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Chemical diversity and biological function of indolediketopiperazines from marine-derived fungi

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Natural products from marine-derived fungi have attracted considerable attention in the recent two decades. Indolediketopiperazines are one of the most important classes of marine natural products, mainly discovered from the fungal genera Penicillium, Aspergillus and Eurotium. These compounds span a wide range of chemical structures and bioactivities. This review summarizes 155 indolediketopiperazines that were discovered from marine-derived fungi from 2000 to early 2019 and primarily focuses on their chemical diversity and biological function.


Marine-derived fungi are defined not in terms of traditional taxonomy but of ecology. Fungi growing in the ocean are termed marine-derived fungi and can be grouped into obligate and facultative marine-derived fungi (Höller 1999). Obligate marine-derived fungi denote those that must live and reproduce in either sea waters or river estuaries, while those that live in both terrestrial and marine environments are termed as facultative marine-derived fungi (Kohlmeyer 1974). Over the years, the chemical investigation of marine-derived fungi has been largely overlooked, partly because of the low abundance of fungi in the marine environment or because researchers suspect the existence of true marine fungi (Imhoff 2016). In the two most recent decades, a large number of obligate marine-derived fungi have been identified through cultivation-dependent studies, with most of them found in algae and sponges (Bugni and Ireland 2004; Paz et al. 2010; Rateb and Ebel 2011; Zhang et al. 2009). In recent years, the research on marine-derived fungi has attracted great attention, and the number of new natural products isolated from marine-derived fungi has increased year by year. Prior to 1992, only 15 new compounds isolated from marine-derived fungi were reported (Fenical and Jensen 1993), while around 270 new compounds were discovered in the following decade (Bugni and Ireland 2004). From 2000 to 2005, about 100 new marine fungal sourced new natural products were discovered (Saleem et al. 2007), while from 2005 to 2010, the number increased to 690 (Rateb and Ebel 2011). This trend continues and marine-derived fungi have been regarded as a diverse community and a rich reservoir of natural products.

Marine-derived fungi produce abundant secondary metabolites including polyketides, terpenes, alkaloids, and polypeptides, among which indolediketopiperazines (IDPs), mainly isolated from the fungal genera Penicillium, Aspergillus, and Eurotium, are an important component (Li et al. 2009). IDPs usually contain two parts in their structures, with the first part being a 3-substituted indole unit and the second part a diketopiperazine moiety. From the perspective of biosynthesis, IDPs are mainly formed by condensation of a complete tryptophan with another amino acid such as tryptophan, proline, phenylalanine, histidine, and leucine through a peptide bond. IDPs have attracted extensive attention not only because they are frequently found in secondary metabolites of marine-derived fungi but also because of their wide-spectrum of biological activities such as antibacterial, antiviral, anti-tumor, antioxidant, immunomodulatory, and insecticidal activities.

Although there are several reviews about the IDPs on various topics (de Carvalho and Abraham 2012; Huang et al. 2014; Jiang and Guo 2011; Ortiz and Sansinenea 2017), there is no comprehensive review on IDPs of marine fungal origin. Ma et al. (2016) summarized 166 IDPs from fungi including both terrestrial- and marine-derived fungi up to mid-2015 and classified them through the types of amino acids in biosynthesis. The present review focuses on the 155 IDPs discovered from marine-derived fungi published from 2000 to early 2019. These compounds are classified by the source of fungi of different genera, and their structures and bioactivities are also described.

IDPs from different marine-derived fungi

IDPs from the fungal genus Penicillium

The fungal genus Penicillium belongs to Ascomycete and is an important research object in the field of natural products on account of its abundant secondary metabolites. The species in this genus are widely distributed in the marine environment and can be found not only in coastal and deep sea but also in mangrove plants, algae, and sponges as endophytes. Penicillium is one of the main sources of IDPs, with a total of 26 new entities (126) having been described from 2000 to early 2019 (Fig. 1).

