsch. 2002, 57C, 21–28. [Google Scholar]
Atta-ur-Rahman; DILDAR AHMED, M. IQBAL CHOUDHARY. Alkaloids from the Leaves of Buxus sempervirens. Journal of Natural Products 1988, 51, 783–786. [Google Scholar] [CrossRef]
Sanchez, V.; Ahond, A.; Guihem, J.; Poupat, C.; Potier, P. Alcaloides des feuilles de Didymeles madagascariensis Willd, des feuilles et des ecorces de racines de Didymeles perrieri Leandri (Didymelacees). Bull. Soc. Chim. Fr. 1987, 5, 877–884. [Google Scholar]
Atta-ur-Rahman; Choudhary, M.I.; Khan, M.R.; Iqbal, M.Z. Three new steroidal amines from Sarcococca saligna. Nat. Prod. Lett. 1998, 11, 81–91. [Google Scholar] [CrossRef]
Zhao, C.; Gan, C.C.; Jin, M.N.; Tang, S.A.; Qin, N.; Duan, H.Q. Antitumor metastasis pregnane alkaloids form Pachysandra terminalis. J. Asian Nat. Prod. Res. 2014, 16, 440–446. [Google Scholar] [CrossRef]
Li, X.Y.; Yu, Y.; Jia, M.; Jin, M.-N.; Qin, N.; Zhao, C.; Duan, H.-Q. Terminamines K–S, Antimetastatic Pregnane Alkaloids from the Whole Herb of Pachysandra terminalis. Molecules 2016, 21, 1283. [Google Scholar] [CrossRef] [PubMed]
Songa, C.W.; Lunga, P.K.; Qina, X.J.; Chenga, G.G.; Gu, J.L. New antimicrobial pregnane glycosides from the stem of Ecdysanthera rosea. Fitoterapia 2014, 99, 267–275. [Google Scholar] [CrossRef] [PubMed]
DUŠKOVÁ, M.; KOLÁTOROVÁ, L.; ŠIMKOVÁ, M.; ŠRÁMKOVÁ, M.; MALÍKOVÁ, M. Steroid Diagnostics of 21st Century in the Light of Their New Roles and Analytical Tools. Physiol Res. 2020, 69, S193–S203. [Google Scholar] [CrossRef] [PubMed]
Kopylov, A.T.; Malsagova, K.A.; Stepanov, A.A.; Kaysheva, A.L. Diversity of Plant Sterols Metabolism: The Impact on Human Health, Sport, and Accumulation of Contaminating Sterols. Nutrients 2021, 13, 1623. [Google Scholar] [CrossRef] [PubMed]
Bayala, B.; Zoure, A.A.; Baron, S.; de Joussineau, C.; Simpore, J.; Lobaccaro, J.-M.A. Pharmacological Modulation of Steroid Activity in Hormone-Dependent Breast and Prostate Cancers: Effect of Some Plant Extract Derivatives. Int. J. Mol. Sci. 2020, 21, 3690. [Google Scholar] [CrossRef] [PubMed]
Rosenfield, R.L. The Search for the Causes of Common Hyperandrogenism, 1965 to circa 2015. Endocrine Reviews 2024. [Google Scholar] [CrossRef] [PubMed]
Nunes, V.O.; Vanzellotti, N.C.; Fraga, J.L.; Pessoa, F.L.P.; Ferreira, T.F.; Amaral, P.F.F. Biotransformation of Phytosterols into Androstenedione-A Technological Prospecting Study. Molecules. 2022, 27, 3164. [Google Scholar] [CrossRef] [PubMed]
Sahu, P.; Gidwani, B.; Dhongade, H.J. Pharmacological activities of dehydroepiandrosterone: A review. Steroids. 2020, 153, 108507. [Google Scholar] [CrossRef]
Chatterton, R.T. Functions of dehydroepiandrosterone in relation to breast cancer. Steroids. 2022, 179, 108970. [Google Scholar] [CrossRef]
Tarkowská, D. Plants are Capable of Synthesizing Animal Steroid Hormones. Molecules. 2019, 24, 2585. [Google Scholar] [CrossRef]
Siddiquia, B.S.; Usmania, S.B.; Alib, S.T.; Beguma, S.; Rizwanib, G.H. Further constituents from the bark of Holarrhena pubescens. Phytochemistry 2001, 58, 1199–1204. [Google Scholar] [CrossRef] [PubMed]
Raeside, J.I. A Brief Account of the Discovery of the Fetal/Placental Unit for Estrogen Production in Equine and Human Pregnancies: Relation to Human Medicine. Yale J Biol Med. 2017, 90, 449–461. [Google Scholar] [PubMed]
