1. Introduction

2. Marine Indole Alkaloids

2.1. Simple indole alkaloids, (SIAs)

Simple indole alkaloids consisting of an indole nucleus with distinct substitution patterns at the N1, C3, C4, C5, C6, C7, and C8 positions [28,29]. In this section, the compounds of this group are ordered according to the complexity of the substituents of the indole moiety, starting from acyclic to cyclic ones.

2.1.1. C-3- acyclic subtituted simple indole alkaloids

The most common substitution in simple indole alkaloids occurs at the C3 position, a characteristic observed in many families of simple alkaloids [8,30]. Various examples showcase the biological activities of these compounds (Figure 4). For instance, 2-(1H-indol-3-yl)ethyl 2-hydroxypropanoate (1), isolated from the yeast strain (USF-HO25) of a marine sponge identified as Pichia membranifaciens, exhibits a mild response as a radical scavenger of 2,2-diphenyl-1-picrylhydrazyl (DPPH) [31]. Another example is methyl 1H-indole-3-carboxylate (2), obtained from Spongosorites sp., a marine sponge, demonstrating cytotoxic attributes against several human cancer cell lines [32]. Additionally, Hainanerectamine B (3), isolated from Hyrtios erecta, a marine sponge from Hainan, has shown the ability to inhibit Aurora A, a serine/threonine kinase involved in the regulation of cell division [33]. Finally, Tryptamine (4), was obtained from Fascaplysinopsis reticulata an lyophilized sponge, has demonstrated antibacterial growth inhibition activity confront Vibriocarchariae (MIC = 1 μM) [34].

The presence of carbonyl or carboxyl groups in the indole ring has demonstrated different and interesting biological activities [28,35,36]. Compound 5, an indole carbaldehyde obtained from E. chevaleri KUFA 0006, a culture of an endophytic fungus, exhibited inhibitory activity against S. aureus ATCC 2592 biofilm settlement [37]. Hytiodoline (6) an indole aminoacid obtained from Hyrtios sponge, demonstrated potent anti-trypanosomal activity [38]. Becillamide A (7), a thiazole indole derivative obtained from Bacillus sp. marine bacterium, showed antibiotic activity against Archangium gephyra, immunosuppressing that myxobacterium [39]. Anthranoside (8) containing a carboxylated aniline was obtained from the sponge-originated actinomycete Streptomyces sp. CMN-62, and it exhibited anti-influenza activity against H1N1 virus and inhibited the reaction to NFκB [40]. Hermanine D (9), isolated from ascidian Herdmania momus, could inhibit mRNA expression of iNOS, consequently provoking an anti-inflammatory effect [36] (Figure 5).

Quia Che and coworkers developed a biogenetic route to obtain Anthranoside C (10), starting with anthranilic acid (11) and D-glucose (12). The process involves linking two 11 molecules to a 12 molecule, which are then condensed to form an indole ring and in one step more the Anthranoside C (10) [40] (Figure 6).

The prenylated simple indoles have also demonstrated diverse and fascinating biological activities [28,35,36]. In this sense, the prenylated indole carbaldehyde (13), obtained from E. chevaleri KUFA 0006, exhibited inhibitory activity against S. aureus ATCC 2592 biofilm settlement [37]. Eurotiumin (14), an amide indole derived from Eurotium sp. SCSIO F452, a sediment-derived fungus from the South China Sea [41], showed antioxidant properties in in DPPH assay [42]. Misszrtine A (15), an unusual N-substituted prenylated indole obtained from Aspergillus sp. SCSIO XWS03F03 sponge-derived fungus, exhibited strong activity against HL60 and LNCaP cell lines [43]. Terpetin (16), a polyamide indole obtained from Aspergillus sp. SpD081030G1f1, acted as a protector against L-glutamate toxicity in cells [44] (Figure 7).

May Zin et al. developed a biogenesis of isomers compounds 17 and 18, starting with L-tryptophan (19). Isomer 16 was obtained in five steps, and isomer 18 required one additional isomerization step (Figure 8) [37].

The compounds described above have underscored the potential of indole alkaloids in both organic and medicinal chemistry, emphasizing the importance of exploring synthetic pathways to obtain simple indole alkaloids. Some straightforward methods for obtaining functionalized simple indole alkaloids include the Bartoli reaction, which involves nitrobenzene (20) and vinylmagnesium bromides (21) [45]. Another reaction involves intramolecular Rh-catalyzed decomposition of ortho-azydostyrenes (22), followed by C-H activation [46]. Additionally, two novel high-yielding, Au(I)-catalyzed reactions have been reported: one involving the intramolecular cyclization reaction of ortho-alkynylanilines (23) [47]; and the other involving the reaction between alkynyl-hydroxycyclohexadienones (24) and primary amines [48] (Figure 9).

2.1.2. C3-(Iminoimidazolidin- and Pirazin-)-subtituted simple indole alkaloids

Usually, simple indole alkaloids are categorized into families based on similar structures, activities, or origins [35]. One example of this classification includes Trachycladindoles and Aplysinopsin, both of which feature an iminoimidazolidine ring in the above position. Trachycladindoles A (25), C (26), G (27), B (28), D (29), E (30) and F (31), isolated from a marine sponge Trachycladus laevispirulifer, have demonstrated cytotoxicity against human cancer cells (HT-29, A549, and MDA-MB-231) [49]. Additionally, Aplysinopsin (32) and its derivatives 33-39 were obtained from Thorectidae sponges (Thorectandra and Smenospongia) [50]. They have demonstrated activity against Staphylococcus epidermidis, with derivative 37 exhibiting the highest antimicrobial activity (MIC = 33 μM). Following this, derivatives 35 (MIC = 36.5 μM), 34 (MIC = 74.6 μM), 33 (MIC = 98.3 μM), and 36 (MIC = 273.8 μM) show decreasing levels of antimicrobial activity [35]. Derivative 33 was discovered in a Jamaican sponge Smenospongia aurea, and it exhibited a high affinity for two receptors, 5-HT2A and 5-HT2C [51]. The latest derivatives, 38-39, were discovered in the marine sponge Fascaplysinopsis reticulata. They exhibited remarkable activity against the bacterium Vibrio natrigens, derivative 38 demonstrated potent activity with a MIC of 0.3 μM, while 39 exhibited significant activity (MIC = 2.4 μM) [34].