Fig. 1

New IDPs isolated from marine-derived fungal species in the genus Penicillium (126)

In 2009, Du et al. (2009a) isolated five IDPs, brevicompanines D–H (15), from Penicillium sp. F1 derived from deep sea sediments (depth of 5080 m) and tested their anti-inflammatory activities. In BV2 microglial cells, compounds 2 and 5 were effective in inhibiting lipopolysaccharide (LPS)-directed nitric oxide (NO) production with IC50 values of 27 and 45 μg/mL, respectively. Substitution of N-6 has an important influence on the inhibition of NO production. In the same year, roquefortines F (6) and G (7), containing an imidazole ring, were obtained from another fungal strain, Penicillium sp. F23-2, by the same group (Du et al. 2009b). The cytotoxicity of these two compounds against MOLT-4, HL-60, A-549, and BEL-7402 was evaluated by MTT and SRB colorimetry but there was no significant activity. In the following year, two other IDPs, roquefortines H (11) and I (12), were reported from the same strain, yet they still showed no significant cytotoxic activity against the above four cell lines (Du et al. 2010).

Zhou et al. (2010) isolated a fungal strain P. griseofulvum from deep sea sediments (depth of 2481 m) and obtained three IDPs, variecolorins M–O (810), from its fermented crude extract. These three compounds showed weak free radical scavenging activity with IC50 values of 135, 120, and 91 μmol/L, respectively, and vitamin C was the positive control with an IC50 value of 26 μmol/L. The cytotoxic activity against BEL-7402, HL-60, and A-549 was also tested, but none of the three compounds were active.

In 2012, after several bioactive screenings against Vibrio cholera, Devi et al. (2012) found a strain of P. chrysogenum MTCC 5108 from the mangrove plant Porteresia coarctata (Roxb). A new IDP, 3,1′-didehydro-3[2″(3‴,3‴-dimethyl-prop-2-enyl)-3″-indolylmethylene]-6-methyl piperazine-2,5-dione (13), was obtained through further separation of the cultural extract. Compound 13 was tested for antimicrobial activity using the standard disk diffusion method and exhibited good inhibitory activity selectively against the human pathogen, Vibrio cholera, with an inhibition zone of 14–16 mm, which is comparable to that of streptomycin (also showing a 14–16 mm inhibition zone).

Quang et al. (2013) isolated two new IDPs, deoxydihydroisoaustamide (14) and 16β-hydroxy-17β-methoxy-deoxydihydroisoaustamide (15), from Penicillium sp. JF-72, a fungus obtained from an unidentified sponge. These two compounds showed no significant activity in the tests of cytoprotective and nitrite inhibitory properties. In the same year, penilloid A (16) was isolated from Penicillium sp. SCSIO 00258, isolated from gorgonian Dichotella gemmacea (He et al. 2013). Compound 16 was tested for inhibiting activities against both Balanus amphitrite and B. neritina larvae, which may cause full fouling, but the anti-fouling activity of compound 16 was not significant.

From co-culture of Penicillium sp. DT-F29 with Bacillus sp. B31, both isolated from marine sediments, ten new IDPs (1726) including 12β-hydroxy-13α-ethoxyverruculogen TR-2 (17), 12β-hydroxy-13α-butoxyethoxyverruculogen TR-2 (18), hydrocycloprostatin A (19) and B (20), 25-hydroxyfumitremorgin B (21), 12β-hydroxy-13α-butoxyethoxyfumitremorgin B (22), 12β-hydroxy-13α-methoxyverruculogen (23), 26α-hydroxyfumitremorgin A (24), 25-hydroxyfumitremorgin A (25), and diprostatin A (26) were identified in 2017 (Yu et al. 2017). This series of compounds was tested for inhibitory activity against the bromodomain protein 4 (BRD4). BRD4 belongs to the BET family and the presence of bromodomains plays an important role in epigenetic changes, regulation of transcriptional activity, and chromatin recombination. Therefore, the study of BRD4 inhibitors is significant to the treatment of cancer, nervous system diseases, obesity, and inflammation. At concentration of 20 μmol/mL, both compounds 21 and 26 showed strong inhibitory activity against BRD4.