Younglai, E.V.; Solomon, S. Formation of estra-1,3,5(10)-triene-3,15 alpha, 16 alpha, 17 beta-tetrol (estetrol) and estra-1,3,5(10)-triene-3,15 alpha, 17 beta-triol from neutral precursors. J Clin Endocrinol Metab. 1968, 28, 1611–1617. [Google Scholar] [CrossRef] [PubMed]
Trifunović, J.; Borčić, V.; Vukmirović, S.; Mikov, M. Structural insights into anticancer activity of D-ring modified estrone derivatives using their lipophilicity in estimation of SAR and molecular docking studies. Drug Test Anal. 2017, 9, 1650. [Google Scholar] [CrossRef] [PubMed]
Butenandt, A.; Jacobi, H. Über die Darstellung eines krystallisierten pflanzlichen Tokokinins (Thelykinins) und seine Identifizierung mit dem α-Follikelhormon. Untersuchungen über das weibliche Sexualhormon. Hoppe Seyler’s Z Physiol Chem 1933, 218, 104–112. [Google Scholar] [CrossRef]
Dohrn, M.; Faure, W.; Poll, H.; Blotevogel, W. Tokokinine, Stoff mit sexualhormonartiger Wirkung aus Pflanzenzellen. Med Klin 1926, 22, 1417–1419. [Google Scholar]
Skarzynski, B. An oestrogenic substance from plant material. Nature 1933, 131, 766. [Google Scholar]
Su, Z.; Yuan, W.; Wang, P.; Li, S. Ethnobotany, phytochemistry, and biological activities of Taxodium Rich. PharmCrops 2013, 4, 1–14. [Google Scholar]
Beall, D. Some notes on the isolation of oestrone and equilin from the urine of pregnant mares. Biochem J. 1936, 30, 577–581. [Google Scholar] [CrossRef]
Schachter, B.; Marrian, G.F. PREGNANT MARES SULFATE FROM THE URINE OF THE ISOLATION OF ESTRONE. J. Biol. Chem. 1938, 126, 663–669. [Google Scholar] [CrossRef]
Bachmann, W.E.; Cole, W.; Wilds, A.L. THE TOTAL SYNTHESIS OF THE SEX HORMONE EQUILENIN. J. Am. Chem. Soc. 1939, 61, 974–975. [Google Scholar] [CrossRef]
Zuhrotun, A.; Suganda, A.G.; Nawawi, A. Phytochemical Study Of Ketapang Bark (Terminaliа Catappa L). International Conference on Medicinal Plants (ICOMP 2010), Surabaya, Indonesia, 21–22 July 2010. [Google Scholar]
Omeje, E.; Osadebe, P.; Procksh, P.; Amal, H.; Debbab, A.; Kawamura, A.; Esimone, C.; Nworu, S. Immunomodulatory and antioxidant constituents of Eastern Nigeria mistletoe, Loranthus micranthus Linn. (Loranthaceae) parasitic on Cola acuminata Schott et Endl. Planta Med 2010, 76, P129. [Google Scholar]
Avsejs, L.A.; Nott, C.J.; Maxwell, J.R.; Evershed, R.P. Hydroxy and ketonic androstanes: a new class of sterol diagenetic product in peat. Organic Geochemistry 1998, 28, 749–753. [Google Scholar] [CrossRef]
Horinouchi, M.; Hayashi, T. Comprehensive summary of steroid metabolism in Comamonas testosteroni TA441: entire degradation process of basic four rings and removal of C12 hydroxyl group. Appl. Environ. Microbiol. 2023, 89, 1–19. [Google Scholar] [CrossRef] [PubMed]
Hitotsuyanagi, Y.; Ozeki, A.; Choo, C.Y.; Chan, K.L.; Itokawa, H.; Takey, K. Malabanones A and B, novel nortriterpenoids from Ailanthus malabarica DC. Tetrahedron 2001, 57, 7477–7480. [Google Scholar] [CrossRef]
Zhang, H.; Ren, J.; Wang, Y.; Sheng, C.; Wu, Q.; Diao, A.; Zhu, D. Effective multi-step functional biotransformations of steroids by a newly isolated Fusarium oxysporum SC1301. Tetrahedron 2013, 69, 184–189. [Google Scholar] [CrossRef]
Šaden-Krehula, M.; Kolbah, D.; Tajić, M.; et al. 17-Ketosteroids in Pinus nigra Ar. Naturwissenschaften 1983, 70, 520–522. [Google Scholar]
Ballou, C.E.; Anderson, A.B. On the cyclitols present in sugar pine (Pinus lambertiana Dougl. ). J. Am. Chem. Soc. 1953, 75, 648–650. [Google Scholar] [CrossRef]