Figure 10. Trachycladindole A-G (25-31), aplysinopsins (32) and their derivatives (33-39).

Figure 10. Trachycladindole A-G (25-31), aplysinopsins (32) and their derivatives (33-39).

A hypothetical method for the biosynthesis of trachycladindoles has been described by A. Hentz. The route starts with tryptophan (19), and trachycladindole A-G (25-31) are obtained in 5 steps [52] (Figure 11).

The synthesis of Aplysinopsins derivate 38 is shown in Figure 12 as was described by Stanovnik and Svete [53]. The key step for the formation of the iminoimidazolinone core was achieved by addition of methylamine to a carbodiimide intermediate followed by intramolecular amidation reaction.

Meridianins A-G (40-46) are a family of SIAs characterized by having pyrazine rings at the C3 position (Figure 7). Meridianins were obtained from several sources, but mainly tunicates. Thus, the first was Aplidium meridianum, from which Meridianins A-E were isolated, [54] but other examples include Aplidium falklandicum and Synoicum sp. [55].

Meridianins B-E (41-44) are notable for their demonstrated cytotoxic effects against adenocarcinoma and murine mammary tumour cell lines (IC₅₀ = 11.4, 9.3, 33.9, 11.1 μM, respectively) [54]. Moreover, 43 has exhibited antibiofilm potential against methicillin-resistant Staphylococcus aureus (MRSA) [35]. In general, Meridianin family has demonstrated a wide biological activity summarized in the Table 1 [55,56].

¹nd: not determited, ²Inhived kinases, ³Antibiofilm activity.

Meridianins can be accessed through several synthetic routes; being the first one developed by Jiang and Yang, from a 7-bromoindolylboronic acid (47) and a 4-chloro-pyrimidini-2-amine (48). In only two steps, 43 was obtained in high yield [57] (Figure 14).

However, Fresneda and Molina’ methodology to obtain Meridianins 42 and 43 is the most used route up to date. Starting from the corresponding brominated indoles, this four-steps route presents high yields in all reactions [58] (Figure 15).

Noteworthy, most methodologies focus on the synthesis of 42 and 43.[57] For example, Karpov et al. improved a three-component palladium-catalyzed carbonylated alkylation [59], while Müller and coworkers achieved it in a one-pot procedure based on Suzuki coupling following a Masuda borylation with a palladium catalyst [60]. Zhou and Chen developed a route to 42 and its derivatives [56], and Penoni employed indolization of nitrosoarenes to obtain 42 derivatives with the indole moiety functionalized [61]. Remarkably, Stanovnik and Svete described the synthesis of all Meridianinds 40-46 and Aplysinopsins derivatives 32-39 [53].

2.1.3. Bis-/tri-indole alkaloids.

Bis- and tris-indole alkaloids are characterized by the linkage of the indole moieties through (hetero)carbonated chains, typically between the C3 positions [35]. Usually, when indole alkaloids are bridged by an imidazole ring, they exhibit interesting biological activity. Examples such case are bis-indoles Dihydrospongotine C (49) and Spongotine C (51) and the tris-indole Tulongicin (53), isolated from the sponge Topsentia. They have demonstrated antiviral activity against HIV, HxB2 and YU2, with IC₅₀ values ranging from 2.7 to 12 μM and 3.5 to 9.5 μM (respectively); as well as antimicrobial and antibacterial properties, particularly against S. aureus (MIC = 1.8 to 7.6 μM) [62] (Figure 7). Furthermore, Rhopaladin C (52), isolated from a marine tunicate, demonstrated antimicrobial efficacy against Sarcina lutea and Corynebacterium xerosis (IC₅₀ = 36.9 μM) [63]. Lastly, Spongotine A (50) was isolated from Topsentia pachastrelloides sponge and showed antibacterial effects to both susceptible and methicillin-resistant strains of S. aureus [64] (Figure 16).

Bromodeoxytopsentin (54) and dibromodeoxytopsentin (55) feature an unsaturated imidazole bridging the indole moiety. 54, isolated from Topsentia pachastrelloides sponge, demonstrated antibacterial effects against both susceptible and methicillin-resistant strains of S. aureus [64]. 55, obtained from a genus of the marine sponge Topsentia, also exhibited antibacterial properties against S. aureus (MIC = 22.7 μM) and shows additional potential as antiviral agent against HIV (YU2, IC₅₀ = 57 μM) [62].

Figure 17. Structure of bromodeoxytopsentin (54) and dibromodeoxytopsentin (55).

Figure 17. Structure of bromodeoxytopsentin (54) and dibromodeoxytopsentin (55).

Eusynstelamides A-B (56-57) and D-F (58-60) are brominated bis-indole bridged by a γ-lactam ring obtained from ascidians [65] and bryozoans [66]. 56 and 57 displayed only weak effectiveness against S. aureus [65]. However, compounds 58-60 proved stronger antibacterial properties, showing activity against S. aureus and Corynebacterium glutamicum (MIC = 7.8-17.4 μM), as well as E. coli and P. aeruginosa (MIC = 16.4-34.7 μM) [66].

Figure 18. Structure of eusynstyelamide A-B and D-F (56-60).

Figure 18. Structure of eusynstyelamide A-B and D-F (56-60).

Hamacanthins A-B (61-62) are bis-indole isomers linked by a pyrazinone ring, isolated from a marine sponge belonging to the genus Hamacantha. Both exhibited antimicrobial properties efficacy against B. Subtilis (MIC = 6.4 and 3.3 μM respectively) [67].

Figure 19. Structure of hamacanthin A-B (61-62).

Figure 19. Structure of hamacanthin A-B (61-62).