IDPs from the fungal genus Aspergillus

Species in the Aspergillius genus exist mostly in an asexual state, propagated by conidia widely found in both land and ocean environments. The growth of Aspergillius fungi usually requires less nutrients, and some can even grow in milieu that are entirely deficient in key nutrients. Chemically, Aspergillus is also one of the important sources of IDPs, with a total of 70 examples (2796) described up to early 2019. Starting from the 21st century, more and more IDPs isolated from Aspergillus have been reported (Figs. S1, S2).

Kato et al. (2007) obtained four new IDPs, notoamides A–D (2730), by isolating the crude extract of Aspergillius sp. from mussel Mytilus edulis. Compounds 2729 showed moderate cytotoxicity against HeLa L1210 with IC50 values in the range of 22–52 μg/mL. Compound 29 can induce G2/M-cell cycle arrest at a concentration of 6.3 μg/mL. In 2008, Tsukamoto et al. (2008) isolated six similar compounds, notoamides F–K (3439), from the same fungus. Compound 37 showed weak cytotoxic activity against HeLa (IC50 = 21 μg/mL), and the IC50 values of the remaining compounds were all greater than 50 μg/mL. In 2009 and 2010, notoamides E2 (47) and E3 (48), (−)-versicolamide B (49), notoamides M–N (5051), and notoamides O–R (5356) were obtained successively from this Aspergillus sp. (Tsukamoto et al. 2009a, b, 2010). Among them, compound 51 contained a chlorine atom, which was a rare phenomenon in this family of prenylated IDPs and also reflected the presence of a halogenase in this fungus. Compound 53 possessed a novel hemiacetal/hemiaminal ether functionality, which was hitherto unknown among this family of prenylated IDPs. In 2010, a similar compound, notoamide S (52) was isolated from marine-derived Aspergillus sp. MF297-2 (Ding et al. 2010).

In 2008, Zhang et al. (2008) obtained three new IDPs from the metabolites of A. sydowi PFW 1–13 isolated from sea driftwood including 6-methoxyspirotryprostatin B (31), 18-oxotryprostatin A (32), and 14-hydroxyterezine D (33), which exhibited weak cytotoxic activity against A-549 with IC50 values of 8.29, 1.28, and 7.31 μmol/L, respectively. Compound 31 also exhibited cytotoxic activity against HL-60 with an IC50 value of 9.71 μmol/L. In the same year, Wang et al. (2008) isolated a strain of A. fumigatus from the sea cucumber Stichopus japonicus and obtained seven new IDPs (4046) from its secondary metabolites. All compounds were tested for cytotoxic activity, in which compound 43 showed good activity against MOLT-4, HL-60, and A-549, with IC50 values of 3.1, 2.3, and 3.1 μmol/L, respectively. In the cytotoxic activity test on BEL-7402, compound 44 showed better activity than others, with an IC50 value of 7.0 μmol/L.

In 2011, Lee et al. (2011) isolated two new IDPs, protubonine A (57) and B (58), from the Aspergillus sp. SF-5044, which was obtained from intertidal sediment samples. In the cytotoxic activity assay, these two compounds showed no activity against HL-60, MDA-MB-231, Hep3B, 3Y1 and K562 at the concentration of 250 μmol/L.

Effusin A (59) and dihydrocryptoechinulin D (60), both occurring as racemates, were isolated from a mangrove rhizosphere soil-derived fungus, A. effuses H1-1 in 2012 (Gao et al. 2012). Compound 60 showed significant inhibitory activity on the growth of P388 and HL-60 with IC50 values of 1.83 and 4.80 μmol/L, respectively. In the further molecular target studies, the two enantiomers resolved by compound 60 showed differences in the inhibitory activity against topoisomerase, and only (12R, 28S, 31S)-60 produced inhibitory activity. In the following year, Gao et al. (2013) obtained dihydrocryptoechinulin B (76), which exhibited weak cytotoxic activities against BEL-7402 (IC50 = 55.1 μmol/L) and A-549 (IC50 = 30.5 μmol/L), from the same fungus.