Horinouchi, M.; Hayashi, T.; Koshino, H.; Malon, M.; Hirota, H.; Kudo, T. Identification of 9α-Hydroxy-17-Oxo-1,2,3,4,10,19-Hexanorandrostan-5-Oic Acid in Steroid Degradation by Comamonas testosteroni TA441 and Its Conversion to the Corresponding 6-En-5-Oyl Coenzyme A (CoA) Involving Open Reading Frame 28 (ORF28)- and ORF30-Encoded Acyl-CoA Dehydrogenases. J. Bacteriol. 2014, 196, 3598–3608. [Google Scholar]
Donova, M.V. Transformation of steroids by actinobacteria: A review. Appl Biochem Microbiol 2007, 43, 1–14. [Google Scholar] [CrossRef]
Donova, M.V. Steroid Bioconversions. In Microbial Steroids: Methods and Protocols, Methods in Molecular Biology Springer Science; Barredo, J.-L., Herráiz, I., Eds.; Business Media LLC, 2017. [Google Scholar]
Bhatti, H.N.; Khera, R.A. Biological transformations of steroidal compounds: A review. Steroids 2012, 77, 1267–1290. [Google Scholar] [CrossRef] [PubMed]
Fernandes, P.; Cruz, A.; Angelova, B.; Pinheiro, H.M.; Cabral, J.M.S. Microbial conversion of steroid compounds: recent developments. Enzyme and Microbial Technology 2003, 32, 688–705. [Google Scholar] [CrossRef]
Atta-ur-Rahman; Ata, A.; Naz, S.; Choudhary, M.I.; Sener, B.; Turkoz, S. New Steroidal Alkaloids from the Roots of Buxus sempervirens. J. Nat. Prod. 1999, 62, 665–669. [Google Scholar] [CrossRef] [PubMed]
Araujo-Castro, M. Cardiometabolic profile and urinary metabolomic alterations in non-functioning adrenal incidentalomas: A review. Clinical Endocrinology. 2022, 97, 693–701. [Google Scholar] [CrossRef] [PubMed]
Araujo-Castro, M.; Valderrábano, P.; Escobar-Morreale, H.F.; et al. Urine steroid profile as a new promising tool for the evaluation of adrenal tumors. Literature review. Endocrine 2021, 72, 40–48. [Google Scholar] [PubMed]
Reincke, M.; Fleseriu, M. Cushing Syndrome. A Review. JAMA 2023, 330, 170–181. [Google Scholar] [CrossRef] [PubMed]
Abooshah, R.; Ardalani, H.; Zarkesh, M.; Hooshmand, K. Metabolomics—A Tool to Find Metabolism of Endocrine Cancer. Metabolites 2022, 12, 1154. [Google Scholar] [CrossRef] [PubMed]
Morfin, R. Les stéroïdes naturels de A à Z; Lavoisier: Paris, France, 2010. [Google Scholar]
Sefid-Sefidehkhan, Y.; Jouyban, A.; Khoshkam, M.; et al. A mini review on materials used for the colorimetric detection of corticosteroids. Chem. Pap. 2022, 76, 4627–4643. [Google Scholar] [CrossRef]
Fujii, T.; Deane, A.M.; Nair, P. Metabolic support in sepsis: corticosteroids and vitamins: the why, the when, the how. Current Opinion in Critical Care 2020, 26, 363–368. [Google Scholar] [CrossRef]
Ingle, D.J. The biologic properties of cortisone: a review. Journal of Clinical Endocrinology 1950, 10, 1312–1354. [Google Scholar] [CrossRef]
Swartz, S.L.; Dluhy, R.G. Corticosteroids: Clinical Pharmacology and Therapeutic Use. Drugs 1978, 16, 238–255. [Google Scholar] [CrossRef] [PubMed]
Jha, S.S. Glucocorticoid-Induced Osteoporosis (GIOP). Indian J Orthop. 2023, 57, 181–191. [Google Scholar] [CrossRef] [PubMed]
de Kloet, ER. Glucocorticoid feedback paradox: a homage to Mary Dallman. Stress 2023, 26, 2247090. [Google Scholar] [CrossRef] [PubMed]
Mao, L.; Wei, W.; Chen, J. Biased regulation of glucocorticoid receptors signaling. Biomed Pharmacother. 2023, 165, 115145. [Google Scholar] [CrossRef] [PubMed]
Barnes, P.J. How corticosteroids control inflammation: Quintiles Prize Lecture. British J. Pharmacol. 2006, 148, 245–254. [Google Scholar] [CrossRef]
Barnes, P.J. Corticosteroids: The drugs to beat. European Journal of Pharmacology 2006, 533, 2–14. [Google Scholar] [CrossRef] [PubMed]