Regarding the synthesis of bis- and tris-indole species, an illustrative example could be the synthesis of Rhopaladin C (55) developed by Janosik et al. [63]. Starting from 1H-indole-3-carbonyl cyanide, the desired product could be obtained by condensation of the nitrile group with the amino group from L-Tryptophan methyl ester to generate the imidazolone core. This transformation yields 55 in two steps with moderate yield (Figure 20).

2.2. Prenylated Indole Alcaloids (PIA)

Prenylated indoles include several different families of compounds. For a better insight for the readers, the PIA are arranged in ascending order of complexity, ranging from indole core with a cyclic prenyl substituent to indole moiety fused with a variable number of prenyl-derived ring system. PIA containing the indole core with acyclic prenyl sustituents have been included in Section 2.1.

2.2.1. Diketopiperazinas (DKPs) indole alkaloids

2.2.1.1. Simple diketopiperazines

Simple 2,5-Diketopiperazines (2,5-DKPs) are cyclodipeptides formed through the condensation of two α-amino acids, establishing two amide linkages to constitute the six membered ring [68,69]. This kind of compounds demonstrated a good catalytic performance in asymmetric synthesis of Reformatsky reaction [70]. Furthermore, they have been used as structural fragments in the desing of novel drugs [52].

Figure 21. Basic structures of Simple Diketopiperizines.

Figure 21. Basic structures of Simple Diketopiperizines.

Based on their chemical structure, simple indole diketopiperazines includes a wide variety of families of compounds [70]. Then, DKPs which have been found to present biological activity, have been orderer of increasing structural complexity into two main groups: monoindole and bisindole DKPs. Also, monoindole DKPs differ in how the indole is attached to the diketopiperazone, being ultimately divided in attached at C-3 with a methylene or ethylidene bridge.

2.3. Annelated indole alkaloids

Within this subsection, alkaloids containing a single indole core fused with no prenyl derived (hetero)cyclic ring systems are disclosed (Figure 45).

2.3.1. Quinazoline(inone)-containing annelated indole

Aspertoryadins F and G (207-208) contain a 2-indolone moiety linked to a quinazolinone ring through five-membered spiro lactone. Both compounds were extracted of Aspergillus sp. from a bivalve mollusk. They exhibited quorum sensing (QS) inhibitory activity against Chromobacterium violaceum CV026, causing skin infections. These compounds prohibited bacterial pathogenicity [141].

Fumigatoside E (209) was obtained from Aspergillus fumigatus SCSIO 41012 and showed moderated to strong antibacterial and antifungal activity, with LC₅₀ values of 6.25 μM against A. baumannii 15122 and S. aureus ATCC 16339, and 12.5 μM against A. Baumannii ATCC 19606 and K. pneumoniae ATCC 14578. Strong activity against F. oxyosporum f. sp. (LC₅₀ = 1.56 μM) was also observed [143].

Fumiquinazoline J (210) was isolated from fungal strain Aspergillus fumigatus H1-04 and exhibited cytotoxicity against the cell lines ts FT210, P388, HL-60, A549 and Bel-7402 [142].

Cottoquinazoline D (211) obtained from marine-derived fungus Aspergillus versicolor was reported to show antifungal activity against C. albicans [144,145].

Scequinadoline A (212) and Scedapin C (213) contain an imidazoindolone ring and were isolated from extract of soft coral-associated fungus S. apiospermum F41-1. Both compounds displayed significant anti-HCV activity against the J8CC recombinant [146].

2.3.2. Imidazolone-containing pyrrolidinone

Securamines H and I (214-216) are hexacyclic annelated indole alkaloids isolated from the bryozoan Securiflustra securifrons that showed potent cytotoxicity against A2058, HT-29 and MCF-7 lines (Figure 46) [147].

2.3.3. β-carbolines

β-Carboline alkaloids (βCs) are a tryptophan-derived family of natural products whose basic structure derives from the tricyclic 9H-pyrido[3,4-b]indole (Figure 47). Although initially discovered in plants, a wide range of these compounds have been isolated over decades from marine sources, such as tunicates [148], sponges [149] and bryozoans [150]. βCs display a wide range of outstanding biological activities and, to the best of our knowledge, several plant-isolated and synthetic representative examples, depicted in Figure 47, have been approved by the FDA and commercialized as drugs at some point: Taladafil [151] and Yohimbine [152], for treating erectile disfunction; Reserpine [153], Deserpidine [154] and Rescinnamine [155], as hypertension; Abecarnil [156], as anxiolytic; and Cipargamin [157], as antimalarial.

However, no example marine-derived βCs has been approved by the FDA to the best of our knowledge. This is quite surprising since, as will be showcased in the next subsections, they can exert a wide variety of biological activity, such as anticancer, antibiotic, antiplasmodial, antiinflamatory, antifungal, among others.

βCs can be found in nature in monomeric or dimeric fashion [158], being the applications of the dimers closely related to their parent monomers. However, some of them do not contain the same monomer twice, but are hybrid structures with two different βC cores. Therefore, monomers and dimers will be disclosed in separate subsections and, attending to the absence or presence of extra fused rings in the basic βC skeleton, monomers will be subsequently grouped as ‘simple’- and annelated-βCs.

2.2.1.1. β-Carboline monomers

• ‘Simple’β-Carbolines

Attending to the saturation of the indole-fused pyridine ring, these compounds can be classified as β-carbolines (βCs), dihydro-β-carbolines (DHβCs) and tetrahydro-β-carbolines (THβCs). It is worth mentioning that N-methyl quaternary salt of β-carboline alkaloids also occur in nature.

The simplest β-carboline, Norharmane (217), firstly isolated from a higher plant, can be found in different marine sponges. In 2007 Herraiz et al. showed that 217 presents possible applications against PD [159].

The presence of substituents in the basic structure of βC and level of reduction of the ring lead to enhanced or new properties in comparison with 217. The rest of the section has been structured according to the substituted position in the βC which is responsible for the therapeutic activity, trying to group them in their corresponding families and making a comparison with their reduced analogues when possible. Therefore, the following subsections will be presented: C1-subtituted-βCs, Manzamines, N2-substituted-βCs and C3-substituted-βCs. It is important to remark that although manzamines belong to C1-substituted-βCs, their specific structure and bioactivities require a separate discussion from their simpler analogues.

