Prerpints.org logo
Preprint
Review

Secondary Metabolites from Genus Eurotium and Their Biological Activities

Altmetrics

Downloads

112

Views

19

Comments

0

A peer-reviewed article of this preprint also exists.

Submitted:

27 October 2023

Posted:

30 October 2023

You are already at the latest version

Alerts
Abstract
Eurotium is the teleomorph genus associated with section Aspergillus. Eurotium comprises approximately 20 species, which are widely distributed in nature and human environments. Eurotium is usually the key microorganism for the ferment ation of traditional food, such as Fuzhuan brick tea, Liupao tea, Meju, and Karebushi, thus Eurotium is an important fungus in food industry. Eurotium has been extensively studied because they contain a series of interesting, structurally diverse, and biologically important secondary metabolites, including anthraquinones, benzaldehyde derivatives, and indol diketopiperazine alkaloids. These secondary metabolites have shown multiple biological activities, including antioxidative, antimicrobial, cytotoxic, antitumor, insecticidal, antimalarial, and anti-inflammatory activities. This study presents an up-to-date review of the phytochemistry and biological activities of all Eurotium species. This review will provide the recent advances on the secondary metabolites and their bioactivities in genus Eurotium for the first time and serve as a database for future research and drug development from the genus Eurotium.
Keywords: 
Subject: Biology and Life Sciences  -   Food Science and Technology

1. Introduction

Eurotium (Eurotiaceae) is the teleomorph genus associated with section Aspergillus. While most of Aspergillus species are asexual, sexual Aspergillus species have been separately summarized and named Eurotium [1,2]. Eurotium is characterized by its golden cleistothecia, lenticular ascospores, uniseriate conidial heads in shades of green or blue, and yellow-, orange- or red-encrusted hyphae [2,3]. The genus Eurotium comprises approximately 20 species [2], of which Eurotium amstelodami, Eurotium cristatum, and Eurotium repens have received the most attention [4,5]. All species of Eurotium are hypertonic fungi, which are widely distributed in nature and human environments, especially in environments of high salt, high sugar, and low water, such as salt lake, desert, plateau, and mangrove. Eurotium species are generally considered to be benign fungi without mycotoxins [6,7,8,9,10]. Moreover, Eurotium species are usually the key microorganism for the fermentation of traditional food, such as Fuzhuan brick tea, Liupao tea, Meju, and Karebushi [11,12,13].
Eurotium contains abundant secondary metabolites, which attract increasing attention. The investigation of secondary metabolites in Eurotium began with the identification of chemical structure of Eurotium’s pigment, which dates back to the 19th century. Great progress has been made on the secondary metabolites of Eurotium over the past few decades [4,5]. Notably, marine environment and fermented food and drink have become important sources of Eurotium species in recent years, leading to the discovery of a variety of new secondary metabolites [14]. Compounds isolated from Eurotium species mainly include anthraquinones, benzaldehyde derivatives, and indol diketopiperazine alkaloids. These secondary metabolites exhibit various bioactivities, such as antioxidative, antimicrobial, cytotoxic, antitumor, insecticidal, antimalarial, and anti-inflammatory activities [13,15,16,17,18,19,20]. However, as far as we know, there is no English review article to systematically summarize the secondary metabolites and their biological activities in the genus Eurotium.
In this context, this review will provide the recent advances in the secondary metabolites and their bioactivities in the genus Eurotium for the first time. Meanwhile, future perspectives and challenges are also outlined in this review.

2. Secondary metabolites from Eurotium

Nearly 180 compounds have been isolated and identified from Eurotium species by nuclear magnetic resonance (NMR) spectroscopy. These compounds mainly include anthraquinones, benzaldehyde derivatives, and indol diketopiperazine alkaloids.

2.1. Anthraquinones

Anthraquinones, which are formed by the merger of three benzene rings, are the largest group of natural pigments of quinoids [21]. Anthraquinones are usually produced by plants and microorganisms [22]. They often give a color (usually yellow, orange, or brown) to the lichens and the mycelium and fruiting bodies of fungi. Usually, there are several side substituents in the benzene ring of fungal anthraquinones. The most widespread in fungi are 1,8 dihydroxy and 1,5,8 or 1,6,8 trihydroxy anthraquinone derivatives [23]. Anthraquinones have shown a variety of pharmacological activities, including antibacterial, antiviral, insecticidal, diuretic, diarrhoeal, immunomodulatory, and anticancer effects [10,24,25].
Research on anthraquinones of Eurotium began in 1980. Anke et al. systematically investigated the structures of pigments in 20 Eurotium species, including Eurotium aeutum, Eurotium glabrum, Eurotium herbariorum, Eurotium pseudoglaucum, E. repens, Eurotium rubrum, Eurotium tonophihtm, Eurotium umbrosum, Eurotium appendiculatum, Eurotium carnoyi, Eurotium echinulatum, Eurotium niveoglaucum, E. amstelodami, Eurotium chevalieri, E. cristatum, Eurotium heterocaryoticum, Eurotium intermedium, Eurotium leucocarpum, Eurotium montevidensis, and Eurotium spiculosum. They found that these pigments were polyhydroxy anthraquinones, including questin (1), physcion (2), erythroglaucin (3), emodin (4), catenarin (5), rubrocristin (6), rubrocristin-8-methylether (7), rubrocristin-6-acetate (8) and querstin-6-methylether (9). Further, rubrocristin, a new yellow pigment, was first discovered in nature. The production of these pigments was seriously affected by the concentrations of glucose and salt in culture medium. It has been proved that the number of hydroxyl groups and their position plays an essential role in the antibacterial activity of these polyhydroxy anthraquinones [21]. In addition, physcion was supposed to play a role in iron transport or metabolism of fungal cell [26]. Three anthraquinones, including 2-O-methyleurotinone (10), 2,12-dimethyleurotinone (11), and eurotinone (12) were isolated from E. echinulatum by Eder et al. These compounds were found to have an antiangiogenic effect; thus, they might be used for preventing and treating malignant diseases [27]. Miyake et al. isolated a strain of E. herbariorum NU-2 during the manufacturing process of Karebushi (a traditional food in Japan), and then identified physcion-10,10'-bianthrone (13), questinol (14), asperflavin (15), as well as questin, physcion, and catenarin in this fungus [15]. Additionally, some pigments of anthraquinones, including variecolorquinone A (16), questin, physcion, erythroglaucin, emodin, catenarin, questinol, and asperflavin, were also found in other Eurotium strains, such as Eurotium sp. M30 XS-2012 [10] or E. cristatum KUFC 7356 [28].
The study of bioactive substances in marine microorganisms has become a hot topic in recent years [1]. Li and co-workers isolated the E. rubrum strain from a marine mangrove plant Hibiscus Tiliaceus, and then identified four new anthraquinones, as well as three known anthraquinones (questin, 2-O-methyleurotinone, and asperflavin) in this fungus. These four new anthraquinones were 2-O-methyl-4-O-(α-D-ribofuranosyl)-9-dehydroxyeurotinone (17; colorless amorphous powder), 2-O-methyl-9-dehydroxyeurotinone (18; colorless amorphous powder), eurorubrin (19; brown amorphous powder), and 3-O-(α-D-ribofuranosyl)-questin (20; orange amorphous powder). Based on the spectral data, 2-O-methyl-9-dehydroxyeurotinone is a 9-dehydroxyl derivative of 2-O-methyleurotinone; eurorubrin is a symmetrical dimeric compound composed of two molecules of asperflavin through a methylene group; 3-O-(α-D-ribofuranosyl)-questin is a glycoside consisted of questin as aglycone and one sugar unit [29]. In addition, Du et al. isolated an endophytic fungus (E. cristatum EN-220) from the marine alga Sargassum thunbergii, and identified one new anthraquinone glycoside named 3-O-(α-D-ribofuranosyl)-questinol (21; red amorphous powder), as well as asperflavin ribofuranoside (22), asperflavin, (+)-variecolorquinone A, eurorubrin, and 3-O-(α-D-ribofuranosyl)-questin. 3-O-(α-D-ribofuranosyl)-questinol and 3-O-(α-D-ribofuranosyl)-questin have the same ribose residue [30]. A new anthraquinone named 9-dehydroxyeurotinone (23; colorless amorphous powder) was also found in the E. rubrum [31]. Zin et al. isolated a new compound named acetylquestinol (24; yellow crystal), as well as four known anthraquinones including questin, physcion, emodin, and questinol from the culture of the mangrove plant Rhizophora mucronata-derived endophytic fungus E. chevalieri KUFA 0006. Acetylquestinol is a 1,3,6,8-tetrasubsituted 9,10-anthraquinone, similar to questinol [19]. Further, the metabolites vary greatly between the E. chevalieri KUFA 0006 and soil-derived strain of E.chevalier [32]. Additionally, questinol was also isolated from the marine-derived E. amstelodami [33].
The endophytes derived from the saline-alkali plants are attracting increasing attention due to the extreme environment of high osmolarity and nutrient deprivation. The chemical investigation of saline-alkali plant-derived endophytic fungi has just begun compared with those of marine mangrove plant-derived endophytes. Zhang et al. found a new anthraquinone named rubrumol (25), as well as emodin, catenarin, rubrocristin, and 2-O-methyleurotinone in a halo-tolerant endophytic fungus E. rubrum. This fungus is derived from the salt-tolerance wild plant Suaeda salsa. These anthraquinones displayed topoisomerase inhibitory activity, which implied that endophytic Eurotium fungus from saline-alkali plants may be one new reservoir for natural products in the future [25] (Figure 1).