Veleiro, A.S.; Burton, G. Structure-activity relationships of neuroactive steroids acting on the GABAA receptor. Current Medicinal Chemistry 2009, 16, 455–472. [Google Scholar] [CrossRef]
Salter, W.T. The Chemistry of the Hormones. Annual Review of Biochemistry 1945, 14, 561–598. [Google Scholar] [CrossRef]
Deng, S.; Li, F.; Peng, S.; Rao, Z.; Wu, H.; Xu, J. Chemical constituents of the South China Sea gorgonian Menella spinifera Kukenthal. Chin. J. Appl. Chem. 1997, 14, 80–82. [Google Scholar] [CrossRef]
Li, F.; Deng, S.; Rao, Z.; Wu, H.; Xu, J. Studies on chemical constituents of South China Sea gorgonian Menella spinifera Kukenthal (II). Guangzhou Chem. 1996, 21, 49–51. [Google Scholar]
Angelova, B.; Mutafov, S.; Avramova, T. Effect of Nitrogen Source in Cultivation Medium on the 9α-Hydroxylation of Pregnane Steroids by Resting Rhodococcus Sp. Cells, Biotechnology & Biotechnological Equipment 2005, 19, 113–116. [Google Scholar]
Lee, S.; Lee, D.; Baek, S.C.; Jo, M.S.; Kang, K.S.; Kim, K.H. (3,16)-3,16-Dihydro-xypregn-5-en-20-one from the Twigs of Euonymus alatus (Thunb) Sieb. Exerts Anti-Inflammatory Effects in LPS-Stimulated RAW-264.7 Macrophages. Molecules 2019, 24, 3848. [Google Scholar] [PubMed]
Ayanoglu, E.; Djerassi, C.; Erdman, T.R.; Scheuer, P.J. Minor and trace sterols in marine invertebrates V. isolation, structure elucidation and synthesis of 3β-hydroxy-26,27-bisnorcholest-5-en-24-one from the sponge Psammaplysilla purpurea. Steroids 1978, 31, 815–822. [Google Scholar]
Laurent, P.; Braekman, J.C.; Daloze, D. Insect chemical defense. In Topics in current chemistry; Band 240; Springer: Berlin, 2005; pp. 167–229. [Google Scholar]
Eisner, T.; Eisner, M.; Siegler, M. Secret weapons; Belknap Press of Harvard University Press: Cambridge, 2005. [Google Scholar]
Gronquist, M.; Meinwald, J.; Eisner, T.; Schroeder, F.C. Exploring uncharted terrain in nature’s structure space using capillary NMR spectroscopy; 13 steroids from 50 fi refl ies. J Am Chem. Soc 2005, 127, 10810–10811. [Google Scholar] [CrossRef]
Bajguz, A. Metabolism of brassinosteroids in plants. Plant Physiology and Biochemistry 2007, 45, 95–107. [Google Scholar] [CrossRef]
Abe, F.; Yamauchi, T. Pregnane glycosides from the roots of Asclepias tuberosa. Chemical and pharmaceutical bulletin 2000, 48, 1017–1022. [Google Scholar] [CrossRef] [PubMed]
Li, C.S.; Yu, H.W.; Li, G.Y.; Zhang, G.L. Chemical constituents from the roots of Dysoxylum densiflorum. Chinese J. Nat. Med. 2010, 8, 270–273. [Google Scholar] [CrossRef]
Abe, F.; Yamauchi, T. Two pregnanes from oleander leaves. Phytochemistry 1992, 31, 2819–2820. [Google Scholar] [CrossRef]
Li, S.W.; Zhao, Y.-H.; Gao, W.-K.; Zhang, L.-H.; Yu, H.-Y.; Wu, H.-H. Steroidal constituents from Solanum nigrum. .Fitoterapia 2023, 169, 105603. [Google Scholar] [CrossRef]
Atta-ur-Rahman; Alam, M.; Nasir, H.; Dagne, E.; Yenesew, A. Three steroidal alkaloids from Buxus hildebrandtii. Phytochemistry 1990, 29, 1293–6. [Google Scholar] [CrossRef]
Atta-ur-Rahman; Naz, S.; Noor-e-ain, F.; Ali, R.A.; Choudhary, M.I.; Sener, B.; Turkoz, S. Alkaloids from Buxus species. Phytochemistry. 1992, 31, 2933–5. [Google Scholar] [CrossRef]
Choudhary, M.I.; Shahnaz, S.; Parveen, S.; Khalid, A.; Mesaik, M.A.; Ayatollahi, S.A.M.; Atta-ur-Rahman. New cholinesterase-inhibiting triterpenoid alkaloids from Buxus hyrcana. Chem Biodivers. 2006, 3, 1039–52. [Google Scholar] [PubMed]