• C1-substituted (DH/TH)-Carbolines:

βCs in which the C1-substitution is responsible for their therapeutic activity represent the largest family of these scaffolds. The variety of functional groups than can be found at C1 is pretty wide, ranging from simple alkyl chains or aryl groups to complex glycosides or polycycles.

Harmane (218) could be isolated from the culture of the marine-sponge associated fungus Neosartorya tsunodae KUFC 9213 [160]. Compound 218 exhibited stronger AChE and BuChE inhibition (Ic₅₀ >10 μM) compared to 217 and a weak, in-vitro antileishmanial activity against Leishmani infantum [161]. 1-Ethyl-β-carboline (219), isolated from the marine bryozoan Orthoscuticella ventricosa, exhibited moderate antiplasmodial activity (IC₅₀ = 18 μM) against P. falciparum K1 strain [150]. The addition of a C4-OMe to the pyridine ring (220) exerted detrimental effect on the activity [162]. Other βCs from the same bryozoan such as 1-Ethyl-4-methylsulfone-β-carboline (222), Orthoscuticelline C (223) and Orthoscuticelline D (224) had lower efficiency, indicating that the addition of C4-sulfone to the ring or hydroxy, amino or sulfonic acid groups to the alkyl chain were not beneficial [150,163].

However, Harmine (221), a C7-OMe analogue of 217 firstly isolated from plants but widely found in marine species, exhibited a wide range of bioactivity: antitumor, antibiotic, antifungal, antioxidant, antiplasmodial, antimutagenic, antigenotoxic, acts on gamma–aminobutyric acid type A and monoamine oxidase A or B receptor, improves insulin sensitivity, exerts vasorelaxant effect, suppress osteoclastogenesis, among others. These properties have been well documented by Patel and coworkers [164].

Eudistalbin A (225), isolated from tunicate Eudistoma album, presented in vitro cytotoxicity (IC₅₀ = 3.2 μg/mL) against KB cells.[148] Plakortamine A (226), isolated from the sponge Plakortis nigra, showed antitumor activity against HCT-116 line ( IC₅₀ = 3.2 μM) [149]. Both Eudistomidin C (227) and J (228), obtained from tunicate Eudistoma glaucus,[165] hold potent cytotoxicity against murine leukemia L1210 (IC₅₀ = 0.36 and 0.047 μg/mL, respectively) [165,166], while only 228 is active also against P388 and KB cancer cells (IC₅₀ = 0.043 and 0.063 μg/mL, respectively) [166]. 14-Methyleudistomidin C (229), from the ascidian Eudistoma gilboverde, demonstrated significant cytotoxicity against four different human tumor cell lines (IC₅₀ < 1.0 μg/mL) [167]. Ingenine E (230), isolated from the sponge Acanthostrongylophora ingens, is strongly cytotoxic against MCF-7, HCT-116 and A549 lines [168]. It is worth to mention that although Orthoscuticelline C (222) is chemically similar to 215-228, its anticancer biological activity has not been tested so far.

Opacalines A (231) and B (232), found in the ascidian Pseudodistoma opacum, exhibited antiplasmodial activity due to alkyl guanidine-substituted chains (IC₅₀ = 2.5 and 4.5 μM, respectively) [169]. As observed, the N9-hydroxylation affects negatively to this activity. Other synthetic debromo- or THβCs derivatives of 231 and 232 were less active than the parent compounds, indicating that the Br atom plays an important role in the activity.

Eudistomins W (233) and X (234), isolated from tunicate Eudistoma sp., hold antifungal activity against C. albicans and B. subtilis, S. aureus, and E. coli, respectively; as well as some antibiotic properties [170].

Imidazolium-containing Gesashidine A (235), first isolated from a Thorectidae sponge, showed antibacterial activity against Micrococcus luteus but no cytotoxicity against cell line L5178Y [171]. Interestingly, the presence of a C3-carboxylate shuts down the antibacterial activity of Dragmacidonamine A (236), isolated from the same sponge, and its sulfoxide Hyrtimomine H (237), obtained from Hyrtios sponge. However, it enhances their cytotoxicity when compared to 235.

Figure 49. C1-substituted βC compounds 218-237.

Figure 49. C1-substituted βC compounds 218-237.

Reduced DHβC and THβC analogues of compounds 218-237 (Figure 50) have similar therapeutic activity as their unsaturated counterparts. Eudistomidins B (238), G (239), H (240) and I (241), isolated from Eudistoma glaucus, exhibited cytotoxicity against L1210, L5178Y, P388 and KB cancer cells, although weaker than related compounds 223-237. Ingenine F (242), obtained from Acanthostrongylophora ingens, showed similar levels of cytotoxic activity against MCF-7, HCT-116, and A549 lines as compound 230 [172]. (+)-7-Bromotrypargine (243), isolated from the marine sponge Ancorina, exerts antimalarial activity as 231, but also weak cytotoxicity against HEK293 [173]. Haploscleridamine (244), isolated from Haplisclerida sponge, was identified as an inhibitor of cathepsin K [174]; while its C3-CO₂H analogue Hainanerectamine C (245), identified from Hyrtios erecta sponge, showed moderate anticancer activity as inhibitor of Aurora kinase A [33].

Hyrtimomine I (246) and J (247), hydroxyimidazolium βCs found in Hyrtios sponge, exhibited antifungal activity against A. niger (IC₅₀ = 8.0 μg/mL each) and C. albicans (IC₅₀ = 2.0 μg/mL each), but only 246 against C. neoform (IC₅₀ 4.0 μg/mL). However, Hyrtimomine H (248), from the same sponge, showed no activity, indicating that C3-CO₂H group is crucial [175]. It is worth noting that this kind of activity has not been reported so far for similar compounds 235-237.