Wang et al. (2012b) isolated four IDPs from A. fumigatus YK-7 including prenylcyclotryprostatin B (61), 20-hydroxycyclotryprostatin B (62), 9-hydroxyfumitremorgin C (63), and 6-hydroxytryprostatin B (64), among which compounds 61 and 63 showed good cytotoxic activity against U937 with IC50 values of 25.3 and 18.2 μmol/L, respectively. Spirotryprostatin F (65) was isolated from the marine isolate of the fungus A. fumigatus KMM 4631 (Afiyatullov et al. 2012). This compound exhibited stimulating action on the growth of sprout roots of Glycine max (L.) Merr, Zea mays L. and Fagopyrum esculentum Moench in low and ultralow doses (10−6–10−17 mol/L). He et al. (2012) obtained cyclotryprostatin E (66) from the crude fermentation extract of A. sydowii SCSIO 00305, isolated from the healthy tissue of the gorgonian coral Verrucella umbraculum. This compound showed no significant inhibitory activity on the growth of A549, A375, and Hela. Miao et al. (2012) isolated a new IDP, 9ξ-O-2(2,3-dimethylbut-3-enyl)brevianamide Q (67), from the culture of A. versicolor, an endophytic fungus isolated from the marine brown alga Sargassum thunbergii. The fungal strain A. versicolor MF030 derived from sediments (depth of 60 m) yielded brevianamides S–V (6871), of which compound 68 exhibited selective inhibitory activity against Bacille Calmette-Guerlin (BCG) with an MIC value of 6.25 μg/mL (Song et al. 2012). Carneamides A–C (7274) were isolated from the marine-derived fungus A. carneus KMM 4538, and the antimicrobial and cytotoxic activities were examined, in which these compounds showed no activities (Zhuravleva et al. 2012).

Cai et al. (2012, 2015) obtained aspergilazine A (75) and okaramines S–U (8688) from the fungal strain A. taichungensis ZHN-7-07, isolated from the mangrove plant Acrostichum aureum, in 2012 and 2015, respectively. Compound 75 had an inhibition rate of 34.1% against influenza A virus H1N1 at a concentration of 50 μg/mL, while compound 86 showed cytotoxic activities against HL-60 and K562 with IC50 values of 0.78 and 22.4 μmol/L, respectively.

Peng et al. (2013) isolated 5-chlorosclerotiamide (77) and 10-epi-sclerotiamide (78) from a deep sea-derived fungus A. westerdijkiae DFFSCS013. In anti-tumor activity experiments, the two compounds showed weak inhibitory activity on the growth of K562 with IC50 values of 44 μmol/L and 53 μmol/L, respectively. In the following year, Peng et al. (2014) described seven new prenylated IDPs, versicamides A-G (7985), from another marine-derived fungus A. versicolor HDN08-60. These seven compounds were tested for cytotoxic activity against HeLa, HCT-116, HL-60, and K562 cells, and unfortunately, none of them showed significant activity.

In 2017, Wakefield et al. (2017) isolated a fungal strain A. fumiga MR2012 from the sediments of the Red Sea and obtained brevianamide X (89) from its culture extract. When the fungus was co-cultured with two desert-derived bacteria, Streptomyces leeuwenhoekii C34 and C58, compound 89 could not be found from the co-cultured crude extract.

In 2018, a diketopiperazine dimer (90) was isolated from the ethyl acetate extract of a marine sponge-derived fungus A. violaceofuscus (Liu et al. 2018). The planar structure of 90 was known, while the absolute configuration had not been reported before. In LPS-induced THP-1 cells, compound 90 showed anti-inflammatory activity against IL-10 expression with an inhibition rate of 78.1% at concentration of 10 μmol/L. In the same year, Cho et al. (2018) found a new IDP dimer SF5280-415 (91) from a sponge-derived Aspergillus sp. SF-5280, which exhibited inhibitory activity against protein tyrosine phosphatase (PTP1B) with IC50 value of 14.2 μmol/L. Also, Xu et al. (2018) isolated three IDP dimers 9294 from the fermented extract of Aspergillus sp. DX4H. Compound 9294 were tested for cytotoxic activity against PC3 and showed weak activity at a concentration of 20 μg/mL.