2.2. Benzaldehyde derivatives

Benzaldehyde derivatives are a class of polyketides that synthesized by the combination of polyketone and terpenoid pathways [34]. It has been reported that benzaldehyde derivatives have various bioactivities, including, antioxidative, antibacterial, antifungal, antitumor, antimalarial, and antileishmanial activities [35,36,37]. Benzaldehyde derivatives, which are a kind of natural pigments, are a class of main metabolites in genus Eurotium [13]. More than 20 benzaldehyde derivatives have been identified in Eurotium.
Four new and seven known benzaldehyde derivatives were identified from E. rubrum, an endophytic fungus isolated from the inner tissue of stems in the mangrove plant Hibiscus tiliaceus by Li et al. These four benzaldehyde derivatives were 2-(2',3-epoxy-1'-heptenyl)-6-hydroxy-5-(3''-methyl-2''-butenyl)-benzaldehyde (26; yellowish amorphous powder), (E)-6-hydroxy-7-(3-methyl-2-butenyl)-2-(3-oxobut-1-enyl)-chroman-5-carbaldehyd (27; yellowish amorphous powder), 2-(1',5'-heptadienyl)-3,6-dihydroxy-5-(3''-methyl-2''-butenyl)-benzaldehyde (28; yellowish amorphous powder), and eurotirumin (29; yellowish amorphous powder). These seven known benzaldehyde derivatives were chaetopyranin (30), flavoglaucin (31), aspergin (32), isotetrahydroauroglaucin (33), isodihydroauroglaucin (34), 2-(2',3-epoxy-1',3'-heptadienyl)-6-hydroxy-5-(3-methyl-2-butenyl)-benzaldehyde (35), and 2-(2',3-epoxy-1',3',5'-heptatrienyl)-6-hydroxy-5-(3-methyl-2-butenyl)-benzaldehyde (36). These four benzaldehyde derivatives possess a penta-substituted benzene ring system bearing a 3-methyl-2-butenyl at C-5 and a phenolic hydroxyl group at C-6. The structures of compounds 26 and 35 are similar, except that two olefinic carbon signals of C-3' and C-4' in the 13C-NMR of compound 35 are replaced by two methylene signals at C-3' and C-4' in compound 26. The structures of compounds 27 and 30 are similar, except that the signals at H-6' and C-6' in compound 30 are replaced by a carbonyl signal at C-6' in compound 27. The structures of compounds 28 and 34 are similar, and the inconsistent position for the two double bonds in the heptadienyl side chain is the only difference [36]. Li et al. also isolated two new benzaldehyde derivatives, eurotirubrin A (37) and eurotirubrin B (38; yellow powder) in E. rubrum in another research [38]. In addition, auroglaucin (39), tetrahydroauroglaucin (40), dihydroauroglaucin (41), flavoglaucin, and isodihydroauroglaucin were identified from Karebushi-derived Eurotium fungi. All four benzaldehyde derivatives are disubstituted gentisaldehyde (2,5-dihydroxybenzaldehyde) derivatives with a prenyl group at C-3 and a seven-carbon unbranched aliphatic chain at C-6 [11]. Bioassay-guided fractionation of E. repens leads to the isolation of two new benzaldehyde compounds, (E)-2-(hept-1-enyl)-3-(hydroxymethyl)-5-(3-methylbut-2-enyl)-benzene-1,4-diol (42; yellow solid) and (E)-4-(hept-1-enyl)-7-(3-methylbut-2-enyl)-2,3-dihydrobenzofuran-2,5-diol (43; yellow oil), along with five known benzaldehyde derivatives, including flavoglaucin, 2-(2',3-epoxy-1',3'-heptadienyl)-6-hydroxy-5-(3-methyl-2-butenyl)-benzaldehyde, auroglaucin, tetrahydroauroglaucin, and dihydroauroglaucin. Compounds 42 and 43 showed high structural similarities except that the carbinol group at C-7 in compound 42 was replaced by a hemiacetal group in compound 43 [39]. Gao et al. also isolated flavoglaucin, 2-(2',3-epoxy-1',3'-heptadienyl)-6-hydroxy-5-(3-methyl-2-butenyl)-benzaldehyde, auroglaucin, tetrahydroauroglaucin, dihydroauroglaucin, and (E)-2-(hept-1-enyl)-3-(hydroxymethyl)-5-(3-methylbut-2-enyl)-benzene-1,4-diol from the fungus E. repens [18].
Two new benzaldehyde derivatives named (3'S*, 4'R*)-6-(3',5-epoxy-4'-hydroxy-1'-heptenyl)-2-hydroxy-3-(3''-methyl-2''-butenyl)-benzaldehyde (44; yellow oil) and 3'-OH-tetrahydroauroglaucin (45; yellow oil) were isolated from a gorgonian-derived Eurotium sp. These two compounds could non-enzymatically transform into pairs of enantiomers or epimers, respectively, with opposite configurations at C-3', thus, they are possibly artefacts formed during the extraction/isolation process [34]. Two new benzaldehyde derivatives named cristaldehyde A (46; yellow powder) and cristaldehyde B (47; yellow powder) were isolated from the fungus E. cristatum in 2019. Compound 46 contains a dibenzannulated 6,6-spiroketal skeleton and is a racemic mixture of easily interconvertible enantiomers [37]. It's worth noting that six benzaldehyde derivatives, including flavoglaucin, isodihydroauroglaucin, 2-(2',3-epoxy-1',3'-heptadienyl)-6-hydroxy-5-(3-methyl-2-butenyl)-benzaldehyde, 2-(2',3-epoxy-1',3',5'-heptatrienyl)-6-hydroxy-5-(3-methyl-2-butenyl)-benzaldehyde, tetrahydroauroglaucin, and dihydroauroglaucin were discovered in Fuzhuan brick tea-derived E. cristatum. E. cristatum is the only dominant fungus in Fuzhuan brick tea, which is responsible for the color, taste, and health benefits of Fuzhuan brick tea [40,41,42,43]. These benzaldehyde derivatives may have a major impact on the sensory quality and health benefits of Fuzhuan brick tea [13] (Figure 2).

2.3. Indole diketopiperazine alkaloids

Indole diketopiperazine alkaloids are a class of important secondary metabolites, which are widely distributed in filamentous fungi, especially in genus Eurotium [17]. Indole diketopiperazine alkaloids are formed by the condensation of some amino acids, including tryptophan, proline, and leucine [44]. Due to their significant biological activities including antimicrobial, antiviral, anticancer, immunomodulatory, antioxidative, and insecticidal activities, indole diketopiperazine alkaloids in genus Eurotium is attracting increasing attention [45,46].
Feed refused by swine contained a high-propagule density of Eurotium sp. Further, echinulin (48) was detected in this feed, and also isolated from this feed-derived E. repens [47]. Although significant differences in the metabolite composition were observed between the feed-derived and marine-derived E. repens, the biosynthesis of echinulin was conserved in E. repens regardless of its origin [48]. Kimoto et al. isolated neoechinulin A (49) from marine fungus E. rubrum Hiji 025, and further synthesized this compound by the natural configuration [49]. Slack et al. investigated the metabolites in E. herbariorum, E. amstelodami, and E. rubrum that are common in the built environment of Canadian homes. Neoechinulin B (50) and neoechinulin A were the major metabolites, but preechinulin (51), neoechinulin E (52), and echinulin were the minor metabolites in E. amstelodami and E. rubrum. E. herbariorum also produced a small amount of neoechinulin E [50]. In addition, a new spirocyclic diketopiperazine alkaloid, 7-O-methylvariecolortide A (53; yellow amorphous powder) was isolated from the mangrove plant Hibiscus tiliaceus-derived E. rubrum, along with variecolortides A-C (54-56). Structurally, compounds 53-56 represent the unique spiro-anthronopyranoid diketopiperazine skeleton with a stable hemiaminal functional group. Further, a hydroxyl group in compound 54 is replaced by a methoxyl group at C-7 in compound 53 [51]. Fructigenine A (57) bearing a reverse-prenyl group was isolated from Eurotium sp. SF-5130 [52].
A new diketopiperazine dimer, namely, eurocristatine (58; white crystals) was isolated and identified from E. cristatum, along with previously reported dioxopiperazine alkaloids including variecolorin J (59), echinulin, neoechinulin A, and neoechinulin E [28]. Yan et al. cultivated the semi-mangrove plant Hibiscus tiliaceus-derived E. rubrum, and further isolated one new dioxopiperazine alkaloid, 12-demethyl-12-oxo-eurotechinulin B (60; colorless amorphous powder) from this fungal strain, together with six known compounds, including variecolorin J, variecolorin G (61), eurotechinulin B (62), cryptoechinuline G (63), alkaloid E-7 (64), and isoechinulin B (65). The structures of compounds 60 and 62 are similar, except that Me-C (12) of compound 62 is replaced by a C (12)=O group in compound 60 [31]. Du et al. also found four new alkaloids named cristatumins A-D (66-69) in the culture extract of E. cristatum EN-220, along with six known congeners including isoechinulin A (70), tardioxopiperazine A (71), echinulin, neoechinulin A, preechinulin, and variecolorin G. This is the first report that the alanine residue in the 2,5-diketopiperazine moiety of compound 49 is replaced by the serine residue in compound 66. The C-20 Me group in compound 48 is replaced by CH2OH group in compound 67. Compound 68 is an almost symmetrical molecule consisting of two indole diketopiperazine moieties. Compound 69 is a ring-opened diketopiperazine derivative of compound 52 [45]. Besides, a pyrrolidinoindoline diketopiperazine alkaloid named cristatumin E (72; yellow amorphous powder) was isolated from the alga-derived E. herbariorum HT-2 [53].
In 2018, three new indole diketopiperazine alkaloids of isoechinulin type named rubrumazines A-C (73-75) and 13 related analogues were isolated and identified from E. rubrum MA-150, a fungus obtained from mangrove-derived rhizospheric soil collected from the Andaman Sea coastline, Thailand. These 13 related analogues were dehydroechinulin (76), variecolorin E (77), dihydroxyisoechinulin A (78), variecolorin L (79), tardioxopiperazine (80), L-alanyl-L-tryptophan anhydride (81), echinulin, neoechinulin A, neoechinulin E, variecolortide B, variecolortide C, variecolorin G, and isoechinulin A. Compounds 73-75 possess an oxygenated prenyl group either at C-7 (73 and 74) or at C-5 (75) [54]. A new prenylated indole diketopiperazine alkaloid named cristatumin F (82; colorless powder) was isolated from the Fuzhuan brick tea-derived E. cristatum, along with four known compounds including variecolorin O (83), echinulin, neoechinulin A, and dehydroechinulin. Structurally, compound 82 is a diketopiperazine congener to compound 48. An alanine unit in compound 48 is replaced by a valine unit in the 2,5-diketopeperazine moiety in compound 82 [46]. Four new indole diketopiperazine derivatives (84-87) and nine known congeners (88-91, 48, 50, 64, 74, 76) were identified from the culture extract of E. cristatum EN-220. Compounds 84-91 were N-(4'-hydroxyprenyl)-cyclo(alanyltryptophyl) (84), isovariecolorin I (85), 30-hydroxyechinulin (86), 29-hydroxyechinulin (87), rubrumline M (88), neoechinulin C (89), didehydroechinulin (90), and variecolorin H (91) [55]. In addition, (11R,14S)-3-(1H-indol-3ylmethyl)6-isopropyl-2,5-piperazinedione (92) was isolated from the culture of E. chevalieri KUFA 0006 [19].
Zhong et al. isolated three pairs of spirocyclic diketopiperazine enantiomers named variecolortins A-C (93-95) from marine-derived fungus Eurotium sp. SCSIO F452. Compound 93 possesses an unprecedented highly functionalized benzo[f]pyrazino[2,1-b][1,3]oxazepine new carbon skeleton comprising a 2-oxa-7-azabicyclo[3.2.1]octane core. Compounds 94-95 represent rare examples of a 6/6/6/6 tetracyclic cyclohexene-anthrone carbon scaffold [56]. Further, Zhong et al. isolated and characterized three new prenylated indole 2,5-diketopiperazine alkaloids named eurotiumins A-C (96-98; white crystals, white solid, and yellow oil, respectively) from Eurotium sp. SCSIO F452 in the same year. Compounds 96 and 97 are a pair of diastereomers presenting a hexahydropyrrolo[2,3-b]indole skeleton. The structures of compounds 96 and 97 are assigned as 2S,3R,9S,12S-cyclo-2-dimethylallyl-3-hydroxy-L-Trp-L-Ala and 2R,3S,9S,12S-cyclo-2-dimethylallyl-3-hydroxy-L-Trp-L-Ala, respectively. The structures of compounds 98 and 50 are similar, except that an olefinic methylene in compound 50 is transformed into an olefinic methine substituted by a doublet methyl in compound 98 [57]. In 2021, Elsebai et al. found a diketopiperazine indole alkaloid named fintiamin (99) in marine sponge Ircinia variabilis-derived Eurotium sp. Compound 99 is a lipophilic terpenoid-dipeptide hybrid molecule, which has similar synthetic pathways to compound 48 [58] (Figure 3).

2.4. Other compounds

Six meroterpenoid-type terpenoids named chevalones A-D (100-103; colorless crystals, colorless crystals, white solid and white solid, respectively) and aszonapyrones A-B (104-105), and terpenoid pyrrolobenzoxazine named CJ-12662 (106) have been isolated from E. chevalieri [32]. Eleven steroids were isolated from E. rubrum: 3β,5α-dihydroxy-10α-methyl-6β-acetoxy-ergosta-7,22-diene (107; colorless crystals), 3β,5α-dihydroxy-6β-acetoxyergosta-7,22-diene (108), (22E,24R)-ergosta-7,22-dien-3β-ol (109), (22E,24R)-ergosta-7,22-dien-6β-methoxy-3β,5α-diol (110), (22E,24R)-ergosta-7,22-dien-3β,5α,6β-triol (111), (22E,24R)-ergosta-7,22-dien-3β,5α,6α-triol (112), (22E,24R)-3β,5α,9α-trihydroxyergosta-7,22-dien-6-one (113), (22E,24R)-3β,5α-dihydroxyergosta-7,22-dien-6-one (114), (22E,24R)-5α,8α-epidioxyergosta-6,22-dien-3β-ol (115), (22E,24R)-5α,8α-epidioxyergosta-6,22-dien-3β-acetate (116), and (22E,24R)-ergosta-4,6,8(14),22-tetraen-3-one (117) [59]. Thirteen salicylaldehyde derivatives, including euroticins A-I (118-126), salicylaldehydiums A-B (127-128), and asperglaucins A-B (129-130) were isolated from Eurotium sp. SCSIO F452 [14,60,61,62] or E. chevalieri SQ-8 [16]. In addition, eight mycotoxins isolated from Eurotium species contain citrinin (131), ochratoxin A (132), gliotoxin (133), aflatoxins (134), and sterigmatocystin (135) from Eurotium group [63]; a benzodiazepine-type mycotoxin cyclopenol (136) from Eurotium sp. SF-5130 [52]; and mycophenolic acid (137) from E. repens [64]. Three indole alkaloids, 2-(2-methyl-3-en-2-yl)-1H-indole-3-carbaldehyde (138) and (2,2-dimethylcyclopropyl)-1H-indole-3-carbaldehyde (139) were isolated from E. chevalieri KUFA 0006 [19], and 2-(1,1-dimethyl-2-propen-1-yl)-1H-indole-3-carboxaldehyde (140) was isolated from Eurotium sp.SCSIO F452 [65].
Other compounds isolated from Eurotium species contain ergosterol (141) [32], 2[(2,2-dimethylbut-3-enoyl)amino]benzoic acid (142; yellow viscous liquid), 6,8-dihydroxy-3-(2-hydroxypropyl)-7-methyl-1H-isochromen-1-one (143; yellow viscous liquid), palmitic acid, ergosterol 5,8-endoperoxide (144) [19], (11S,14R)-cyclo(tryptophylvalyl) (145; white crystal), cinnalutein (146), cyclo-L-Trp-L-Ala (147) [66], eurochevalierine (148; yellow needles) and sequiterpene (149) [32] from E. chevalieri; zinniol (150), butyrolactone I (151), aspernolide D (152), vermistatin (153), methoxyvermistatin (154), eurothiocin A (155; colorless oil), eurothiocin B (156; white amorphous solid) [67], and 7-isopentenylcryptoechinuline D (157) [31] from E. rubrum; methyl linoleate (158; yellow oil) [65], cyclo-(L-Pro-L-Phe) (159) [57], eurotinoids A-C (160-162), dihydrocryptoechinulin D (163) [68], and (±)-Eurotone A (164) [69] from Eurotium sp. SCSIO F452; 5,7-dihydroxy-4-methylphthalide (165) from E. repens [39]; cristatumside A (166) from E. cristatum EN-220 [30]; (±)-eurotiumides A-G (167-173) from Eurotium sp. XS-200900E6 [20]; alkaloid viridicatol (174) from Eurotium sp. SF-5130 [52]; a β-hydroxy acid named monacolin K (175) [70] and a quinone derivative, cristaquinone A (176) [37] from E. cristatum; a glycoside isotorachrysone 6-O-α-D–ribofuranoside (177) from E. cristatum EN-220 [30] (Figure 4).