Figure 51. C1-substituted βC compounds 246-248.

Figure 51. C1-substituted βC compounds 246-248.

Blunt and Munro indicated that C1-vinyl groups might be beneficial for antitumor activity. 1-Vinyl-8-hydroxy-β-carboline (249), collected from bryozoan Cribricellina cribaria [176], and Plakortamine B (250), produced by the sponge Plakortis nigra [149], were found to be active against P388 (IC₅₀ = 100 ng/mL) and HCT-116 line (IC₅₀ = 3.2 μM) respectively. C1-aryl compound Chaetogline F (251), obtained from fish-derived fungus Chaetomium globosum 1C51 through biotransformation [177], represents a more promising structure for the design of anti-Alzheimer drugs [178], and presented antibiotic activity against Veillonella parvula, Bacteroides vulgatus, Streptococcus sp., and Pepto streptococcus sp. [179]. Apart from antibiotic activities, other authors found that some synthetic C1-aryl derivatives exhibited activity against Leishmania donovani [180].

Figure 52. C1-substituted βC compounds 249-251.

Figure 52. C1-substituted βC compounds 249-251.

C1-furyl-subtituted Flazin (252), obtained from the oyster Crassostrea sikamea,[181] is a promising candidate for the development of anti-HIV drugs [182]. An exhaustive SAR study carried out by Liu et al. identified the synthetic Flazinamide (253) as the most promising drug. Eudistomin I (254), isolated from Eudistoma olivaceum tunicate, contains a dihydropyrrole ring that confers its antibacterial effect [183,184,185]. Indole-substituted Eudistomin U (255) and Isoeudistomin U (256), isolated from Lissoclinum fragile, and their synthetic analogues, have been reported to have antibacterial, antimalarial, and anticancer properties, as extensively reviewed by Kolodina and Serdyuk [186]. Plakortamine D (257), a C1-isoxazolidine-substituted scaffold obtained from Plakortis nigra sponge, bestows antitumor activity against HCT-116 line (IC₅₀ = 15 μM) [149]. Finally, Annomontine (258), Ingenine C (259) and Ingenine D (260), all of them bearing aminopyrimidine rings and isolated from the Indonesian sponge Acanthostrongylophora ingens, exhibited cytotoxic activities against MCF-7 and HCT-116 [168,187].

Figure 53. C1-substituted βC compounds 252-260.

Figure 53. C1-substituted βC compounds 252-260.

1-Acetyl-β-carboline (261), isolated from Marinactinospora thermotolerans, showed weak cytotoxicity against NCI-H460 cells (IC₅₀ = 18.73 μg/mL)[188] and antibiotic properties against S. Aureus [189]. Eudistomidin K (262), from the tunicate Eudistoma glaucus, exhibited weak cytotoxicity against P388, L1210 and KB cells (IC₅₀ > 10.0 μg/mL) [166]. Marinacarbolines A-D (263-266), obtained from Marinactinospora thermotolerant, and their synthetical derivatives, bear an additional C3-amido moiety with pendant aryl rings. Their cytotoxicity was firstly investigated in 2015 [190], but Hong and Lee have performed very recently and in-depth SAR study against ocetaxel-Resistant Triple-Negative Breast Cancer [191]. Compounds 263-266 also exhibit promising antimalarial activity [128]. Eudistalbin A (267), isolated from Eudistoma album tunicate, exerts cytotoxic activity in vitro against KB cells (IC₅₀ = 3.2 μg/mL).[148] Eudistomin T (268), from the tunicate Eudistoma olivaceum, exhibited only weak phototoxicity, but also antibiotic properties [184].

Figure 54. C1-substituted βC compounds 261-268.

Figure 54. C1-substituted βC compounds 261-268.

Eudistomin Y (269), isolated from Eudistoma tunicates, and its synthetic analogues, tend to exhibit antifungal [192] and antibiotic [192,193], but also significant cytotoxic and antiproliferative activity [192,194,195]. SAR analyses indicated that an increasing number of Br atoms in the aromatic rings increased their antibiotic effect. Reduction of the benzoyl moiety does not affect its properties, as found for Eudistomin Y₁₁ (270).

Figure 55. C1-substituted βC compounds 269-270.

Figure 55. C1-substituted βC compounds 269-270.

Xestomanzamine A (271), isolated from sponge Acanthostrongylophora sp., presented moderate antibiotic, anti-HIV and antifungal activity, but no cytotoxicity against A594 and HCT-116 [196]. However, imidazol-containing Hyrtiocarboline (272), from Hyrtios reticulatus sponge, showed significant cytotoxicity against H522-T1, MDA-MB-435 and U937 lines (IC₅₀ = 1.2, 3.0 and 1.5 μg/mL, respectively) [197]. Imidazolium-containing Hyrtiomanzamine (273), from Hyrtios erecta sponge, and Dragmacidonamine A (274), from Dragmacidon sponge, exhibited some cytotoxicity [171,197]. Also, 273 exhibited some immunosuppressive activity [198]. Indolyl-substituted Pityriacitrin (275), firstly isolated from a Paracoccus marine bacterium, exerts promising anticancer activity against MCF-7, MDA-231, and PC3 lines [199]. In-depth SAR analysis of Pityriacitrin analogues showed that C3 amide, hydrazide, hydrazones, 1,3,4-oxadiazole, 1,2,4-triazole, and pyrazole moieties are essential for potent anticancer activity [200].

Hyrtiosulawesine (276), found in the Indonesian sponge Hyrtios erectus, present a great variety of applications, such as antioxidant [201], antiphospholipase A2 [202], antidiabetic [203], anti-inflammatory [204], antimalarial [205], and cytotoxicity towards Hep-G2 line (IC₅₀ = 19.3 μmol/L) [206]. 6-O-(β-glucopyranosyl)hyrtiosulawesine (277), from the same marine species, is only slightly cytotoxic on hepatic cells, and have antimalarial activity (IC₅₀ = 5 μM).

Figure 56. C1-substituted βC compounds 271-277.