Atta-ur-Rahman; Naz, S.; Noor-e-ain, F.; Ali, R.A.; Choudhary, M.I.; Sener, B.; Turkoz, S. Alkaloids from Buxus species. Phytochemistry 1992, 31, 2933–2935. [Google Scholar] [CrossRef]
Szabó, L.U.; Kaiser, M.; Mäser, P.; Schmidt, T.J. Antiprotozoal Nor-Triterpene Alkaloids from Buxus sempervirens L. Antibiotics 2021, 10, 696. [Google Scholar] [CrossRef] [PubMed]
García, V.P.; Bermejo, J.; Rubio, S.; Quintana, J.; Estévez, F. Pregnane steroidal glycosides and their cytostatic activities. Glycobiology 2011, 21, 619–624. [Google Scholar] [CrossRef] [PubMed]
Xue, J.; Wu, P.; Xu, L.; Wei, X. Penicillitone, a Potent in Vitro Anti-inflammatory and Cytotoxic Rearranged Sterol with an Unusual Tetracycle Core Produced by Penicillium purpurogenum. Org. Lett. 2014, 16, 1518–1521. [Google Scholar] [CrossRef] [PubMed]
Wu, J.; Tokuyama, S.; Nagai, K.; Yasuda, N.; Noguchi, K. Strophasterols A to D with an Unprecedented Steroid Skeleton: From the Mushroom Stropharia rugosoannulata. Angewandte Chemie 2012, 124, 10978–10980. [Google Scholar] [CrossRef]
Nakada, T.; Yamamura, S. Three New Metabolites of Hybrid Strain KO 0231, Derived from Penicillium citreo-viride IFO 6200 and 4692. Tetrahedron 2000, 56, 2595–2602. [Google Scholar] [CrossRef]
Han, J.J.; Bao, L.; Tao, Q.-Q.; Yao, Y.-J.; Liu, X.-Z.; Yin, W.-B.; Liu, H.-W. Gloeophyllins A−J, Cytotoxic Ergosteroids with Various Skeletons from a Chinese Tibet Fungus Gloeophyllum abietinum. Org. Lett. 2015, 17, 2538−2541. [Google Scholar] [CrossRef]
Li, J.; Chen, C.; Fang, T.; Wu, L.; Liu, W.; Tang, J.; Long, Y. New Steroid and Isocoumarin from the Mangrove Endophytic Fungus Talaromyces sp. SCNU-F0041. Molecules 2022, 27, 5766. [Google Scholar] [CrossRef]
Shin, A.Y.; Lee, H.-S.; Lee, Y.-J.; Lee, J.S.; Son, A. Oxygenated Theonellastrols: Interpretation of Unusual Chemical Behaviors Using Quantum Mechanical Calculations and Stereochemical Reassignment of 7α-Hydroxytheonellasterol. Mar. Drugs 2020, 18, 607. [Google Scholar] [CrossRef] [PubMed]
Chang, Y.-C.; Kuo, L.-M.; Su, J.-H.; Hwang, T.-L.; Kuo, Y.-H.; Lin, C.-S.; Wu, Y.-C.; Sheu, J.-H.; Sung, P.-J. Pinnigorgiols A–C, 9,11-secosterols with a rare ring arrangement from a gorgonian coral Pinnigorgia sp. Tetrahedron 2016a, 72, 999–1004. [Google Scholar] [CrossRef]
Chang, Y.C.; Hwang, T.L.; Sheu, J.H.; Wu, Y.C.; Sung, P.J. New anti-inflammatory 9,11-secosterols with a rare tricyclo[5,2,1,1]decane ring from a Formosan Gorgonian Pinnigorgia sp. Mar. Drugs 2016b, 14, 218. [Google Scholar] [CrossRef] [PubMed]
Shen, Y.C.; Cheng, Y. B.; Kobayashi, C.J.; Kubota, T.; Takahashi, Y.; Mikami, Y. Nitrogen-containing verticillene diterpenoids from the Taiwanese soft coral Cespitularia taeniata. J. Nat. Prod. 2007, 70, 1961–1965. [Google Scholar] [CrossRef] [PubMed]
Hegazy, M.F.; Mohamed, T.A.; Alhammady, M.A.; Shaheen, A.M.; Reda, E.R.; Elshamy, A.I. Molecular architecture and biomedical leads of terpenes from red sea marine invertebrates. Mar. Drugs 2015, 13, 3154–3181. [Google Scholar] [CrossRef] [PubMed]
Elshamy, A.I.; Nassara, M.I.; Mohamed, T.A.; Hegazy, M.E.F. Chemical and biological profile of Cespitularia species: A mini review. J. Advan. Res. 2016, 7, 209–224. [Google Scholar] [CrossRef] [PubMed]
Chao, C.H.; Chou, K.J.; Huang, C.Y.; Wen, Z.H.; Hsu, C.H.; Wu, Y.C.; Dai, C.F.; Sheu, J.H. Steroids from the Soft Coral Sinularia crassa. Mar. Drugs 2012, 10, 439–450. [Google Scholar] [CrossRef] [PubMed]