3. Bioactivities of secondary metabolites from Eurotium

Pharmacological studies have confirmed that the structurally unique compounds isolated from Eurotium species have multiple biological activities, including antioxidative, antimicrobial, cytotoxic, antitumor, insecticidal, antimalarial, and anti-inflammatory activities.

3.1. Antioxidative activity

Numerous studies have proved that the metabolites isolated from Eurotium species showed excellent antioxidative activity. Further, the absolute and stereoscopic configurations affect the antioxidative activity of these compounds [56,57]. Ishikawa et al. found that flavoglaucin (31) was an excellent antioxidant and synergist with tocopherol. The antioxidative and synergistic effects of flavoglaucin and its derivatives largely depend on their hydroxy group, which does not form hydrogen bonds with the formyl group in the molecule [71]. Li et al. evaluated the antioxidative activity of metabolites isolated from a marine mangrove plant-derived endophytic fungus E. rubrum by using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay. They found that neoechinulin E (52) showed a strong radical scavenging activity with half maximal inhibitory concentration (IC50) values of 46.0 μM, which were stronger than that of well-known synthetic antioxidants butylated hydroxytoluene (IC50 = 82.6 μM) [72]. Eurorubrin (19) and 2-O-methyleurotinone (10) also displayed strong radical scavenging activity with IC50 values of 44.0 and 74.0 μM, respectively, while 2-O-methyl-4-O-(α-D-ribofuranosyl)-9-dehydroxyeurotinone (17), 3-O-(α-D-ribofuranosyl)-questin (20), 2-O-methyl-9-dehydroxyeurotinone (18), asperflavin (15), and questin (1) only showed weak or moderate activity [29]. In 2009, a study by Miyake et al. demonstrated that isodihydroauroglaucin (34), auroglaucin (39), dihydroauroglaucin (41), tetrahydroauroglaucin (40), and flavoglaucin exhibited high radical scavenging capacities of DPPH and superoxide when compared to α-tocopherol (a standard antioxidant for the scavenging capacity). The structures of 1'-monoene or 1',3'-diene in the substituent formed by the seven-carbon aliphatic chain of dihydroauroglaucin and tetrahydroauroglaucin may be related to their high radical scavenging activity [11]. Subsequently, Miyake et al. found that isoechinulin A (70) exhibited higher radical scavenging activity than α-tocopherol. Asperflavin, isoechinulin B, neoechinulin B (50), and variecolorin O (83) were found to have the similar activity to α-tocopherol in respect of DPPH-radical scavenging [15].
Compounds eurotiumin C (98), dehydroechinulin (76), variecolorin G (61), isoechinulin A, variecolorin O, neoechinulin B, and echinulin (48) showed significant radical scavenging activity against DPPH with IC50 values of 13, 19, 4, 3, 24, 13, and 18 μM, respectively, which were comparable or superior to that of ascorbic acid (Vc) (IC50 = 23 μM). Further, diprenylated analogs (compounds 61 and 70) were found to have higher radical scavenging activity than the monoprenylated ones (compounds 96-98, 83, and 50) and triprenylated ones (compounds 76 and 48). The absolute configurations of the C-2 and C-3 in eurotiumin A (96) and B (97) may affect their radical scavenging activity [57]. (+)-variecolortin A (93) showed the radical scavenging activity against DPPH with an IC50 value of 58.4 μM, while the IC50 value of (-)-variecolortin A (93) was 159.2 μM. This implied that the stereoscopic configuration affects the biological activities of these two compounds [56]. In addition, the compounds (±)-eurotinoids A-C (160-162) and dihydrocryptoechinulin D (163) showed significant antioxidative activity against DPPH with IC50 values ranging from 3.7 to 24.9 μM, which were more potent than that of the positive control Vc [68]. The compounds (+)-euroticins B and (-)-euroticins B (119) showed remarkable DPPH radical scavenging activity with concentration for 50% of maximal effect (EC50) values of 37.5 and 21.6 μM, which were superior or comparable to that of the positive control Vc (EC50 = 27.9 μM) [14]. In 2021, Zhong et al. found that (+)-euroticin C and (-)-euroticin C (120) showed the significant DPPH radical scavenging activity with EC50 values of 27.00 and 30.27 μM [60], but (±)-euroticin F (123) and G (124) showed week activity with EC50 values ranging from 41.40 to 77.07 μM [62]. In addition, compound Neoechinulin A (49) showed antioxidative activity against peroxynitrite derived from SIN-1 in the neuronal PC12 cells [49]. Nonetheless, the antioxidative activity of the metabolites isolated from Eurotium species was mainly measured by in vitro experiments, in vivo tests in animal models should be encouraged.

3.2. Antimicrobial activity

Microbial interference is an important threat to human health. Screening for antimicrobial compounds from Eurotium species is a promising way to overcome the increasing threat of human and plant pathogen, especially drug-resistant strains. Further, the antimicrobial activity of Eurotium species may be related to anthraquinones [73,74,75]. As early as in 1980, erythroglaucin (3) was found to have slight antibacterial activity against Bacillus brevis, Bacillus subtilis, and Streptomyces viridochromogenes. However, rubrocristin (6) and physcion (2) had no significant antimicrobial activity, indicating that the number and location of hydroxyl groups might play an important role in the antibacterial activity of polyhydroxyanthraquinones [21]. Chevalone C (102), eurochevalierine (148), and CJ-12662 (106) also showed the antimycobacterial activity against Mycobacterium tuberculosis with the minimal inhibitory concentration (MIC) values of 6.3, 50.0, and 12.5 μg/mL, respectively [32]. In 2012, Du et al. evaluated the antimicrobial activities of compounds isolated from E. cristatum against two bacteria (Staphylococcus aureus and Escherichia coli) and five plant-pathogenic fungi (Valsa mali, Sclerotinia miyabeana, Alternaria brassicae, Physalospora obtuse and Alternaria solania). The MIC value of positive control chloramphenicol against E. coli and S. aureus was 4 μg/mL. Cristatumin A (66) and tardioxopiperazine A (71) displayed potent inhibitory activity against E. coli and S. aureus with the MIC values of 64 and 8 μg/mL, whereas cristatumin D (69) and echinulin showed weak activity against S. aureus, each giving the inhibition zone of 8 mm at 100 μg/disk (MICs were not determined) [45]. In addition, the compound 9-dehydroxyeurotinone (23) isolated from E. rubrum showed a weak antibacterial activity against E. coli with an inhibition zone of 7.0 mm at 100 μg/disk, while amphotericin B had an inhibition zone of 11.0 mm at 20 μg/disk as control [31].
Gao et al. evaluated the antimicrobial activities of isolated metabolites from E. repens against five bacteria (S. aureus, methicillin-resistant S. aureus, P. aeruginosa, M. intracellulare, and E. coli) and five pathogenic fungi (Candida. albicans, Candida glabrata, Candida krusei, Cryptococcus neoformans, and Aspergillus fumigatus). Flavoglaucin, tetrahydroauroglaucin, and 2-(2',3-epoxy-1',3'-heptadienyl)-6-hydroxy-5-(3-methyl-2-butenyl)-benzaldehyde (35) exhibited antibacterial activity against S. aureus with IC50 values of 14.32, 13.51, and 7.75 μg/mL, respectively; (E)-2-(hept-1-enyl)-3-(hydroxymethyl)-5-(3-methylbut-2-enyl)-benzene-1,4-diol (42) and compounds 31 and 35 were active against S. aureus with IC50 values of 11.97, 10.41, and 5.40 μg/mL, respectively; auroglaucin, dihydroauroglaucin, and compound 35, 40, and 42 showed antifungal activity against C. glabrata with IC50 values of 7.33, 2.39, 1.13, 6.15, and 7.17 μg/mL, respectively. Compound 35 and 5,7-dihydroxy-4-methylphthalide (165) showed antifungal activity against C. neoformans with IC50 values of 5.31 and 18.08 μg/mL, respectively; only auroglaucin exhibited moderate antifungal activity against C. krusei with an IC50 value of 10.93 μg/mL [18]. In addition, cristatumin E (72) showed weak antibacterial activity against E. aerogenes and E. coli with IC50 and MIC values of 8.3, 44.0, and 44.0 μM, respectively [53]. Compounds 3-O-(α-D-ribofuranosyl)-questinol (21) and eurorubrin showed a weak inhibitory activity against E. coli with the MIC values of 32 and 64 μg/mL, while chloramphenicol had a MIC value of 4 μg/mL as control [30]. Emodin (4) not only showed moderate antibacterial activity against the Gram-positive bacteria but also exhibited a strong synergistic association with oxacillin against methicillin-resistant S. aureus (MRSA) [19]. In 2019, asperflavin was found to be active against S. aureus (MIC of 64 μg/mL) and S. pneumoniae Monza-82 (MIC of 32 μg/mL). Dihydroauroglaucin was active against the Gram-positive bacteria with MIC values of 128 μg/mL, 64 μg/mL, and 8 μg/mL on S. aureus, E. faecalis, and S. pneumoniae, respectively. Compound 41 was previously considered inactive against reference and MRSA S. aureus strains [66]. Neoechinulin A, L-alanyl-L-tryptophan anhydride (81), dihydroxyisoechinulin A (78), and questin showed obvious antibacterial activity against B. cereus and P. vulgaris with the MIC values of 1.56 to 25 μM when ciprofloxacin (MIC values of 0.78 and 0.20 μM, respectively) was used as the positive control and DMSO (25 μM) was used as the negative control [10]. Asperglaucins A (129) and B (130) exhibited potent antibacterial activities against Pseudomonas syringae pv actinidae and B. cereus, with all MIC values of 6.25 μM. Compound 129 also exhibited a weak inhibitory effect against MRSA with a MIC value of 25 μM. The activity of compounds 129 and 130 is probably due to their heterocyclic fraction [16]. Notably, the above intriguing new compounds, which exhibit excellent antimicrobial properties, could be used as the leading compounds for the development of new drugs in the future.