In 2019, a pair of enantiomers, (+)- and (−)-brevianamide X (95 and 96), was isolated from chemical-epigenetic cultures of A. versicolor OUCMDZ-2738 with 10 μmol/L fluinostat (SAHA). Compared to cultures in the same medium without SAHA, these two compounds were solely observed under SAHA condition (Liu et al. 2019).

IDPs from the fungal genus Eurotium

Eurotioum belongs to the Aspergillus family and was previously classified as Aspergillus. While most of the Aspergillus are asexual, the sexual Aspergillus are separately summarized and assigned the general name Eurotioum. Most of Eurotioum are hyperosmotic fungi, which can survive in areas with high salinity. The genus Eurotioum is also one of the main sources of indolediketopiperazines, and a large number of novel IDPs were isolated from this genus. Since 2000, a total of 38 new IDPs have been reported from Eurotioum (Fig. S3).

Li et al. (2008, 2010) obtained dehydrovariecolorin L (97), dehydroechinulin (98), and 7-O-methylvariecolortide A (99) from E. rubrum, isolated from inner tissue of stems of Hibiscus tiliaceus in 2008 and 2010. Among these three compounds, compound 99 is complex in structure, which is composed of IDP and xanthene. This fungus was reinvestigated using solid rice fermentation in 2012, and 12-demethyl-12-oxo-eurotechinulin B (103) was isolated from the crude extract (Yan et al. 2012). In the anti-tumor activity assay, this compound exhibited cytotoxic activity against SMMC-7721 with an IC50 value of 30 μg/mL.

In 2012, cristatums A–C (100102) were isolated from a strain of E. cristatum EN-220 which was obtained from marine alga Sargassum thunbergii, among which compound 102 is an IDP dimer (Du et al. 2012). Compound 100 showed inhibitory activity against the growth of two pathogenic bacteria Escherichia coli and Staphyloccocus aureus, with MIC values of 64 and 8 μg/mL, respectively. Compound 101 exhibited lethal activity against brine shrimp with an LD50 value of 74.4 μg/mL (Du et al. 2012). Five years later, four new IDPs (122125) were reported from the same strain (Du et al. 2017). In the subsequent bioactivity assays, compound 123 showed better activities than others. It showed brine shrimp lethality and nematicidal activity with LD50 values of 19.4 and 110.3 μg/mL, respectively, and exhibited moderate antioxidative activity with an IC50 value of 20.6 μg/mL.

In 2012, Gomes et al. (2012) isolated a new IDP dimer eurocristatine (104) from the culture of the sponge-associated fungus E. cristatum KUFC 7356. Compound 104 exhibited cytotoxic activity against MCF-7, NCI-H-460, and A375-C5 at a concentration of 150 μmol/L. In antibacterial activity experiments, it showed no activity against Candida albicans, Aspergillus fumigatus, Trichophyton rubrum, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa.

A new IDP dimer, cristatumin E (105), was isolated from the fermentation broth of Eurotium herbariorum HT-2, associated with marine alga Enteromorpha prolifera in (Li et al. 2013). This compound exhibited inhibitory activity against Bacillus subtilis and Escherichia coli, with both MIC values of 44 μmol/L. In addition, compound 105 showed cytotoxic activity against K562 with an IC50 value of 8.3 μmol/L.

Chen et al. (2015) isolated a series of prenylated IDPs rubrumline A–O (106120) from the organic extracts of E. rubrum F33 derived from deep sea sediments (− 2067 m) collected in the South Atlantic. In MDCK cells, compound 109 showed potent antiviral activity against H1N1 with an IC50 value of 126.0 μmol/L and was able to inhibit influenza virus strains including amantadine- and oseltamivir-resistant clinical isolates.

Kamauchi et al. (2016) studied the metabolite diversity of a marine-derived E. rubrum MPUCI136 between cultivation on wheat medium and Czapek-Dox agar medium. Iseechinulin D (121) was isolated from the crude extract of wheat medium, while this compound was not discovered when fermented in Czapek-Dox agar medium. Compound 121 exhibited certain inhibitory activity on melanin formation with an IC50 value of 60 μmol/L but was cytotoxic to melanoma cells at a concentration of 50 μmol/L.