Kawagishi, H.; Kawagishi, H.; Choi, J.H.; Choi, J.H.; Ogawa, A.; Ogawa, A.; Yazawa, K. Chaxines B, C, D, and E from the edible mushroom Agrocybe chaxingu. Tetrahedron 2009, 65, 9850–9853. [Google Scholar]
Liu, J.; Wu, X.; Yang, M.; Gu, Y.C.; Yao, L.G.; Huan, X.J.; Miao, Z.H.; Luo, H.; Guo, Y.W. Erectsterates A and B, a pair of novel highly degraded steroid derivatives from the South China Sea soft coral Sinularia erecta. Steroids 2020, 161, 108681. [Google Scholar] [CrossRef]
Wang, S.K.; Dai, C.F.; Duh, C.Y. Cytotoxic pregnane steroids from the Formosan Soft Coral Stereonephthya crystalliana. J. Nat. Prod. 2006, 69, 103–106. [Google Scholar] [CrossRef]
An, F.; Wang, X.; Yang, M.; Luon, J.; Kong, L. Bioactive A-ring rearranged limonoids from the root barks of Walsura robusta. Acta Pharm. Sinica 2019, 9B, 545–556. [Google Scholar] [CrossRef]
Song, Y.Y.; Miao, J.H.; Qin, F.Y.; Yan, Y.M.; Yang, J.; Qin, D.P.; Hou, F.H.; Zhou, L.L.; Cheng, Y.X. Belamchinanes A–D from Belamcanda chinensis: Triterpenoids with an unprecedented carbon skeleton and their activity against age-related renal fibrosis. Org. Lett. 2018, 20, 5506–5509. [Google Scholar] [CrossRef] [PubMed]
Song, Y.P.; Shi, Z.Z.; Miao, F.P.; Fang, S.T.; Yin, X.L.; Ji, N.Y. Tricholumin A, a highly transformed ergosterol derivative from the alga-endophytic fungus Trichoderma asperellum. Org. Lett. 2018, 20, 6306–6309. [Google Scholar] [CrossRef] [PubMed]
Li, J.; Xu, B.; Cui, J.; Deng, Z.; de Voogd, N.J.; Proksch, P.; Lin, W. Globostelletins A–I, cytotoxic isomalabaricane derivatives from the marine sponge Rhabdastrella globostellata. Bioorg. Med. Chem. 2010, 18, 4639–4647. [Google Scholar] [CrossRef]
Kolesnikova, S.A.; Lyakhova, E.G.; Kozhushnaya, A.B.; Kalinovsky, A.I.; Berdyshev, D.V.; Popov, R.S.; Stonik, V.A. New isomalabaricane-derived metabolites from a Stelletta sp. marine sponge. Molecules 2021, 26, 678. [Google Scholar] [CrossRef] [PubMed]
Tanaka, N.; Momose, R.; Shibazaki, A.; Gonoi, T.; Fromont, J.; Kobayashi, J. Stelliferins JeN, isomalabaricane-type triterpenoids from Okinawan marine sponge Rhabdastrella cf. globostellata. Tetrahedron 2011, 67, 6689–6696. [Google Scholar] [CrossRef]
Heretsch, P.; Giannis, A. The Veratrum and Solanum alkaloids. The Alkaloids: Chemistry and Biology 2015, 74, 201–232. [Google Scholar]
Luis, J.G.; Lahlou, E.H.; Andrés, L.S.; Sood, G.H.N.; Ripoll, M.M. Apiananes: C23 terpenoids with a new type of skeleton from Salvia apiana. Tetrahedron Lett. 1996, 37, 4213–4216. [Google Scholar] [CrossRef]
Miura, K.; Kikuzaki, H.; Nakatani, N. Apianane terpenoids from Salvia officinalis. Phytochemistry 2001, 58, 1171–1175. [Google Scholar] [CrossRef]
Cao, S.; Ross, L.; Tamayo, G.; Clardy, J. Asterogynins: Secondary metabolites from a Costa Rican endophytic fungus. Org. Lett. 2010, 12, 4661–4663. [Google Scholar] [CrossRef]
Turner, A.B. Terpenoids and steroids. Annu. Rep. Prog. Chem., Sect. B: Org. Chem. 1968, 65, 409–440. [Google Scholar] [CrossRef]
Su, L.H.; Geng, C.A.; Li, T.Z.; Huang, X.Y.; Ma, Y.B. Spiroseoflosterol, a rearranged ergostane-steroid from the fruiting bodies of Butyriboletus roseoflavus. J. Nat. Prod. 2020, 83, 1706–1710. [Google Scholar] [CrossRef] [PubMed]
Ren, Y.H.; Liu, Q.-F.; Chen, L.; He, S.-J.; Zuo, J.-P.; Fan, Y.-Y.; Yue, J.-M. Urceoloids A and B, Two C19 Steroids with a Rearranged Spirocyclic Carbon Skeleton from Urceola quintaretii. Org. Lett. 2019, 21, 1904–1907. [Google Scholar] [CrossRef] [PubMed]