3.3. Cytotoxicity and antitumour activities

The cytotoxicity and antitumor activities of Eurotium species have been extensively studied since the 1970s. Podojil et al. reported that physcion had cytotoxicity towards HeLa cells with an IC50 value of 0.1 μg/mL [3]. Smetanina et al. found that physcion, asperflavin, and tetrahydroauroglaucin exhibited cytotoxic activity against sex cells of sea urchin Strongylocentrotus intermedius at a concentration of 25 μg/mL, 10 μg/mL, and 0.5 μg/mL, respectively [48]. In addition, compounds chevalone C, chevalone D, eurochevalierine, and CJ-12662 had respective IC50 values against the BC1 human breast cancer cells of 8.7, 7.8, 5.9, and 7.6 μg/mL, respectively. Compounds chevalone B (101) and eurochevalierine exhibited cytotoxicity against KB human epidermoid carcinoma cells and NCI-H187 small cell lung cancer cells with IC50 values in the range from 2.9 to 9.8 μg/mL [32]. In 2012, Yan et al. investigated the cytotoxic activities of some E. rubrum-derived alkaloids and anthraquinones against seven tumor cell lines, including MCF-7, SW1990, SMMC-7721, Hela, HepG2, NCI-H460, and Du145. 9-dehydroxyeurotinone exhibited cytotoxic activity with IC50 values of 25 μg/mL against SW1990; variecolorin G exhibited cytotoxic activity with IC50 values of 20, 22, and 20 μg/mL against HepG2, NCI-H460, and Hela, respectiveiy; alkaloid E-7 (64) exhibited cytotoxic activity with IC50 values of 20, 20, 20, and 30 μg/mL against MCF-7, SW1990, SMMC-7721 and Hela cells, respectively; 12-demethyl-12-oxo-eurotechinulin B (60) exhibited slight cytotoxic activity with IC50 values of 30 μg/mL against SMMC-7721, and only emodin exhibited moderate cytotoxic activity with IC50 values of 15 μg/mL against Du145 [31]. Besides, cristatumin E showed cytotoxicity against K562 tumor cell line with an IC50 value of 8.3 mM [53].
Rubrumol (25) showed the relaxation activity for topoisomerase I, with the IC50 value of 23 μM [25]. In 2018, Zhong et al. found that (+)-variecolortin B (94) showed moderate cytotoxicities against SF-268 and HepG2 cell lines with IC50 values of 12.5 and 15.0 μM, while (+)-variecolortin C (95) had the values of 30.1 and 37.3 μM. Compounds (-)-variecolortin B and (-)-variecolortin C were inactive (>100 μM) for SF-268 and HepG2 cells [56]. In addition, compound (+)-dihydrocryptoechinulin D showed moderate cytotoxicities against SF-268 and HepG2 cell lines with IC50 values of 51.7 and 49.9 μM, and (-)-dihydrocryptoechinulin D had the values of 97.3 and 98.7 μM, respectively. Thus, (+)-enantiomers exhibited more valid activities than corresponding (-)-enantiomers [68]. Flavoglaucin displayed weak cytotoxic activity against HepG2 and HeLa with IC50 values of 41.48 and 33.60 μM, respectively [37]. (-)-Salicylaldehydium A (127) showed cytotoxic activity against SF-268 and HepG2 cells with IC50 values of 91.0 and 95.5 μM, respectively [61]. (±)-Euroticin F, (±)-euroticin I (126) and (±)-eurotirumin (29) exhibited moderate cytotoxic activities with IC50 values ranging from 12.74 to 55.5 μM [62]. Euroticin C exerted moderate cytotoxic activity against human SF-268, MCF-7, HepG-2, and A549 cells [60]. However, the compounds’ relative toxicities are unknown; few literatures of target organ toxicities or even side effects exist in the report.

3.4. Insecticidal activity

Brine shrimp (Artemia salina), which is an aquatic species featuring with high sensitivity to toxic and easy culture to researchers, is usually used as a model organism to screen substances with insecticidal activity [54,55]. In 2012, Du et al. reported that cristatumin B (67), isoechinulin A, and variecolorin G exhibited moderate lethal activity against brine shrimp with the median lethal dose (LD50) values of 74.4, 16.9, and 42.6 μg/mL, respectively. The structure–activity relationships indicated that the number and substituted position of isoprenic chain is important for the insecticidal activities of these compounds [45]. As for the lethality against brine shrimp, eurorubrin exhibited moderate activity with the lethal rate 41.4% at a concentration of 10 μg/mL [30]. Rubrumazine B (74), dehydroechinulin, and neoechinulin E exhibited potent activity against brine shrimp with the LD50 values of 2.43, 3.53, and 3.93 μM, respectively, which were lower than that of the positive control colchicine (LD50 19.4 μM) [54]. In addition, Du et al. showed that isovariecolorin I (85), neoechinulin C (89), alkaloid E-7, and didehydroechinulin (90) displayed potent activity against brine shrimp with the LD50 values of 19.4, 70.1, 19.8, and 27.1 μg/mL, respectively [55].
Some Eurotium-derived compounds were evaluated for their antifouling activities against the larval settlement of barnacle Balanus amphitrite, which is one of the representative marine fouling organisms. Compounds (±)-eurotiumides A-D (167-170) inhibited the barnacle larval settlement with the EC50 values < 25.0 μg/mL, which was lower than the standard requirement established by the U.S. Navy. Specifically, (+)-eurotiumide B, (-)-eurotiumide B, (+)-eurotiumide D, and (-)-eurotiumide D with the cis configurations of H-3/H-4 exhibited better antifouling activities (EC50 values of 1.5, 0.7, 2.3, and 1.9 μg/mL) than corresponding (+)-eurotiumide A, (-)-eurotiumide A, (+)-eurotiumide C, and (-)-eurotiumide C (trans configurations of H-3/H-4; EC50 values of 19.4, 22.5, 20.2, and 23.2 μg/mL). This suggested that the relative configuration of H-3/H-4 might be an important factor affecting antifouling activity [20]. In addition, compounds neoechinulin A and echinulin inhibited the barnacle larval settlement with EC50 values of 15.0 and 17.5 μg/mL, respectively [76].

3.5. Antimalarial activity

In 2012, Gao et al. measured the antiprotozoal activity of secondary metabolites from the fungus E. repens in vitro against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. Compounds flavoglaucin, 2-(2',3-epoxy-1',3'-heptadienyl)-6-hydroxy-5-(3-methyl-2-butenyl)-benzaldehyde, auroglaucin, tetrahydroauroglaucin and (E)-2-(hept-1-enyl)-3-(hydroxymethyl)-5-(3-methylbut-2-enyl)-benzene-1,4-diol exhibited moderate antimalarial activities with IC50 values in the range of 1.1-3.0 μg/mL, among which compound 39 displayed the highest antimalarial activity. This suggested the three consecutive double bonds in compound 39 might contribute to the enhancement of antimalarial activity [18]. In addition, chevalone D, eurochevalierine, and CJ-12662 exhibited antimalarial activity against Plasmodium falciparum with IC50 values of 3.1, 3.4, and 6.5 μg/mL, respectively [32].

3.6. Anti-inflammatory activity

Kim et al. demonstrated that neoechinulin A had an anti-inflammatory effect on lipopolysaccharide-stimulated RAW264.7 macrophages. Further, compound 49 blocked the activation of nuclear factor-kappa B (NF-κB) by inhibiting the phosphorylation and degradation of inhibitor kappa B-α, and decreased p38 mitogen-activated protein kinase (MAPK) phosphorylation. The anti-inflammatory effect of compound 49 was thus attributed to the inhibition of NF-κB and p38 MAPK pathways [77]. In addition, compounds flavoglaucin, isotetrahydroauroglaucin (33), and asperflavin were found to inhibit the production of pro-inflammatory mediators and cytokines, including tumor necrosis factor-α, interleukin-1β, interleukin-6, nitric oxide (NO), prostaglandin E2, nitric oxide synthase, and cyclooxygenase-2 [33,35,78]. Cristaldehyde A (46) and cristaquinone A (176) inhibited the NO production in lipopolysaccharide-induced RAW264.7 cells, with the IC50 values of 12.26 and 1.48 μM, when paclitaxel was used as a positive control with the IC50 value of 41.00 μM [37].

3.7. Other activities

Several isolated compounds have some unique biological activities, including a good binding affinity for human opioid or cannabinoid receptors activity, inhibiting the protein tyrosine phosphatase 1B activity, alleviating insulin resistance activity, inhibiting caspase-3 activity, inhibiting α-glucosidase activity, and antiviral activity.
Compounds flavoglaucin, auroglaucin, tetrahydroauroglaucin, (E)-2-(hept-1-enyl)-3-(hydroxymethyl)-5-(3-methylbut-2-enyl)-benzene-1,4-diol and (E)-4-(hept-1-enyl)-7-(3-methylbut-2-enyl)-2,3-dihydrobenzofuran-2,5-diol showed a good binding affinity for human opioid or cannabinoid receptors. This finding may contribute to the discovery of new selective ligands for opioid or cannabinoid receptors [39]. Fructigenine A (57), viridicatol (174), echinulin, flavoglaucin, and cyclopenol (136) were found to inhibit the protein tyrosine phosphatase 1B activity with the IC50 values of 10.7, 64.0, 29.4, 13.4, and 30.0 μM, respectively. This indicated that these compounds had potential for the treatment of type 2 diabetes and obesity [52]. In addition, eurocristatine (58) alleviated insulin resistance by increasing glucose consumption, glucose uptake, and glycogen content in high glucose-induced HepG2 cells in vitro. Further, compound 58 improved glucose metabolism and alleviated insulin resistance in db/db diabetic mice by activating the phosphatidylinositol 3-kinase/protein kinase B signaling pathway [79].
Compounds 7-O-methylvariecolortide A (53), variecolortide B (55), and variecolortide C (56) showed an inhibitory effect on caspase-3 in vitro, with the IC50 values of 1.7, 0.8, and 15.7 μM, respectively, when Ac-DEVD-CHO was used as a positive control (IC50 = 13.7 μM) [80]. Secondary metabolites isolated from the fungus E. rubrum SH-823 were examined for their α-glucosidase inhibitory activity. Eurothiocin A (155) and eurothiocin B (156) showed potent inhibitory potential (IC50 of 17.1 and 42.6 μM, respectively). Further, compounds 155 and 156 were competitive inhibitors of α-glucosidase [67]. In addition, compounds (±)-euroticin H (125) and (+)-euroticin G (124) exhibited significant inhibition against α-glucosidase with IC50 values of 16.31 and 38.04, which are even better than that of positive control acarbose (IC50 of 32.92 μM) [62]. It is worth mentioning that significant antiviral activity for physcion and dihydroauroglaucin was discovered against two important human viral pathogens (herpes simplex virus 1 and influenza A virus) [66] (Figure 5).

4. Conclusion

Eurotium, which has been proven to be an important source of active compounds, is a crucial genus in the Aspergillus family. Several reasons contribute to importance of Eurotium's: (1) an extensive distribution, (2) the key microorganism for the fermentation of traditional food and drink (e.g., Fuzhuan brick tea), and (3) an abundance of secondary metabolites with promising bioactivities. Nearly 180 chemical components have been isolated from Eurotium species, including anthraquinoes, benzaldehyde derivatives, indol diketopiperazine alkaloids, and some other compounds. Various pharmacological activities, including antioxidative, antimicrobial, cytotoxic, antitumor, insecticidal, antimalarial, and anti-inflammatory activities, have been demonstrated in Eurotium species through numerous test models. Nevertheless, the most of activity studies were carried out by using in vitro models, and in vivo models are needed in the further. The most of researches focused on three Eurotium species–E. amstelodami, E. cristatum, and E. repens. The other species in genus Eurotium should be further studied, and this study will also provide information on taxonomic relationships within Eurotium species. In addition, more attention should focus on the discovery of new secondary metabolites and their biological activities from fermented food/drink-derived and marine-derived Eurotium species (Table 1).

Author Contributions

Conceptualization: Mingzhi Zhu, Kunbo Wang, Jiantianye Deng; Methodology: Yong Yuan, Feiyan Yin, Jin Chao; Software: Yilong Li, Jiantianye Deng; Validation: Zhonghua Liu, Kunbo Wang, Mingzhi Zhu; Formal analysis: Jiantianye Deng; Investigation: Jiantianye Deng, Yilong Li; Data Curation: Jiantianye Deng, Yilong Li, Yong Yuan; Writing - Original Draft: Jiantianye Deng; Writing - Review & Editing: Yilong Li, Yong Yuan, Feiyan Yin, Jin Chao, Jianan Huang, Zhonghua Liu, Kunbo Wang, Mingzhi Zhu; Visualization: Yilong Li, Jiantianye Deng; Supervision: Kunbo Wang, Mingzhi Zhu; Project administration: Jianan Huang, Zhonghua Liu, Kunbo Wang, Mingzhi Zhu; Funding acquisition: Jianan Huang , Zhonghua Liu, Kunbo Wang, Mingzhi Zhu.