In 2018, Zhong et al. (2018a, b) obtained three IDPs eurotiumins A–C (126128) and three pairs of spirocyclic IDP enantiomers variecolortins A − C (129134) from marine-derived fungus Eurotium sp. SCSIO F452. Compound 128 exhibited antioxidant activity with an IC50 value of 13 μmol/L, while compounds 126 and 127 exhibited different antioxidant activities due to their different configurations, with IC50 values of 37 and 69 μmol/L, respectively. In the same assay, compound 129 exhibited antioxidant activity with an IC50 value of 58.4 μmol/L, which is much stronger than its enantiomeric isomer 130 (IC50 = 159.2 μmol/L). Compounds 131 showed cytotoxicity against SF-268 and HepG2 cell lines with IC50 values of 12.5 and 15.0 μmol/L, while those of 133 were 30.1 and 37.3 μmol/L, respectively. However, their respective enantiomers, 132 and 134, were inactive.

IDPs from other fungal sources

In addition to the above three fungal genera, some other fungi are also disclosed as the source of IDPs. These fungi include Acrostalagmus luteoalbus, Gliocladium sp., Leptosphaeria sp., Neosartorya glabra, Plectosphaerella cucumerina, and Pseudallescheria ellipsoidea. Statistically, most of the novel IDPs isolated from these genera fungi are dimers (Fig. S4).

Yamada et al. (2002) isolated a fungal strain Leptosphaeria sp. from the marine alga Sargassum tortile and obtained four new IDP dimers leptosins M (135), M1 (136), N (137), and N1 (138) from its crude extract. All these compounds exhibited significant cytotoxic activity against cultured P388 cells, with compounds 137 and 138 being approximately ten times more active than that of 135 and 136. In addition, compound 135 showed significant inhibitory activity against PTK and CaMKIII protein kinases at a concentration of 10 μg/mL, with inhibition rates of 40%–70%. However, this compound showed no inhibitory activity against the other three protein kinases, PKA, PKC and EGFR, at 100 μg/mL, indicating that it is selective for inhibiting protein kinase. Compound 135 also exhibited selective inhibitory activity against topoisomerase II with an IC50 value of 59.1 μmol/L, with no inhibitory activity displayed against topoisomerase I. Two years later, leptosins O–S (140144) were isolated from the same fungal strain, in which compounds 140 and 141 showed good cytotoxic activity against P388 cells with IC50 values of 1.1 and 0.1 μg/mL, respectively (Yamada et al. 2004).

In 2013, a novel IDP (139) was isolated from the culture extracts of marine-derived fungal strain M-3 which was unidentified and associated to laver Porphyra yezoensis. This compound exhibited significant inhibitory activity against the growth of Pyricularia oryzae, a severe fungal disease of rice, with an MIC value of 0.36 μmol/L (Byun et al. 2003). This compound can induce morphological changes of mycelium during the growth of P. oryzae, which is similar to the mechanism of the antifungal drug rhizoxin already on the market.

Usami et al. (2004) obtained four IDPs gliocladins A–C (145148) from Gliocladium roseum OUPS-N132, originally separated from Aplysia kurodai, of which compound 146 was a structurally unique trioxopiperazine. Compound 146 showed significant cytotoxic activity against P388 cells with an ED50 value of 2.4 μg/mL.

In 2009, three IDPs with new skeletons, plectosphaeroic acids A–C (149151), were isolated from the metabolites of Plectosphaerella cucumerina, obtained from marine sediments collected in Barkley Sound, British Columbia (Carr et al. 2009). These compounds, which contain two anthracene ring substitutions and one molecule of phenoxazinone substitution at the N-6 position, are inhibitors of indoleamine 2,3-dioxygenase (IDO). The IC50 values of the three compounds were approximately 2 μmol/L.

Luteoalbusins A (152) and B (153) were isolated from the fungus Acrostalagmus luteoalbus SCSIO F457 originating from deep sea sediments at a depth of 2801 meters in 2012 (Wang et al. 2012a). The two compounds showed significant cytotoxicity against SF-268, MCF-7, NCI-H460, and HepG-2 cell lines.