Figure 2. 1-Ketosteroids derived from some marine invertebrates and plants.

Figure 5. 3-Ketosteroids derived from fungal endophytes, sponges, and plants.

Figure 7. 4-Ketosteroids derived from fungi and plants.

Figure 8. 6-Ketosteroids derived from fungal endophytes and plants.

Figure 9. 7-Ketosteroids derived from fungi, fungal endophytes, plants.

Figure 10. 11-Keto steroids and triterpenoids derived from diferent sources.

Figure 12. 15-Ketosteroids derived from fungi, marine invetevrates and plants.

Figure 13. 16-Ketosteroids derived from marine invertebrates, and plants.

Figure 14. 17-Ketosteroids derived from animals, fungi, and plants.

Table 1. Summarized biological activity of 1-ketosteroids.

No. Steroids	Reported Activity of 1-ketosteroids	Ref.
9,10	Growth inhibitory effects on HeLa S3 cells and human diploid cells	[34]
11-13	Cytotoxic activity	[35]
35	Cytotoxic activity	[46]
40	Cytotoxicity towards colon and pancreatic cancer cells	[51]
42	Antibacterial activity	[53]
54	Selective glucocorticoid receptor modulator	[61]
56	Quinone reductase inducer	[63]
57,58	Cancer chemopreventive activities	[64]

Table 2. Summarized biological activity of 2-ketosteroids.

No. Steroids	Reported Activity of 2-ketosteroids	Ref.
71	Calcium-binding activity	[75]
78,79	Anti-helminthic activity	[78,79]
81	Antibacterial activity against Gram-positive bacteria	[81]
82	Anti-acetylcholinesterase activity	[82,83]
83	Antibacterial activity against Gram-positive bacteria	[81]
85,86	Anti-inflammatory activity	[85]
93	Cytotoxic activity	[89]
98.99	Cytotoxic activity against P388 cells	[93]

Table 3. Summarized biological activity of 3-ketosteroids.

No. Steroids	Reported Activity of 3-ketosteroids	Ref.
111	Cytotoxic activity	[110]
116	Larvicidal properties against the yellow fever mosquito	[113]
117	Antitumor activity	[114,115]
118	Antitumor activity against P388 and L1210	[116]
129	Cytotoxic activity against P-388 (leukemia) and HT-29 cells	[123]
133,134	Human placental aromatase inhibitor	[127]
155-158	Strong cytotoxic activities against tumor cells P-388, KB, A-549, HT-29	[138]
159	Strong toxicity against some tumor cells	[139]
160,161	Cytotoxic properties	[140]
174,175	Cytotoxicity against A375, K562, and A549 cancer cell lines	[151]
177,178	Cytotoxic activity	[153]
182	Antibacterial activity	[157]
184-186	Cytotoxicity against the human hepatoma cell line Bel-7402	[158]
190	Cytotoxicity against a panel of three human tumor cell lines	[161]
191,192	Strong cytotoxicity	[162]
193,194	Anti-inflammatory activity	[162]
204	Cytotoxicity against human cytomegalovirus (HCMV)	[167]
205-208	Antiviral activity against P388 and HSV-I (human α-herpesvirus)	[168,169]

Table 4. Summarized biological activity of 4-ketosteroids.

No. Steroids	Reported Activity of 4-ketosteroids	Ref.
216	Anti-ulcer effect	[180]
225,226	Nitric oxide inhibitory effects	[184]

Table 5. Summarized biological activity of 6-ketosteroids.

No. Steroids	Reported Activity of 6-ketosteroids	Ref.
229	Cholesterol synthesis inhibitor	[194]
236	Neuraminidase inhibitory activity	[198]
239	Inhibitor of Ca2+-ATPase	[199]
240,241	Cholinesterase inhibitor	[200,201]
242	Cytotoxic activity against Hep3B, HepG2, and Huh-7	[202]
243	β-hexosaminidase inhibitor	[205]
244	Inhibition of TNF-α secretion	[206]
245-247	NO production inhibitor	[207]
248	Cytotoxic activity against HepG2 and SGC-7901	[210]
249	Cytotoxic activity against HepG2 cells	[210]
251	Antiviral activity against the EV-71 virus	[211]
252,253	Strong cytotoxicity against tumor cells	[213]
254	NO production inhibitor	[214]

Table 6. Summarized biological activity of 7-ketosteroids.

No. Steroids	Reported Activity of 7-ketosteroids	Ref.
264	Cytotoxicity against glioma cell lines	[229]
267	Cytotoxic activity towards the A-549 cell line	[177]
268	Nitric oxide production inhibitor	[232]
271	Cytotoxic activity against HGC-27	[234]
272	Cytotoxic activity against human gastric cancer cell line HGC-27	[235]
274,275	Cytotoxic activity against various cancer cell lines	[237]
276	Cytotoxicity against A549	[237]
278	NO production inhibitor	[241]
282-285	Cytotoxic activity against four different cancer cell lines	[244]
290	Cytotoxic activity against L-1210 cells	[250]
301	Anti-proliferative activity toward A-549, HT-29, H-116, MS-1, and PC-3 tumor cells	[259]

Table 7. Summarized biological activity of 11-ketosteroids.