Funding

This research was financially supported by Major Project of Science and Technology of Guangxi Zhuang Autonomous Region (AA20302018-9), Natural Science Foundation of China (32002095), Key Research and Development Program of Hunan Province (2020WK2017), Hunan “Three Top” Innovative Talents Project (2022RC1142), Natural Science Foundation of Hunan Province for Outstanding Young Scholars (2022JJ20028) and Training Program for Excellent Young Innovators of Changsha (kq2107015).

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

Yong Yuan, Feiyan Yin and Jin Chao were employed by the company Hunan Tea Group Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

  1. Cao, J.; Wang, B.G. Chemical Diversity and Biological Function of Indolediketopiperazines from Marine-Derived Fungi. Marine Life Science & Technology 2020, 2, 31–40. [Google Scholar] [CrossRef]
  2. Hubka, V.; Kolarik, M.; Kubatova, A.; Peterson, S.W. Taxonomic Revision of Eurotium and Transfer of Species to Aspergillus. Mycologia 2013, 105, 912–937. [Google Scholar] [CrossRef]
  3. Podojil, M.; Sedmera, P.; Vokoun, J.; Betina, V.; Barathova, H.; Durackova, Z.; Horakova, K.; Nemec, P. Eurotium (AspergiUus) repens Metabolites and Their Biological Activity. Folia Microbiol 1978, 23, 438–443. [Google Scholar] [CrossRef]
  4. Liu, Y.H.; Gao, L. Research Progress on the Secondary Products of Eurotium. Journal of Pharmaceutical Research 2017, 30, 542–547. [Google Scholar]
  5. Xu, A.Q. Research Progress of Secondary Metabolites From Genus Eurotium and Their Biological Activities. Science and Technology of Food Industry 2013, 34. [Google Scholar] [CrossRef]
  6. Samson, R.A.; Mouchacca, J. Additional notes on species of Aspergillus, Eurotium and Emericella from Egyptian desert soil. Antonie Van Leeuwenhoek International Journal of General and Molecular Microbiology 1975, 41, 343–351. [Google Scholar] [CrossRef]
  7. Kis-Papo, T.; Oren, A.; Wasser, S.P.; Nevo, E. Survival of Filamentous Fungi in Hypersaline Dead Sea Water. Microbial Ecology 2003, 45, 183–190. [Google Scholar] [CrossRef]
  8. Jin, Y.; Weining, S.; Nevo, E. A MAPK Gene from Dead Sea Fungus Confers Stress Tolerance to Lithium Salt and Freezing-Thawing: Prospects for Saline Agriculture. Proceedings of the National Academy of Sciences of the United States of America 2005, 102, 18992–18997. [Google Scholar] [CrossRef]
  9. Gbaguidi-Haore, H.; Roussel, S.; Reboux, G.; Dalphin, J.C.; Piarroux, R. Multilevel Analysis of the Impact of Environmental Factors and Agricultural Practices on the Concentration in Hay of Microorganisms Responsible for Farmer’s Lung Disease. Annals of Agricultural and Environmental Medicine 2009, 16, 219–225. [Google Scholar]
  10. Zhao, D.; Cao, F.; Guo, X.J.; Zhang, Y.R.; Kang, Z.J.; Zhu, H.J. Antibacterial Indole Alkaloids and Anthraquinones from a Sewage-Derived Fungus Eurotium sp. Chemistry of Natural Compounds 2018, 54, 399–401. [Google Scholar] [CrossRef]
  11. Miyake, Y.; Ito, C.; Itoigawa, M.; Osawa, T. Antioxidants Produced by Eurotium herbariorum of Filamentous Fungi Used for the Manufacture of Karebushi, Dried Bonito (Katsuobushi). Bioscience, Biotechnology, and Biochemistry 2009, 73, 1323–1327. [Google Scholar] [CrossRef] [PubMed]
  12. Hong, S.B.; Kim, D.H.; Samson, R.A. Aspergillus Associated with Meju, a Fermented Soybean Starting Material for Traditional Soy Sauce and Soybean Paste in Korea. Mycobiology 2015, 43, 218–224. [Google Scholar] [CrossRef] [PubMed]
  13. Shi, J.; Liu, J.X.; Kang, D.D.; Huang, Y.M.; Kong, W.P.; Xiang, Y.X.; Zhu, X.C.; Duan, Y.W.; Huang, Y. Isolation and Characterization of Benzaldehyde Derivatives with Anti-inflammatory Activities from Eurotium cristatum, the Dominant Fungi Species in Fuzhuan Brick Tea. ACS Omega 2019, 4, 6630–6636. [Google Scholar] [CrossRef]
  14. Zhong, W.M.; Chen, Y.C.; Mai, Z.M.; Wei, X.Y.; Wang, J.F.; Zeng, Q.; Chen, X.Y.; Tian, X.P.; Zhang, W.M.; Wang, F.Z.; et al. Euroticins A and B, Two Pairs of Highly Constructed Salicylaldehyde Derivative Enantiomers from a Marine-Derived Fungus Eurotium sp. SCSIO F452. The Journal of Organic Chemistry 2020, 85, 12754–12759. [Google Scholar] [CrossRef]
  15. Miyake, Y.; Ito, C.; Kimura, T.; Suzuki, A.; Nishida, Y.; Itoigawa, M. Isolation of Aromatic Compounds Produced by Eurotium herbariorum NU-2 from Karebushi, a Katsuobushi, and Their DPPH-Radical Scavenging Activities. Food Science and Technology Research 2014, 20, 139–146. [Google Scholar] [CrossRef]
  16. Lin, L.B.; Gao, Y.Q.; Han, R.; Xiao, J.; Wang, Y.M.; Zhang, Q.; Zhai, Y.J.; Han, W.B.; Li, W.L.; Gao, J.M. Alkylated Salicylaldehydes and Prenylated Indole Alkaloids from the Endolichenic Fungus Aspergillus chevalieri and Their Bioactivities. Journal of Agriculture and Food Chemistry 2021, 69, 6524–6534. [Google Scholar] [CrossRef]
  17. Ma, Y.M.; Liang, X.A.; Kong, Y.; Jia, B. Structural Diversity and Biological Activities of Indole Diketopiperazine Alkaloids from Fungi. Journal of Agriculture and Food Chemistry 2016, 64, 6659–6671. [Google Scholar] [CrossRef]
  18. Gao, J.; Radwan, M.M.; Leon, F.; Wang, X.; Jacob, M.R.; Tekwani, B.L.; Khan, S.I.; Lupien, S.; Hill, R.A.; Dugan, F.M.; et al. Antimicrobial and Antiprotozoal Activities of Secondary Metabolites from the Fungus Eurotium repens. Medicinal Chemistry Research 2012, 21, 3080–3086. [Google Scholar] [CrossRef]
  19. May Zin, W.W.; Buttachon, S.; Dethoup, T.; Pereira, J.A.; Gales, L.; Inacio, A.; Costa, P.M.; Lee, M.; Sekeroglu, N.; Silva, A.M.S.; et al. Antibacterial and Antibiofilm Activities of the Metabolites Isolated from the Culture of the Mangrove-Derived Endophytic Fungus Eurotium chevalieri KUFA 0006. Phytochemistry 2017, 141, 86–97. [Google Scholar] [CrossRef]
  20. Chen, M.; Shao, C.L.; Wang, K.L.; Xu, Y.; She, Z.G.; Wang, C.Y. Dihydroisocoumarin Derivatives with Antifouling Activities from a Gorgonian-Derived Eurotium sp. Fungus. Tetrahedron 2014, 70, 9132–9138. [Google Scholar] [CrossRef]
  21. Anke, H.; Kolthoum, I.; Zahner, H.; Laatsch, H. The Anthraquinones of the Aspergillus glaucus Group. I. Occurrence, Isolation, Identification and Antimicrobial Activity. Archives of Microbiology 1980, 126, 223–230. [Google Scholar] [CrossRef]
  22. Li, Dong-Li; Li, Xiao-Ming; Bin-Gui, W. Natural anthraquinone derivatives from a marine mangrove plant －derived endophytic fungus Eurotium rubrum: structural elucidation and DPPH radical scavenging activity. Microbiol Biotechnol 2009. [Google Scholar]
  23. Gessler, N.N.; Egorova, A.S.; Belozerskaya, T.A. Fungal Anthraquinones. Applied Biochemistry and Microbiology 2013, 49, 85–99. [Google Scholar] [CrossRef]
  24. Masi, M.; Evidente, A. Fungal Bioactive Anthraquinones and Analogues. Toxins 2020, 12. [Google Scholar] [CrossRef] [PubMed]
  25. Zhang, Y.G.; Jia, A.; Chen, H.B.; Wang, M.H.; Ding, G.; Sun, L.Y.; Li, L.; Dai, M.X. Anthraquinones from the Saline-Alkali Plant Endophytic Fungus Eurotium rubrum. The Journal of Antibiotics 2017, 70, 1138–1141. [Google Scholar] [CrossRef]
  26. Engstrom, G.W.; McDorman, D.J.; Maroney, M.J. Iron Chelating Capability of Physcion, a Yellow Pigment from Aspergillus ruber. Journal of Agricultural and Food Chemistry 1980, 28, 1139–1141. [Google Scholar] [CrossRef]
  27. Eder, C.; Kogler, H.; Toti, L. Eurotinones, and Derivatives Thereof, Processes for Preparing Them, and Their Use. 2004.
  28. Gomes, N.M.; Dethoup, T.; Singburaudom, N.; Gales, L.; Silva, A.M.S.; Kijjoa, A. Eurocristatine, a New Diketopiperazine Dimer from the Marine Sponge-Associated Fungus Eurotium cristatum. Phytochemistry Letters 2012, 5, 717–720. [Google Scholar] [CrossRef]
  29. Li, D.L.; Li, X.M.; Wang, B.G. Natural Anthraquinone Derivatives from a Marine Mangrove Plant-Derived Endophytic Fungus Eurotium rubrum: Structural Elucidation and DPPH Radical Scavenging Activity. Journal of Microbiology and Biotechnology 2009, 19, 675–680. [Google Scholar]
  30. Du, F.Y.; Li, X.M.; Song, J.Y.; Li, C.S.; Wang, B.G. Anthraquinone Derivatives and an Orsellinic Acid Ester from the Marine Alga-Derived Endophytic Fungus Eurotium cristatum EN-220. Helvetica Chimica Acta 2014. [Google Scholar] [CrossRef]
  31. Yan, H.J.; Li, X.M.; Li, C.S.; Wang, B.G. Alkaloid and Anthraquinone Derivatives Produced by the Marine-Derived Endophytic Fungus Eurotium rubrum. Helvetica Chimica Acta 2012, 95, 163–168. [Google Scholar] [CrossRef]
  32. Kanokmedhakul, K.; Kanokmedhakul, S.; Suwannatrai, R.; Soytong, K.; Prabpai, S.; Kongsaeree, P. Bioactive Meroterpenoids and Akaloids from the Fungus Eurotium chevalieri. Tetrahedron 2011, 67, 5461–5468. [Google Scholar] [CrossRef]
  33. Yang, X.; Kang, M.C.; Li, Y.; Kim, E.A.; Kang, S.M.; Jeon, Y.J. Anti-inflammatory Activity of Questinol Isolated from Marine-Derived Fungus Eurotium amstelodami in Lipopolysaccharide-Stimulated RAW 264.7 Macrophages. Journal of Microbiology and Biotechnology 2014, 24, 1346–1353. [Google Scholar] [CrossRef] [PubMed]
  34. Chen, M.; Zhao, Q.; Hao, J.D.; Wang, C.Y. Two Benzaldehyde Derivatives and Their Artefacts from a Gorgonian-Derived Eurotium sp. Fungus. Natural Product Research 2017, 31, 268–274. [Google Scholar] [CrossRef] [PubMed]
  35. Kim, K.S.; Cui, X.; Lee, D.S.; Ko, W.; Sohn, J.H.; Yim, J.H.; An, R.B.; Kim, Y.C.; Oh, H. Inhibitory Effects of Benzaldehyde Derivatives from the Marine Fungus Eurotium sp. SF-5989 on Inflammatory Mediators Via the Induction of Heme Oxygenase-1 in Lipopolysaccharide-Stimulated RAW264.7 Macrophages. International Journal of Molecular Sciences 2014, 15, 23749–23765. [Google Scholar] [CrossRef] [PubMed]
  36. Li, D.L.; Li, X.M.; Li, T.G.; Dang, H.Y.; Proksch, P.; WANG, B.G. Benzaldehyde Derivatives from Eurotium rubrum, an Endophytic Fungus Derived from the Mangrove Plant Hibiscus tiliaceus. Chemical & Pharmaceutical Bulletin 2008, 56, 1282–1285. [Google Scholar]
  37. Zhang, P.; Jia, C.; Deng, Y.; Chen, S.; Chen, B.; Yan, S.; Li, J.; Liu, L. Anti-inflammatory Prenylbenzaldehyde Derivatives Isolated from Eurotium cristatum. Phytochemistry 2019, 158, 120–125. [Google Scholar] [CrossRef] [PubMed]
  38. Li, D.L. Secondary Metabolities and Their Bioactivities of a Hibiscus tiliaceus-Derived Endophytic Fungus Eurotium rubrum and a Mangrove Plant Rhizophora stylosa griff. 2008.
  39. Gao, J.; Leon, F.; Radwan, M.M.; Dale, O.R.; Husni, A.S.; Manly, S.P.; Lupien, S.; Wang, X.; Hill, R.A.; Dugan, F.M.; et al. Benzyl Derivatives with in Vitro Binding Affinity for Human Opioid and Cannabinoid Receptors from the Fungus Eurotium repens. Journal of Natural Products 2011, 74, 1636–1639. [Google Scholar] [CrossRef]
  40. Gong, Z.P.; Ouyang, J.; Wu, X.L.; Zhou, F.; Lu, D.M.; Zhao, C.J.; Liu, C.F.; Zhu, W.; Zhang, J.C.; Li, N.X.; et al. Dark tea extracts: Chemical constituents and modulatory effect on gastrointestinal function. Biomedicine & Pharmacotherapy 2020, 130, 110514. [Google Scholar] [CrossRef]
  41. Zhu, M.Z.; Li, N.; Zhou, F.; Ouyang, J.; Lu, D.M.; Xu, W.; Li, J.; Lin, H.Y.; Zhang, Z.; Xiao, J.B.; et al. Microbial bioconversion of the chemical components in dark tea. Food Chemistry 2020, 312, 126043. [Google Scholar] [CrossRef]
  42. Zhou, F.; Li, Y.L.; Zhang, X.; Wang, K.B.; Huang, J.A.; Liu, Z.H.; Zhu, M.Z. Polyphenols from Fu Brick Tea Reduce Obesity via Modulation of Gut Microbiota and Gut Microbiota-Related Intestinal Oxidative Stress and Barrier Function. Journal of Agricultural and Food Chemistry 2021, 69, 14530–14543. [Google Scholar] [CrossRef]