In 2016, felutanine A (154) was isolated from the ethyl acetate extract of the culture of the marine sponge-associated fungus Neosartorya glabra KUFA 0702 (May Zin et al. 2016). In the same year, Wang et al. (2016) isolated a strain of Pseudallescheria ellipsoidea F43-3 from the soft coral Lobophytum crassum and obtained pseudellone D (155) containing a thiomethyl group. The bioactivity of these two compounds was not reported.

Biosynthesis of IDPs

The basic skeleton of IDPs consists of a C-3 substituted indole unit and a diketopiperazine unit. Through the connection of the indole unit to the diketopiperazine unit, IDPs can be divided into three types (Fig. 2): open loop IDPs, closed loop IDPs, and spiral ring IDPs (Jia et al. 2018). All IDPs structurally fall into these three types, and the representative IDPs notoamide S (52), 9-hydroxyfumitremorgin C (63), and 6-methoxyspirotryprostatin B (31) are selected to discuss their biosynthetic pathways.

Fig. 2

Three types of IDPs

Biosynthesis of notoamide S

The biosynthesis of notoamide S (52) starts with the combination of tryptophan and proline to obtain brevianamide F by the coupling reaction (Scheme 1). With available dimethylallyl diphosphate (DMAPP), deoxybrevianamide F is converted to brevianamide E, which is further oxidized to form 6-hydroxy-deoxybrevianamide E, and the latter transformed into notoamide S (52) by combination with DMAPP (Ding et al. 2010).

Scheme 1

Biosynthetic pathway for notoamide S (52)

Biosynthesis of 9-hydroxyfumitremorgin C

The biosynthetic pathway for 9-hydroxyfumitremorgin C (63, Scheme 2) is similar to that for compound 52, which also begins with the formation of brevianamide F. Tryprostatin B is another compound derived from the combination of brevianamide F and DMAPP, and it can be transformed into tryprostatin A by oxidation and methylation. Next, the prenyl moiety of tryprostatin A and the diketopiperazine ring are connected to form fumitremorgin C. The final compound, 9-hydroxyfumitremorgin C (63), is the oxidation product of fumitremorgin C (Ma et al. 2016; Wang et al. 2012b).

Scheme 2

Biosynthetic pathway for 9-hydroxyfumitremorgin C (63)

Biosynthesis of 6-methoxyspirotryprostatin B

6-Methoxyspirotryprostatin B (31) belongs to spiral ring IDPs, and the biosynthetic pathway for compound 31 was first postulated by Zhang et al. (2008). The biosynthesis starts with the reaction between methoxylated brevianamide F and mevalonic acid (Scheme 3), and compound 32a is formed at the same time as the formation of 18-oxotryprostatin A (32). The oxidative product 32b may be subjected to intramolecular aldol reaction to transform into 32c, which could be deoxygenated and dehydrogenated to yield 6-methoxyspirotryprostatin B (31).

Scheme 3

Postulated biosynthetic pathway for 6-methoxyspirotryprostatin B (31)


From 2000 to early 2019, a total of 155 new IDPs were reported. The number of new IDPs has generally shown an increasing trend over time (Fig. 3). Among them, only four new IDPs were reported from 2000 to 2002. But in the 3 years from 2012 to 2014, this number increased to 42. Although the number between 2015 and 2017 has slightly declined, there were 33 new IDPSs obtained. As a result, the number of newly discovered IDPs is still on the rise.

Fig. 3

New IDPs reported every 3 years from 2000 to early 2019, according to the year of publication

The fungal genera Penicillium, Aspergillus, and Eurotium are the main sources of fungi for production of IDPs (Fig. 4a), with 70, 38, and 26 new IDPs described, respectively, from 2000 to early 2019. In addition, there were 21 new IDPs isolated from other genera of the fungal kingdom.