No. Steroids	Reported Activity of 11-ketosteroids	Ref.
308-310	Cytotoxic activity against A549, HepG2, THP-1 IL-6 immune-suppressive activity and TNF-secretion inhibition	[275]
313	Antibacterial activity	[276]
332	Cytotoxic effects against A549, HepG2, and THP-1 cell lines	[284]
323,325	Anti-inflammatory properties	[285]
333	Protein synthesis inhibitor	[290,291,292]
339-342	Antihypertensive properties	[299,300,301]

Table 8. Summarized biological activity of 12-ketosteroids.

No. Steroids	Reported Activity of 12-ketosteroids	Ref.
343	Cytotoxic effects against HL-60 and BEL-7402 cells	[305]
345,346	Antiproliferative activity against four tumor cell lines	[307]
350,351	Inhibitors growth various cancer cell lines	[312]
358,359	Anticancer agents against Du-145, Hela, K562, K562/ADR, SH-SY5Y, HepG2, and MCF-7	[314]
362	Strong inhibitory effects againt human glioblastoma cancer SF295 cells	[317]
373,374	Strong anticancer properties	[328]

Table 9. Summarized biological activity of 15-ketosteroids.

No. Steroids	Reported Activity of 15-ketosteroids	Ref.
381	Cytotoxic activity against the HL-60 cell line	[340]
382	Anti-proliferative activity toward RAW264.7 cells NO production inhibitor	[342]
383	Antibacterial activity; Cytotoxic activity against cancer cell lines HL-60, SMMC-7721, A549, MCF-7, and SW480	[17,342]
384	Cytotoxic activity against HL-60	[342]
400,401	Cytotoxic activity against P388 cell line	[344,345]
406	Strong antiviral activity against HIV-1 replication in H9 cells	[355]

Table 10. Summarized biological activity of 16-ketosteroids.

No. Steroids	Reported Activity of 16-ketosteroids	Ref.
425-427	Strong anti-inflammatory activity and NO inhibition inhibitor	[367]
430	NO production inhibitor	[369]
449	Anticomplement activity	[376]
454-456	Anticomplement activity	[375]
461,462	Proliferation of human umbilical vein endothelial cells (HUVEC)	[380]
473	Antibacterial activity	[389]

Table 11. Summarized biological activity of 17-ketosteroids.

No. Steroids	Reported Activity of 17-ketosteroids	Ref.
475	Estrogenic activity	[399,400,401]
485, 487, 518-526	Estrogenic activity, and adrenal antitumor agents	[425,426,427]

Table 12. Summarized biological activity of 20-ketosteroids.

No. Steroids	Reported Activity of 20-ketosteroids	Ref.
552	Strong cytotoxic activities against SW480 and Hep3B cells	[451]
557	Strong antiprotozoal aqctivity	[455,456]
558-565	Strong cytostatic activity against HL-60, A-431, and SK-MEL-1 cells	[457]

Table 12. Summarized biological activity of miscellaneous ketosteroids.

No. Steroids	Reported Activity of miscellaneous ketosteroids	Ref.
573	Inhibitory activity against cholinesterase	[462]
575,576	Inhibitors on the generation of superoxide anions and the release of elastase by human neutrophils	[464,465]
581	Cytotoxic activity against cancer cell lines, A549, HT-29, SNU-398, Capan-1 (human pancreatic ductal adenocarcinoma)	[471]
582,583	Strong cytotoxicity against A549, HT-29, and P-388 cancer cells	[472]
595	Strong antimicrobial activity	[475]
597,598	Strong antimicrobial activity	[478]
606	Strong antimalarial properties	[482]
608	Cytotoxicity against liver cancer cell lines	[484]
609,610	Immune-suppressive activities	[485]

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

Copyright: This open access article is published under a Creative Commons CC BY 4.0 license, which permit the free download, distribution, and reuse, provided that the author and preprint are cited in any reuse.

MDPI Initiatives

Important Links

Choose an area of interest and we will send you notifications of new preprints at your preferred frequency.

Disclaimer

Chemical Diversity of Ketosteroids as Potential Therapeutic Agents

Abstract

Introduction

1-Ketosteroids

2-Ketosteroids

3-Ketosteroids

4-Ketosteroids

6-Ketosteroids

7-Ketosteroids

11-Ketosteroids

12-Ketosteroids

15-Ketosteroids

16-Ketosteroids

17-Ketosteroids

20-Ketosteroids

Miscellaneous Ketosteroids Derived from Natural Sources

Conclusions

Funding

Institutional Review Board Statement

Informed Consent Statement

Data Availability Statement

Conflicts of Interest

References

MDPI Initiatives

Important Links

Subscribe