  43. Chen, Y.L.; Chen, J.X.; Chen, R.Y.; Xiao, L.K.; Wu, X.; Hu, L.; Li, Z.J.; Wang, Y.L.; Zhu, M.Z.; Liu, Z.H.; et al. Comparison of the Fungal Community, Chemical Composition, Antioxidant Activity, and Taste Characteristics of Fu Brick Tea in Different Regions of China. Frontiers in Nutrition 2022, 9, 900138. [Google Scholar] [CrossRef]
  44. Jia, B.; Ma, Y.M.; Chen, D.; Chen, P.; Hu, Y. Studies on Structure and Biological Activity of Indole Diketopiperazine Alkaloids. Progress in Chemistry 2018, 30, 1067–1081. [Google Scholar]
  45. Du, F.Y.; Li, X.M.; Li, C.S.; Shang, Z.; Wang, B.G. Cristatumins A-D, New Indole Alkaloids from the Marine-Derived Endophytic Fungus Eurotium cristatum EN-220. Bioorganic & Medicinal Chemistry Letters 2012, 22, 4650–4653. [Google Scholar] [CrossRef]
  46. Zou, X.W.; Li, Y.; Zhang, X.N.; Li, Q.; Liu, X.; Huang, Y.; Tang, T.; Zheng, S.J.; Wang, W.M.; Tang, J.T. A New Prenylated Indole Diketopiperazine Alkaloid from Eurotium cristatum. Molecules 2014, 19, 17839–17847. [Google Scholar] [CrossRef]
  47. Vesonder, R.F.; Lamber, R.; Wicklow, D.T.; Biehl, M.L. Eurotium spp. and Echinulin in Feed Refused by Swine. ApPLIED AND ENVIRONMENTAL MICROBIOLOGY 1988, 54, 830–831. [Google Scholar] [CrossRef] [PubMed]
  48. Smetanina, O.F.; Kalinovskii, A.I.; Khudyakova, Y.V.; Slinkina, N.N.; Pivkin, M.V.; Kuznetsova, T.A. Metabolites from the Marine Fungus Eurotium repens. Chemistry of Natural Compounds 2007, 43, 327–329. [Google Scholar] [CrossRef]
  49. Kimoto, K.; Aoki, T.; Shibata, Y.; Kamisuki, S.; Sugawara, F.; Kuramochi, K.; Nakazaki, A.; Kobayashi, S.; Kuroiwa, K.; Watanabe, N.; et al. Structure-Activity Relationships of Neoechinulin A Analogues with Cytoprotection Against Peroxynitrite-induced PC12 Cell Death. The Journal of Antibiotics 2007, 60, 614–621. [Google Scholar] [CrossRef] [PubMed]
  50. Slack, G.J.; Puniani, E.; Frisvad, J.C.; Samson, R.A.; Miller, J.D. Secondary Metabolites from Eurotium Species, Aspergillus calidoustus and A. insuetus Common in Canadian Homes with a Review of Their Chemistry and Biological Activities. Mycological Research 2009, 113, 480–490. [Google Scholar] [CrossRef] [PubMed]
  51. Li, D.L.; Li, X.M.; Proksch, P.; Wang, B.G. 7-O-Methylvariecolortide A, a New Spirocyclic Diketopiperazine Alkaloid from a Marine Mangrove Derived Endophytic Fungus, Eurotium rubrum. Natural Product Communications 2010, 5, 1583–1586. [Google Scholar] [CrossRef]
  52. Sohn, J.H.; Lee, Y.R.; Lee, D.S.; Kim, Y.C.; Oh, H. PTP1B Inhibitory Secondary Metabolites from Marine-Derived Fungal Strains Penicillium spp. and Eurotium sp. Journal of Microbiology and Biotechnology 2013, 23, 1206–1211. [Google Scholar] [CrossRef] [PubMed]
  53. Li, Y.; Sun, K.L.; Wang, Y.; Fu, P.; Liu, P.P.; Wang, C.; Zhu, W.M. A Cytotoxic Pyrrolidinoindoline Diketopiperazine Dimer from the Algal Fungus Eurotium herbariorum HT-2. Chinese Chemical Letters 2013, 24, 1049–1052. [Google Scholar] [CrossRef]
  54. Meng, L.H.; Du, F.Y.; Li, X.M.; Pedpradab, P.; Xu, G.M.; Wang, B.G. Rubrumazines A-C, Indolediketopiperazines of the Isoechinulin Class from Eurotium rubrum MA-150, a Fungus Obtained from Marine Mangrove-Derived Rhizospheric Soil. Journal of Natural Products 2015, 78, 909–913. [Google Scholar] [CrossRef] [PubMed]
  55. Du, F.Y.; Li, X.; Li, X.M.; Zhu, L.W.; Wang, B.G. Indolediketopiperazine Alkaloids from Eurotium cristatum EN-220, an Endophytic Fungus Isolated from the Marine Alga Sargassum thunbergii. Marine Drugs 2017, 15. [Google Scholar] [CrossRef] [PubMed]
  56. Zhong, W.M.; Wang, J.F.; Wei, X.Y.; Chen, Y.C.; Fu, T.D.; Xiang, Y.; Huang, X.N.; Tian, X.P.; Xiao, Z.H.; Zhang, W.M.; et al. Variecolortins A-C, Three Pairs of Spirocyclic Diketopiperazine Enantiomers from the Marine-Derived Fungus Eurotium sp. SCSIO F452. Organic Letters 2018, 20, 4593–4596. [Google Scholar] [CrossRef] [PubMed]
  57. Zhong, W.M.; Wang, J.F.; Shi, X.F.; Wei, X.Y.; Chen, Y.C.; Zeng, Q.; Xiang, Y.; Chen, X.Y.; Tian, X.P.; Xiao, Z.H.; et al. Eurotiumins A–E, Five New Alkaloids from the Marine-Derived Fungus Eurotium sp. SCSIO F452. Marine Drugs 2018, 16. [Google Scholar] [CrossRef] [PubMed]
  58. Elsebai, M.F.; Schoeder, C.T.; Muller, C.E. Fintiamin: A Diketopiperazine from the Marine Sponge-Derived Fungus Eurotium sp. Archiv der Pharmazie 2021, 354. [Google Scholar] [CrossRef]
  59. Qiao, M.F.; Yi, Y.W.; Deng, J. Steroids from an Endophytic Eurotium rubrum Strain. Chemistry of Natural Compounds 2017, 53, 678–681. [Google Scholar] [CrossRef]
  60. Zhong, W.M.; Chen, Y.C.; Wei, X.Y.; Wang, J.F.; Zeng, Q.; Tian, X.P.; Zhang, W.M.; Wang, F.Z.; Zhang, S. Euroticins C–E, Three Pairs of Polycyclic Salicylaldehyde Derivative Enantiomers from a Marine-Derived Fungus Eurotium sp. SCSIO F452. Organic Chemistry Frontiers 2021, 8, 1466–1473. [Google Scholar] [CrossRef]
  61. Zhong, W.M.; Chen, Y.C.; Wei, X.Y.; Wang, J.F.; Zhang, W.M.; Wang, F.Z.; Zhang, S. Salicylaldehyde Derivatives from a Marine-Derived Fungus Eurotium sp. SCSIO F452. The Journal of Antibiotics 2020, 74, 273–279. [Google Scholar] [CrossRef]
  62. Zhong, W.M.; Wei, X.Y.; Chen, Y.C.; Zeng, Q.; Wang, J.F.; Shi, X.F.; Tian, X.P.; Zhang, W.M.; Wang, F.Z.; Zhang, S. Structurally Diverse Polycyclic Salicylaldehyde Derivative Enantiomers from a Marine-Derived Fungus Eurotium sp. SCSIO F452. Marine Drugs 2021, 19. [Google Scholar] [CrossRef]
  63. El-Kady, I.; El-Maraghy, S.; Zohri, A.N. Mycotoxin Producing Potential of Some Isolates of Aspergillus favus and Eurotium Groups From Meat Products. Microbiological Research 1994, 149, 297–307. [Google Scholar] [CrossRef] [PubMed]
  64. Séguin, V.; Gente, S.; Heutte, N.; Vérité, P.; Kientz-Bouchart, V.; Sage, L.; Goux, D.; Garon, D. First Report of Mycophenolic Acid Production by Eurotium repens Isolated from Agricultural and Indoor Environments. World Mycotoxin Journal 2014, 7, 321–328. [Google Scholar] [CrossRef]
  65. Ｗang, Z.F.; Huang, Z.; Shi, X.F.; Chen, X.C.; Tian, X.P.; Li, J.; Zhang, W.M.; Zhang, S. Analysis of Secondary Metabolites Produced by Eurotium sp. SCSIO F452 Isolated from the South China Sea Sediment. Chinese Journal of Marine Drugs 2013, 32, 7–12. [Google Scholar] [CrossRef]
  66. Bovio, E.; Garzoli, L.; Poli, A.; Luganini, A.; Villa, P.; Musumeci, R.; McCormack, G.P.; Cocuzza, C.E.; Gribaudo, G.; Mehiri, M.; et al. Marine Fungi from the Sponge Grantia Compressa: Biodiversity, Chemodiversity, and Biotechnological Potential. Marine Drugs 2019, 17. [Google Scholar] [CrossRef] [PubMed]
  67. Liu, Z.M.; Xia, G.P.; Chen, S.H.; Liu, Y.Y.; Li, H.X.; She, Z.G. Eurothiocin A and B, Sulfur-Containing Benzofurans from a Soft Coral-Derived Fungus Eurotium rubrum SH-823. Marine Drugs 2014, 12, 3669–3680. [Google Scholar] [CrossRef]
  68. Zhong, W.M.; Wang, J.F.; Wei, X.Y.; Fu, T.D.; Chen, Y.C.; Zeng, Q.; Huang, Z.H.; Huang, X.N.; Zhang, W.M.; Zhang, S.; et al. Three Pairs of New Spirocyclic Alkaloid Enantiomers From the Marine-Derived Fungus Eurotium sp. SCSIO F452. Frontiers in Chemistry 2019, 7, 350. [Google Scholar] [CrossRef] [PubMed]
  69. Zhong, W.M.; Wang, J.F.; Wei, X.Y.; Zeng, Q.; Chen, X.Y.; Xiang, Y.; Tian, X.P.; Zhang, S.; Long, L.J.; Wang, F.Z. (+)- and (−)-Eurotone A: A Pair of Enantiomeric Polyketide Dimers from a Marine-Derived Fungus Eurotium sp. SCSIO F452. Tetrahedron Letters 2019, 60, 1600–1603. [Google Scholar] [CrossRef]
  70. Lu, X.J.; Jing, Y.; Li, Y.Y.; Zhang, N.S.; Cao, Y.G. Eurotium cristatum Produced β-hydroxy Acid Metabolite of Monacolin K and Improved Bioactive Compound Contents as well as Functional Properties in Fermented Wheat Bran. LWT-Food Science and Technology 2022, 158. [Google Scholar] [CrossRef]
  71. Ishikawa, Y.; Morimoto, K.; Hamasaki, T. Metabolites of Eurotium Species, Their Antioxidative Synergism with Tocopherol. 1985.
  72. Li, D.L.; Li, X.M.; Li, T.G.; Dang, H.Y.; Wang, B.G. Dioxopiperazine Alkaloids Produced by the Marine Mangrove Derived Endophytic Fungus Eurotium rubrum. Helvetica Chimica Acta 2008, 91, 1888–1893. [Google Scholar] [CrossRef]
  73. Bamunuarachchi, N.I.; Khan, F.; Kim, Y.M. Antimicrobial Properties of Actively Purified Secondary Metabolites Isolated from Different Marine Organisms. Current Pharmaceutical Biotechnology 2021, 22, 920–944. [Google Scholar] [CrossRef]
  74. Othman, L.; Sleiman, A.; Abdel-Massih, R.M. Antimicrobial Activity of Polyphenols and Alkaloids in Middle Eastern Plants. Frontiers in Microbiology 2019, 10. [Google Scholar] [CrossRef]
  75. Yu, H.; Zhang, L.; Li, L.; Zheng, C.; Guo, L.; Li, W.; Sun, P.; Qin, L. Recent Developments and Future Prospects of Antimicrobial Metabolites Produced by Endophytes. Mycological Research 2010, 165, 437–449. [Google Scholar] [CrossRef] [PubMed]
  76. Chen, M.; Wang, K.L.; Wang, C.Y. Antifouling Indole Alkaloids of a Marine-Derived Fungus Eurotium sp. Chemistry of Natural Compounds 2018, 54, 207–209. [Google Scholar] [CrossRef]
  77. Kim, K.S.; Cui, X.; Lee, D.S.; Sohn, J.H.; Yim, J.H.; Kim, Y.C.; Oh, H. Anti-inflammatory Effect of Neoechinulin A from the Marine Fungus Eurotium sp. SF-5989 Through the Suppression of NF-kb and p38 MAPK Pathways in Lipopolysaccharide-Stimulated RAW264.7 Macrophages. Molecules 2013, 18, 13245–13259. [Google Scholar] [CrossRef]
  78. Yang, X.D.; Kang, M.C.; Li, Y.; Kim, E.A.; Kang, S.M.; Jeon, Y.J. Asperflavin, an Anti-Inflammatory Compound Produced by a Marine-Derived Fungus, Eurotium amstelodami. Molecules 2017, 22. [Google Scholar] [CrossRef] [PubMed]
  79. Zhang, H.; Hui, J.F.; Yang, J.; Deng, J.J.; Fan, D.D. Eurocristatine, a Plant Alkaloid from Eurotium cristatum, Alleviates Insulin Resistance in db/db Diabetic Mice Via Activation of PI3K/AKT Signaling Pathway. European Journal of Pharmacology 2020, 887. [Google Scholar] [CrossRef] [PubMed]
  80. Chen, G.D.; Bao, Y.R.; Huang, Y.F.; Hu, D.; Li, X.X.; Guo, L.D.; Li, J.; Yao, X.S.; Gao, H. Three Pairs of Variecolortide Enantiomers from Eurotium sp. with Caspase-3 Inhibitory Activity. Fitoterapia 2014, 92, 252–259. [Google Scholar] [CrossRef]
Preprints 88914 g001
Figure 1. Structures of anthraquinones (compounds 1-25).
Figure 1. Structures of anthraquinones (compounds 1-25).
Preprints 88914 g001
Preprints 88914 g002
Figure 2. Structures of benzaldehyde derivatives (compounds 26-47).
Figure 2. Structures of benzaldehyde derivatives (compounds 26-47).
Preprints 88914 g002
Preprints 88914 g003
Figure 3. Structures of indole diketopiperazine alkaloids (compounds 48-99).
Figure 3. Structures of indole diketopiperazine alkaloids (compounds 48-99).
Preprints 88914 g003
Preprints 88914 g004
Figure 4. Structures of other compounds (compounds 100-177).
Figure 4. Structures of other compounds (compounds 100-177).
Preprints 88914 g004
Preprints 88914 g005
Figure 5. Overview of main biological activities.
Figure 5. Overview of main biological activities.
Preprints 88914 g005
Table 1. Secondary metabolites from the genus Eurotium and their biological activities.
Table 1. Secondary metabolites from the genus Eurotium and their biological activities.
NO. Compound class and name Bioactivity Source Ref.
Anthraquinones
1 questin antimicrobial activity