Figure 56. C1-substituted βC compounds 271-277.

Finally, Shishijimicin A-C (278-280) (Figure 57), isolated from sea squirt Didemnum proliferum, presents antitumor activity against P388 cells [207]. This property is attributed to the intricate conjugated en-diyne group, being 278 the most powerful enediyne-based antitumor antibiotic identified to date. Remarkably, the total synthesis of compound 278 was accomplished in 2015 by Nicolaou [208].

• Manzamines:

Manzamines are a special family of C1-substituted βCs in which the C1-moiety generally consists of a characteristic complex penta- or tetracyclic system, or a monomacrocycle. Manzamine A (281) (also named Keramamine A) [209] was the first reported member of these compounds [210]. 281 showed a broad spectrum of biological effects: potent antileishmanial and antimycobacterial activity [211]; cytotoxicity against pancreatic cancer, P388, and human colorectal carcinoma [210,212,213]; and anti-Alzheimer activity [214]. It also exhibited antiviral effects against HSV-1, HSV-2 and HIV [211,215,216]. Compound 281 exhibited potent antitubercular activity against M. tuberculosis (H37Rv) [217]. 8-Hydroxymanzamine A (282) (also named manzamine G or manzamine K) exhibited moderate antitumor activity against KB and LoVo lines and anti-HSV-2 activity [216]. ent-8-Hydroxymanzamine A (283) is active against P388 (IC₅₀ = 0.25 µg/mL) and exert in vitro antitrypanosomal effect [218]. Manzamine M (284) proved cytotoxicity against L1210 cells (IC₅₀ = 0.3 µg/mL), and antibacterial activity against Sarcina lutea (MIC = 2.3 µg/mL) and Corynebacterium xerosis (MIC = 5.7 µg/mL) [219].

12,34-Oxamanzamine A (285), with a C12–C34 ether bridge, exhibited lower antimalarial and antituberculosis activity compared to the other manzamines [220]. 12,28-Oxamanzamine A (286) and 12,28-Oxa-8-hydroxymanzamine A (287), with C12-C28 or C12-C34 ether bridges, showed effective antifungal, anti-inflammatory and anti-HIV-1 activities [221].

3,4-Dihydro-6-hydroxymanzamine A (288) presented cytotoxicity against L1210 cells (IC₅₀ = 1.4 µg/mL), and antibacterial activity against Sarcina lutea (MIC = 6.3µg/mL) and Corynebacterium xerosis (MIC = 3.1 µg/mL) [219]. N-Methyl-epi-manzamine D (289) and epi-Manzamine D (290) showed cytotoxicity against HeLa and B16-F10 cells [220]. 1,2,3,4-Tetrahydro-2-N-methyl-8-hydroxymanzamine A (291) (8-Hydroxy-2-N-methylmanzamine D) is cytotoxic toward P388 line (ED₅₀ = 0.8 µg/mL) [222].

Figure 58. Chemical structures of Manzamines 281-291.

Figure 58. Chemical structures of Manzamines 281-291.

Biologically active pentacyclic manzamines having a ketone or alcohol group in their eight-membered ring instead of a double bond have been also reported. Manzamine E (292) and Manzamine F (Keramamine B) (293) displayed cytotoxicity toward L5178Y and P388 cells [223]. Ent-manzanine F (294) inhibited H37Rv (IC₅₀ < 12.5 µg/mL) [218]. ent-12,34-oxamanzamines E (295) and F (296) showed weak inhibitory activity against M. tuberculosis (IC₅₀ value of 128 µg/mL) [220]. Pre-neo-kauluamine (297) exhibited proteasome inhibitory activity, potent antitrypanosomal effect and antimalarial activity [224,225].

Figure 59. Chemical structures of Manzamines 292-297.

Figure 59. Chemical structures of Manzamines 292-297.

Several biologically active manzamines containing a βC ring system with a C1-tetracyclic scaffold have been reported. Manzamine J (298) showed cytotoxic activity against KB cells (IC₅₀ >10 µg/mL), while its N-oxide (299) against L1578Y (IC₅₀ = 1.6 µg/mL). Additionally, 298 has anti-tubercular activity against H37Rv [217]. Manzamine B N-oxide (300) displayed weak activity against several Gram-positive and Gram-negative bacteria [226]. Acanthomanzamines D (301) and E (302), presented a strong proteasome inhibitory effect (IC₅₀ = 0.63 and 1.5 µg/mL, respectively) [227].

Manzamines H (303) and L (304) hold cytotoxicity against KB cells (IC₅₀ = 4.6 and 3.5, respectively). Compound 304 also possess weak activity antibiotic activity. [226] Ma’eganedin A (305), proved to be a potent antibiotic against Sarcina lutea and B. subtilis (MIC = 2.8 µg/mL each) [228].

Furthermore, 3,4-Dihydromanzamine J (306) and all the aforementioned manzamines 291,303-305 showed cytotoxic activity against L1210 line (IC₅₀ = 5.0, 2.6, 1.3, 3.7 and 4.4 µg/mL, respectively) [217].

Figure 60. Chemical structures of Manzamines 298-306.

Figure 60. Chemical structures of Manzamines 298-306.

Finally, other types of monomacrocyclic, and diverse hexa- and heptacyclic biologically active manzamines have been reported. Manzamine C (307) exhibited cytotoxicity against A549, HT-29 and P388 cells with (IC₅₀ = 3.5, 1.5, and 2.6 μg/mL, respectively) [229]. Pyrrolizine-substituted Kepulauamine A (308) unveiled weak inhibition against K562 and A549 cells and is moderate antibiotic activity [226]. Manzamine X (309) exhibited cytotoxic activity against KB cells (IC₅₀ = 7.9 μg/mL) [230], while 6-Deoxymanzamine X (310) against L5178 cells (ED₅₀ = 1.8 µg/mL) [231]. Manadomanzamines A (311) and B (312) exhibited anti-tubercular effect (MIC = 1.9 and 1.5 µg/mL, respectively); antiviral activity against HIV-1 (EC₅₀ = 7.0 and 16.5 µg/mL, respectively); cytotoxicity against A549 (IC₅₀ = 2.5 µg/mL, only 311) and HCT-116 cells (IC₅₀ = 2.5 and 5.0 µg/mL, respectively); and antifungal effect against C. albicans (MIC = 20 µg/mL, only 312) and C. neoformans (MIC = 3.5 µg/mL, only 311) [196].