antioxidative activity		 Eurotium sp. M30 XS-2012
E. herbariorum NU-2
E. chevalieri KUFA 0006
Eurotium
E. rubrum 		[10]

[15]
[19]

[21]
[29]
2 physcion


cytotoxic activity
antiviral activity		 E. herbariorum NU-2
E. chevalieri KUFA 0006
E. repens
E. chevalieri MUT 2316		 [15]
[19]

[48]
[66]
3 erythroglaucin antimicrobial activity Eurotium
E. cristatum KUFC 7356		 [21]
[28]
4 emodin antimicrobial activity





cytotoxic activity		 E. chevalieri KUFA 0006
Eurotium
E. rubrum
E. cristatum KUFC 7356
E. rubrum 		[19]

[21]
[25]
[28]

[31]
5 catenarin E. herbariorum NU-2
Eurotium
E. rubrum
E. cristatum KUFC 735		 [15]
[21]
[25]
[28]
6 rubrocristin Eurotium
E. rubrum 		[21]
[25]
7 rubrocristin-8-methylether Eurotium [21]
8 rubrocristin-6-acetate Eurotium [21]
9 querstin-6-methylether Eurotium [21]
10 2-O-methyleurotinone
antioxidative activity		 E. echinulatum
E. rubrum 		[27]
[29]
11 2,12-dimethyleurotinone E. echinulatum [27]
12 eurotinone E. echinulatum [27]
13 physcion-10,10’-bianthrone E．herbariorum NU-2 [15]
14 questinol




anti-inflammatory activity		 Eurotium sp. M30 XS-2012
E．herbariorum NU-2
E. chevalieri KUFA 0006
E. amstelodami 		[10]

[15]
[19]

[33]
15 asperflavin


antioxidative activity

cytotoxic activity
antimicrobial activity
anti-inflammatory activity		 Eurotium sp. M30 XS-2012
E．herbariorum NU-2
E. rubrum
E. cristatum EN-220
E. repens
E. chevalieri MUT 2316
E. amstelodami 		[10]

[15]
[29]
[30]
[48]
[66]
[78]
16 variecolorquinone A Eurotium sp. M30 XS-2012
E. cristatum EN-220		 [28]

[30]
17 2-O-methyl-4-O-(α-D-ribofuranosyl)-9-dehydroxyeurotinone antioxidative activity E. rubrum [29]
18 2-O-methyl-9-dehydroxyeurotinone antioxidative activity E. rubrum [29]
19 eurorubrin antioxidative activity
antimicrobial activity
insecticidal activity		 E. rubrum
E. cristatum EN-220		 [29]
[30]
20 3-O-(α-D-ribofuranosyl)-questin antioxidative activity E. rubrum
E. cristatum EN-220		 [29]
[30]
21 3-O-(α-D-ribofuranosyl)-questinol antimicrobial activity E. cristatum EN-220 [30]
22 asperflavin ribofuranoside E. cristatum EN-220 [30]
23 9-dehydroxyeurotinone cytotoxic activity
antimicrobial activity		 E. rubrum [31]
24 acetylquestinol E.chevalieri KUFA 0006 [19]
25 rubrumol cytotoxic activity E. rubrum [25]
Benzaldehyde derivatives
26 2-(2’,3-epoxy-1’-heptenyl)-6-hydroxy-5-(3’’-methyl-2’’-butenyl)-benzaldehyde E. rubrum [36]
27 (E)-6-hydroxy-7-(3-methyl-2-butenyl)-2-(3-oxobut-1-enyl)-chroman-5-carbaldehyd E. rubrum [36]
28 2-(1’,5’-heptadienyl)-3,6-dihydroxy-5-(3’’-methyl-2’’-butenyl)-benzaldehyde E. rubrum [36]
29 eurotirumin
cytotoxic activity		 E. rubrum
Eurotium sp. SCSIO F452		 [36]
[62]
30 chaetopyranin E. rubrum [36]
31 flavoglaucin antioxidative activity

antimicrobial activity
antimalarial activity
anti-inflammatory activity

cytotoxic activity
 Eurotium
E. cristatum
E. repens

Eurotium sp. SF-5989
E. rubrum
E. cristatum
E. repens 		[11]
[13]
[18]

[35]
[36]
[37]
[39]
32 aspergin E. rubrum [36]
33 isotetrahydroauroglaucin anti-inflammatory activity Eurotium sp. SF-5989 E. rubrum [35]
[36]
34 isodihydroauroglaucin antioxidative activity Eurotium
E. cristatum
E. rubrum
E. repens 		[11]
[13]
[36]
[39]
35 2-(2’,3-epoxy-1’,3’-heptadienyl)-6-hydroxy-5-(3-methyl-2-butenyl)-benzaldehyde
antimicrobial activity
antimalarial activity		 E. cristatum
E. repens

E. rubrum
E. repens 		[13]
[18]

[36]
[39]
36 2-(2’,3-epoxy-1’,3’,5’-heptatrienyl)-6-hydroxy-5-(3-methyl-2-butenyl)-benzaldehyde E. rubrum
E. cristatum 		[36]
[13]
37 eurotirubrin A E. rubrum [38]
38 eurotirubrin B E. rubrum [38]
39 auroglaucin antioxidative activity
antimicrobial activity
antimalarial activity		 Eurotium
E. repens
 [11]
[18]
40 tetrahydroauroglaucin antioxidative activity

antimicrobial activity
antimalarial activity

cytotoxic activity		 Eurotium
E. cristatum
E. repen
s
E. repens
E. repens 		[11]
[13]
[18]

[39]
[48]
41 dihydroauroglaucin antioxidative activity

antimicrobial activity

antiviral activity		 Eurotium
E. cristatum
E. repens
E. repens
E. chevalieri MUT 2316		 [11]
[13]
[18]
[39]
[66]
42 (E)-2-(hept-1-enyl)-3-(hydroxymethyl)-5-(3-methylbut-2-enyl)-benzene-1,4-diol antimicrobial activity
antimalarial activity		 E. repens

E. repens 		[18]

[39]
43 (E)-4-(hept-1-enyl)-7-(3-methylbut-2-enyl)-2,3-dihydrobenzofuran-2,5-diol E. repens [39]
44 (3’S*,4’R*)-6-(3’,5-epoxy-4’-hydroxy-1’-heptenyl)-2-hydroxy-3-(3’’-methyl-2’’-butenyl)-benzaldehyde Eurotium [34]
45 3’-OH-tetrahydroauroglaucin Eurotium [34]
46 cristaldehyde A anti-inflammatory activity E. cristatum [37]
47 cristaldehyde B E. cristatum [37]
Indole diketopiperazine alkaloids
48 echinulin
antimicrobial activity







antioxidative activity

insecticidal activity		 E. cristatum
E. cristatum EN-220
E. cristatum
E. repens
E. repens
E. amstelodami
E. rubrum
E. herbariorum
E. cristatum EN-220
Eurotium sp. SCSIO F452
Eurotium 		[28]
[45]
[46]
[47]
[48]
[50]


[55]
[57]