Figure 61. Chemical structures of Manzamines 307-312.

Figure 61. Chemical structures of Manzamines 307-312.

• N2-substituted (DH/TH)β-Carbolines:

N2-methyl-β-carbolinium salts Irene-carbolines A (313) and B (314), isolated from ascidian Cnemidocarpa irene, exerted anti-Alzheimer activity [232]. Notably, other non-brominated derivatives identified in the same species didn’t afford any activity.

N2-aryl-β-carbolinium species Reticulatol (315), Reticulatine (316) and Reticulatate (317) could be obtained from Fascaplysinopsis reticulata sponge. 316 and 317 presented modest antitumor activity, while 315 showed significant selectivity for leukemia [233].

Figure 62. N2-substituted βC compounds 313-317.

Figure 62. N2-substituted βC compounds 313-317.

• C3-substituted (DH/TH)β-Carbolines:

Variabines A (318) and B (319), with a C3-ester, were isolated from the sponge Luffariealla variabilis, have respectively little and significant effect in the inhibition of chymotrypsin-like activity of the proteasome and breast cancer metastasis [234]. Therefore, the inhibitory activities are lost by sulfonation of the 6-OH group. Stolonine C (320), from tunicate Cnemidocarpa stolonifera, induced apoptosis in PC3 line.[235] Tiruchanduramine (321), obtained from the ascidian Synoicum macroglossum, could be identified as a promising inhibitor of α-glucosidase due to the presence of a cyclic guanidine group [236].

C3-indole-subtituted βCs have been also found in marine sources, such as the family of Hyrtioerectines isolated from the sponge Hyrtios erectus. Hyrtioerectine A (322) showed moderate cytotoxicity against HeLa cells (IC₅₀ = 10 μg/mL) [237]. Hyrtioerectines D-F (323–325) exhibited antibacterial behavior against C. albicans, S. Aureus and Pseudomonas aeruginosa; antioxidant activity; and weak antitumor activity against MDA-MB-231, A549 and HT-29 lines, being 323 and 324 more active than compound 325. Therefore, methylation of the phenol group hampers the antioxidant activity, while a C4-CO₂H moiety is more beneficial than an amido group for antitumor properties.

Figure 63. C3-substituted βC compounds 318-325.

Figure 63. C3-substituted βC compounds 318-325.

Regarding saturated carbolines, Hyrtioerectine B (326) prompted moderate cytotoxicity against HeLa cells (IC₅₀ = 5.0 μg/mL).

Figure 64. Chemical structures of Hyrtioerectine B (326).

Figure 64. Chemical structures of Hyrtioerectine B (326).

Annelated β-carbolines

Several βCs with different 5-, 6- or 7-membered fused rings in different positions have been isolated from marine sources over decades, and some of them exhibited promising activities. Fascaplysin (327), 3-Bromofascaplysin (328), 10-Bromofascaplysin (329), 3,10-Dibromofascaplysin (330), 6-Oxofascaplysin (331) and Homofascaplysate A (332) are pentacyclic compounds isolated from sponge Fascaplysinopsis sp. in which the βC core is fused to a 5-membered ring through C1 and N2. In general, Fascaplysin natural and synthetic derivatives represent excellent lead drugs since they exert multiple activities, namely anticancer, against Human Alveolar Rhabdomyosarcoma cells, leukemia, liver cancer cells, melanoma, small lung cancer cells, ovarian cancer cells, among others; analgesic; anti-thrombotic; anti-Alzheimer; and antimalarial [238]. Thorectandramine (333), from the marine sponge Thorectandra sp., presented weak cytotoxicity against MCF-7, OVCAR-3 and A549 cell lines (EC₅₀ 27.0–55.0 μg/mL) [239].

Eudistomins C (334), E (335), K (336) and L (337), Eudistomin K sulfoxide (338) and Debromoeudistomin K (339), are tetracyclic THβC isolated from different marine ascidians, featuring a fused oxathiazepine ring between C1 and N2 responsible of their antiviral activity against HSV-1 and other DNA- or RNA-viruses [183]. Additionally, 336 presents potent antitumor activity against L1210, A549, HCT-8 and P388 lines [240].

Figure 65. Annelated C1-N2 βC compounds 327-339.

Figure 65. Annelated C1-N2 βC compounds 327-339.

Hyrtimomines D (340) and E (341), which contain a fused D-ring between C1 and N9 forming a lactam unit, belonging to the canthin-6-ones family. Both present antifungal activity against C. albicans (IC₅₀ = 4 and 8 μg/mL, respectively) and C. neoformans (IC₅₀ = 4 and 8 μg/mL, respectively), but only 340 showed inhibitory activity against T. mentagrophytes (IC₅₀ = 16 μg/mL) and S. Aureus (IC₅₀ = 4 μg/mL). From their results, the authors inferred that the presence of a carboxylic acid is less beneficial for its antifungal properties [175].

Figure 66. Annelated βC compounds 340-341.

Figure 66. Annelated βC compounds 340-341.

2.2.2.2. β-Carboline dimers

Some recent research has showcased a potential trend in which they tend to be more active than their corresponding monomer [158]. Therefore, several authors have turned to their attention to the synthesis and evaluation of these scaffolds. According to the linked positions of the βC monomers, they can be divided in 1,1-, 2,2-, 3,3-, 9,9-linked and ‘hybrid’ dimers, in which the two βC units are not equivalent.

However, these structures are not that commonly found in marine species compared to plants and, to the best of our knowledge, only a couple of marine-isolated or marine-inspired synthetic dimers with biological activity have been reported to date.