[76]
49 neoechinulin A antimicrobial activity




antioxidative activity



insecticidal activity

anti-inflammatory activity		 Eurotium sp. M30 XS-2012
E. cristatum
E. cristatum EN-220
E. cristatum
E. rubrum Hiji 025
E. amstelodami
E. rubrum.
E. herbariorum
E. rubrum MA-150
Eurotium
Eurotium sp. SF-5989 		[10]

[28]
[45]
[46]
[49]
[50]


[54]
[76]
[77]
50 neoechinulin B antioxidative activity E. herbariorum NU-2
E. amstelodami
E. rubrum.
E. herbariorum
E. cristatum EN-220
Eurotium sp. SCSIO F452 		[15]
[50]


[55]
[57]
51 preechinulin E. cristatum EN-220
E. amstelodami
E. rubrum
E. herbariorum 		[45]
[50]
52 neoechinulin E


insecticidal activity
antioxidative activity		 E. cristatum
E. amstelodami
E. herbariorum
E. rubrum MA-150
E. rubrum 		[28]
[50]

[54]
[72]
53 7-O-methylvariecolortide A
caspase-3 inhibitory activity		 E. rubrum
Eurotium 		[51]
[80]
54 variecolortide A E. rubrum [51]
55 variecolortide B

caspase-3 inhibitory activity		 E. rubrum
E. rubrum MA-150
Eurotium 		[51]
[54]
[80]
56 variecolortide C

caspase-3 inhibitory activity		 E. rubrum
E. rubrum MA-150
Eurotium 		[51]
[54]
[80]
57 fructigenine A Eurotium sp. SF-5130 [52]
58 eurocristatine E. cristatum [28]
59 variecolorin J E. cristatum
E. rubrum 		[28]
[31]
60 12-demethyl-12-oxo-eurotechinulin B cytotoxic activity E. rubrum [31]
61 variecolorin G cytotoxic activity
insecticidal activity

antioxidative activity		 E. rubrum
E. cristatum EN-220
E. rubrum MA-150
Eurotium sp. SCSIO F452		 [31]
[45]
[54]
[57]
62 eurotechinulin B E. rubrum [31]
63 cryptoechinuline G E. rubrum [31]
64 alkaloid E-7 cytotoxic activity
insecticidal activity		 E. rubrum
E. cristatum EN-220		 [31]
[55]
65 isoechinulin B antioxidative activity E. herbariorum NU-2 E. rubrum 31 [15]
[31]
66 cristatumin A antimicrobial activity E. cristatum EN-220 [45]
67 cristatumin B insecticidal activity E. cristatum EN-220 [45]
68 cristatumin C E. cristatum EN-220 [45]
69 cristatumin D antimicrobial activity E. cristatum EN-220 [45]
70 isoechinulin A antioxidative activity
insecticidal activity		 E. herbariorum NU-2
E. cristatum EN-220
E. rubrum MA-150
Eurotium sp. SCSIO F452		 [15]
[45]
[54]
[57]
71 tardioxopiperazine A antimicrobial activity E. cristatum EN-220 [45]
72 cristatumin E antimicrobial activity
cytotoxic activity		 E. herbariorum HT-2 [53]
73 rubrumazine A E. rubrum MA-150 [54]
74 rubrumazine B insecticidal activity E. rubrum MA-150
E. cristatum EN-220		 [54]
[55]
75 rubrumazine C E. rubrum MA-150 [54]
76 dehydroechinulin
insecticidal activity

antioxidative activity		 E. cristatum
E. rubrum MA-150
E. cristatum EN-220
Eurotium sp. SCSIO F452		 [46]
[54]
[55]
[57]
77 variecolorin E E. rubrum MA-150 [54]
78 dihydroxyisoechinulin A antimicrobial activity Eurotium sp. M30 XS-2012
E. rubrum MA-150		 [10]
[54]
79 variecolorin L E. rubrum MA-150 [54]
80 tardioxopiperazine B E. rubrum MA-150 [54]
81 L-alanyl-L-tryptophan anhydride antimicrobial activity Eurotium sp. M30 XS-2012
E. rubrum MA-150		 [10]
[54]
82 cristatumin F E. cristatum [46]
83 variecolorin O antioxidative activity E. herbariorum NU-2
E. cristatum
Eurotium sp. SCSIO F452 		[15]
[46]
[57]
84 N-(4’-hydroxyprenyl)-cyclo(alanyltryptophyl) E. cristatum EN-220 [55]
85 isovariecolorin I insecticidal activity E. cristatum EN-220 [55]
86 30-hydroxyechinulin E. cristatum EN-220 [55]
87 29-hydroxyechinulin E. cristatum EN-220 [55]
88 rubrumline M E. cristatum EN-220 [55]
89 neoechinulin C insecticidal activity E. cristatum EN-220 [55]
90 didehydroechinulin insecticidal activity E. cristatum EN-220 [55]
91 variecolorin H E. cristatum EN-220 [55]
92 (11R,14S)-3-(1H-indol-3ylmethyl)6-isopropyl-2,5-piperazinedione E. chevalieri KUFA 0006 [19]
93 variecolortin A antioxidative activity Eurotium sp. SCSIO F452 [56]
94 variecolortin B cytotoxic activity Eurotium sp. SCSIO F452 [56]
95 variecolortin C cytotoxic activity Eurotium sp. SCSIO F452 [56]
96 eurotiumin A antioxidative activity Eurotium sp. SCSIO F452 [57]
97 eurotiumin B antioxidative activity Eurotium sp. SCSIO F452 [57]
98 eurotiumin C antioxidative activity Eurotium sp. SCSIO F452 [57]
99 fintiamin Eurotium [58]
Other compounds
100 chevalone A E. chevalieri [32]
101 chevalone B cytotoxic activity E. chevalieri [32]
102 chevalone C antimicrobial activity
cytotoxic activity		 E. chevalieri [32]
103 chevalone D antimalarial activity
cytotoxic activity		 E. chevalieri [32]
104 aszonapyrone A E. chevalieri [32]
105 aszonapyrone B E. chevalieri [32]
106 CJ-12662 antimalarial activity
antimicrobial activity
cytotoxic activity		 E. chevalieri [32]
107 3β,5α-dihydroxy-10α-methyl-6β-acetoxy-ergosta-7,22-diene E.rubrum [59]
108 3β,5α-dihydroxy-6β-acetoxyergosta-7,22-diene E.rubrum [59]
109 (22E,24R)-ergosta-7,22-dien-3β-ol E.rubrum [59]
110 (22E,24R)-ergosta-7,22-dien-6β-methoxy-3β,5α-diol E.rubrum [59]
111 (22E,24R)-ergosta-7,22-dien-3β,5α,6β-triol E.rubrum [59]
112 (22E,24R)-ergosta-7,22-dien-3β,5α,6α-triol E.rubrum [59]
113 (22E,24R)-3β,5α,9α-trihydroxyergosta-7,22-dien-6-one E.rubrum [59]
114 (22E,24R)-3β,5α-dihydroxyergosta-7,22-dien-6-one E.rubrum [59]
115 (22E,24R)-5α,8α-epidioxyergosta-6,22-dien-3β-ol E.rubrum [59]
116 (22E,24R)-5α,8α-epidioxyergosta-6,22-dien-3β-acetate E.rubrum [59]
117 (22E,24R)-ergosta-4,6,8(14),22-tetraen-3-one E.rubrum [59]
118 euroticin A Eurotium sp. SCSIO F452 [14]
119 euroticin B antioxidative activity Eurotium sp. SCSIO F452 [14]
120 euroticin C antioxidative activity
cytotoxic activity		 Eurotium sp. SCSIO F452 [60]
121 euroticin D Eurotium sp. SCSIO F452 [60]
122 euroticin E Eurotium sp. SCSIO F452 [60]
123 euroticin F cytotoxic activity
antioxidative activity		 Eurotium sp. SCSIO F452 [62]
124 euroticin G antioxidative activity
α-glucosidase inhibitory activity		 Eurotium sp. SCSIO F452 [62]
125 euroticin H cytotoxic activity
α-glucosidase inhibitory activity		 Eurotium sp. SCSIO F452 [62]
126 euroticin I cytotoxic activity Eurotium sp. SCSIO F452 [62]
127 salicylaldehydium A cytotoxic activity Eurotium sp. SCSIO F452 [61]
128 salicylaldehydium B Eurotium sp. SCSIO F452 [61]
129 asperglaucin A antimicrobial activity Aspergillus chevalieri SQ-8 [16]
130 asperglaucin B antimicrobial activity Aspergillus chevalieri SQ-8 [16]
131 citrinin Eurotium [63]
132 ochratoxin A Eurotium [63]
133 gliotoxin Eurotium [63]
134 aflatoxins Eurotium [63]
135 sterigmatocystin Eurotium [63]
136 cyclopenol Eurotium sp. SF-5130 [52]
137 mycophenolic acid E. repens [64]
138 2-(2-methyl-3-en-2-yl)-1H-indole-3-carbaldehyde E. chevalieri KUFA 0006 [19]
139 (2,2-dimethylcyclopropyl)-1H-indole-3-carbaldehyde E. chevalieri KUFA 0006 [19]
140 2-(1,1-dimethyl-2-propen-1-yl)-1H-indole-3-carboxaldehyde Eurotium sp.SCSIO F452 [65]
141 ergosterol E. chevalieri [32]
142 2[(2,2-dimethylbut-3-enoyl)amino]benzoic acid E. chevalieri KUFA 0006 [19]
143 6,8-dihydroxy-3-(2-hydroxypropyl)-7-methyl-1H-isochromen-1-one E. chevalieri KUFA 0006 [19]
144 ergosterol 5,8-endoperoxide E. chevalieri KUFA 0006 [19]
145 (11S,14R)-cyclo(tryptophylvalyl) E. chevalieri KUFA 0006 [19]
146 cinnalutein E. chevalieri MUT 2316 [66]
147 cyclo-L-Trp-L-Ala E. chevalieri MUT 2316 [66]
148 eurochevalierine antimalarial activity
antimicrobial activity
cytotoxic activity		 E. chevalieri [32]
149 sequiterpene E. chevalieri [32]
150 zinniol E.rubrum SH-823 [67]
151 butyrolactone I E.rubrum SH-823 [67]
152 aspernolide D E.rubrum SH-823 [67]
153 vermistatin E.rubrum SH-823 [67]
154 methoxyvermistatin E.rubrum SH-823 [67]
155 eurothiocin A α-glucosidase inhibitory activity E.rubrum SH-823 [67]
156 eurothiocin B α-glucosidase inhibitory activity E.rubrum SH-823 [67]
157 7-isopentenylcryptoechinuline D E.rubrum [31]
158 methyl linoleate Eurotium sp.SCSIO F452 [65]
159 cyclo-(L-Pro-L-Phe) Eurotium sp. SCSIO F452 [57]
160 eurotinoid A antioxidative activity Eurotium sp. SCSIO F452 [68]
161 eurotinoid B antioxidative activity Eurotium sp. SCSIO F452 [68]
162 eurotinoid C antioxidative activity Eurotium sp. SCSIO F452 [68]
163 dihydrocryptoechinulin D cytotoxic activity
antioxidative activity		 Eurotium sp. SCSIO F452 [68]
164 eurotone A Eurotium sp. SCSIO F452 [69]
165 5,7-dihydroxy-4-methylphthalide antimicrobial activity E. repens
E. repens 		[18]
[39]
166 cristatumside A E. cristatum EN-220 [30]
167 eurotiumide A insecticidal activity Eurotium sp. XS-200900E6 [20]
168 eurotiumide B insecticidal activity Eurotium sp. XS-200900E6 [20]
169 eurotiumide C insecticidal activity Eurotium sp. XS-200900E6 [20]
170 eurotiumide D insecticidal activity Eurotium sp. XS-200900E6 [20]
171 eurotiumide E Eurotium sp. XS-200900E6 [20]
172 eurotiumide F Eurotium sp. XS-200900E6 [20]
173 eurotiumide G Eurotium sp. XS-200900E6 [20]
174 viridicatol Eurotium sp. SF-5130 [52]
175 monacolin K E. cristatum [70]
176 cristaquinone A anti-inflammatory activity E. cristatum [37]
177 6-O-α-D–ribofuranoside E. cristatum EN-220 [30]
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.
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.
Prerpints.org logo

Preprints.org is a free preprint server supported by MDPI in Basel, Switzerland.

facebook logotwitter logolinkedin logo
MDPI Initiatives
Important Links
Subscribe

Disclaimer

Terms of Use

Privacy Policy

© 2024 MDPI (Basel, Switzerland) unless otherwise stated