• 1,1-Linked dimers

As far as we can ascertain, only three examples of biologically active marine naturally occurring 1,1-dimers have been reported to date, varying the nature of the organic linker from simple alkyl chains to complex polycyclic structures. Orthoscuticellines A (342), a dimer derived from Plakortamine B (250) obtained from bryozoan Orthoscuticella ventricosa, present a 1,2-cyclobutane unit as linker. Although its trans dimer presented no activity, 342 demonstrated higher cytotoxicity than parent 250 and moderate antiplasmodial activity [150]. Plakortamine C (343), that can be regarded as Plakortamine A (226) dimer and was isolated from the same Plakortis nigra sponge, exhibited higher cytotoxic activity than 226 against HCT-116 line (IC₅₀ = 2.15 mM) [149]. Finally, manzamine 1,1-dimer Neo-kauluamine (344), isolated from Indonesian Acanthostrongylophora ingens sponge, exhibited potent cytotoxic activity against H12999 (IC₅₀ = 1.0 mM), proteasome inhibitory (IC₅₀ = 0.13 mM) and accumulation of cholesterol esters inhibitory activities [224].

Figure 67. Naturally occurring marine βC 1,1-dimers 342-344.

Figure 67. Naturally occurring marine βC 1,1-dimers 342-344.

It is worth to mention that, inspired by these structures, Chatwichien et al. developed the synthesis of 1,1-dimers of simple Norharmane (217) linked by aminoalkylether chains [241]. Surprisingly, their biological activity against various cancer cell lines was as good as the one exerted by Neo-kualamine (344). Given the potential of these compounds, this area is still a hot topic of research with promising expectations.

• 9,9-Linked dimers

Interestingly, an N-N bonded 9,9-dimer (345) of Norharmane (217) was isolated from the Didemnum sp. ascidian. Although this species’ antibiotic activity was diminished in comparison to 217, other synthetic derivatives a wide application. In fact, the double N-methylated carbolinium salt was found to be more active for some strains such as S. Aureus [242].

Figure 68. Structure of marine βC 9,9-dimer 345.

Figure 68. Structure of marine βC 9,9-dimer 345.

• ‘Hybrid’ dimers

Some manzamine derivatives, in particular in the family of Zamamidines, were found to bear a second pendant βC unit, usually exhibiting N2-C1’ linkage. Zamamidine C (346) demonstrated potent antitrypanosomal effect against Trypanosoma brucei brucei and antimalarial activity against P. falciparum [225]. Zamamidines A (347) and B (348) displayed cytotoxic activity against P388 cells (IC₅₀ = 13.8 and 14.8 µg/mL, respectively) [217].

Figure 69. Structure of manzamine hybrid-dimers 346-348.

Figure 69. Structure of manzamine hybrid-dimers 346-348.

Finally, an interesting example of a 1,1’-hybrid manzamine dimer Kauluamine (349), isolated from the sponge Prianos sp., revealed moderate immunosuppressive effect in a mixed lymphoma reaction [243].

Figure 70. Structure of Kauluamine (349).

Figure 70. Structure of Kauluamine (349).

General syntheses of β-Carboline alkaloids

Within the last decade, the synthesis of βCs has been quite extensively reviewed from diverse perspectives, focusing in the construction of the 9H-pyrido[3,4-b]indole [244]. Some of these authors distinguished between classical and current approaches, and a brief summary of each is provided below.

Classical routes, summarized in Figure 71 and Figure 72, are mostly dominated by the use acid-/base-catalyzed or photochemical metal-free approaches. The most commonly exploited synthetic route for the formation of the βCs core, even nowadays, is the Pictet-Spengler reaction (Figure 71A) [245], starting from readily available trytophan derivatives and carbonyl compounds. Other variation of this method includes in situ reduction of nitriles (Figure 71B) [246]. A third variation of this methodology is the Bilschler-Napieralski reaction (Figure 71C) [247], in which amido-trypthophan derivatives are converted to electrophilic chlorimines using P₂O₅ or POCl₃. All this three routes yield tetrahydro-βC derivatives (THβCs), which require further oxidation steps to generate dihydro-βC (DHβC) or βCs. An important feature of Pictet-Spengler approach for the synthesis of saturated carbolines is the posibility of inducing chirality employing enantioselective aid catalysts [245].

Other early works reported the synthesis of βCs from 3-vinylindoles (Figure 72A) [248], Diels-Alder reactions (Figure 72B) [249], Pd-catalyzed intramolecular arylation of anilinobromopyridines Figure 72C) [250], Graebe-Ullmann reactions (Figure 72D) [251], intramolecular nucleophilic substitutions of anilinofluoropyridines (Figure 72E) [252], and photocyclization of anilinopyridines (Figure 72F) [253]. However, some of these procedures lacked of functional group tolerance, accessing only simple βC structures.

Over the past two decades, the number or chemical tools for organic synthesis has grown exponentially and, given the promising application of βCs as drug, several new methodologies have been developed to build its azacarbazol skeleton. Mordi and Arshad performed an extensive review about these new methodologies [254], grouping them into the following cathegories: Larock heteroannulation (Figure 73A), C-H activation reactions (Figure 73B), Cycloaddition reactions (Figure 73C), 6π-Electrocyclizations (Figure 73D), Electrophilic cycloaromatization (not reported for βC so far), Cross-coupling reactions (Figure 73E), and Radical nucleophilic substitution (Scheme 3F). Summarizing all of these processes is a difficult quest, given the wide range of chemical structures that could be potential starting materials and transformations reported. Therefore, only one example of each it appears represented in Figure 73.

In this scenario, the elaboration of these scaffolds remains a hot area of research, although classical approaches are still preferred in most drug discovery programs. Notably, the development of valuable synthetic intermediates through these methodologies has allowed to also explored a great number of further derivatization processes [255].

2.3.4. Other annelated indole alkaloids

In this section some examples of annelated indole alkaloids (350-353) with varied structures have been included due to their cytotoxic activity against several human cancer cell lines (Table 2).

3. Conclusions

Abbreviations

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