Fig. 4

The distribution of new IDPs from marine-derived fungi (a) Divided by the source of fungal genera/species (b) Divided by the source of fungal strains

Sediments, algae, and sponges are the most common sources for the isolation of fungal strains that can produce IDPs (Fig. 4b). From 2000 to early 2019, there were 12 fungi isolated from sediment with metabolic production of new IDPs, which was a large part of all statistical fungi. Seven fungi isolated from algae and five sponge-derived fungi can also produce IDPs, indicating that these fungi are important sources of IDPs.

IDPs have complex and variable structures, and in addition to the basic skeleton formed by tryptophan and other amino acids, IDPs with isopentenyl and sulfur bridge substitutions were reported. The complex structural diversity of IDPs presents great challenges in determining final chemical architectures, especially for those compounds containing multichiral centers. Because of the diversity in structures of IDPs, the biological activities are also very extensive. In addition to potent anti-tumor activities, some IDPs also have good performance in antibacterial, antioxidant, and insecticidal activities. Due to the good biological activities, IDPs have also received extensive attention in the field of organic synthesis. A large number of reports have been described on the total synthesis of IDPs. However, it is sometimes difficult to accomplish the stereocontrolled synthesis of IDPs, especially those containing various stereo configurations.

IDPs are common in secondary metabolites of fungi, especially in the genera Penicillium, Aspergillus, and Eurotium, which are widely found in terrestrial and marine environments. Studies on terrestrial fungi have been ongoing for many years, while research on marine-derived fungi has been slowly attracting researchers’ attention in recent years. The number of marine-derived fungi is unknown at present, and the natural products produced by these fungi have not been estimated. Therefore, the study of secondary metabolites of marine-derived fungi is of great significance not only for the discovery of new active IDPs but also for the discovery of other types of compounds with potent bioactivities. IDPs are only a portion of the total natural products from marine-derived fungi, which hold significance for the development of new drugs. It is believed that in the near future, research on natural products of marine-derived fungi will become more prolific and better promote the healthy development of human beings.


  1. Afiyatullov SS, Zhuravleva OI, Chaikina EL, Anisimov MM (2012) A new spirotryprostatin from the marine isolate of the fungus Aspergillus fumigatus. Chem Nat Compd 48:95–98

  2. Bugni TS, Ireland CM (2004) Marine-derived fungi: a chemically and biologically diverse group of microorganisms. Nat Prod Rep 21:143–163

  3. Byun HG, Zhang H, Mochizuki M, Adachi K, Shizuri Y, Lee WJ, Kim SK (2003) Novel antifungal diketopiperazine from marine fungus. J Antibiot 56:102–106

  4. Cai S, Kong X, Wang W, Zhou H, Zhu T, Li D, Gu Q (2012) Aspergilazine A, a diketopiperazine dimer with a rare N-1 to C-6 linkage, from a marine-derived fungus Aspergillus taichungensis. Tetrahedron Lett 53:2615–2617

  5. Cai S, Sun S, Peng J, Kong X, Zhou H, Zhu T, Gu Q, Li D (2015) Okaramines S-U, three new indole diketopiperazine alkaloids from Aspergillus taichungensis ZHN-7-07. Tetrahedron 71:3715–3719

  6. Carr G, Tay W, Bottriell H, Andersen SK, Mauk AG, Andersen RJ (2009) Plectosphaeroic acids A, B, and C, indoleamine 2, 3-dioxygenase inhibitors produced in culture by a marine isolate of the fungus Plectosphaerella cucumerina. Org Lett 11:2996–2999

  7. Chen X, Si L, Liu D, Proksch P, Zhang L, Zhou D, Lin W (2015) Neoechinulin B and its analogues as potential entry inhibitors of influenza viruses, targeting viral hemagglutinin. Eur J Med Chem 93:182–195

  8. Cho KH, Sohn JH, Oh H (2018) Isolation and structure determination of a new diketopiperazine dimer from marine-derived fungus Aspergillus sp. SF-5280. Nat Prod Res 32:214–221

  9. de Carvalho MP, Abraham WR (2012) Antimicrobial and biofilm inhibiting diketopiperazines. Curr Med Chem 19:3564–3677

  10. Devi P, Rodrigues C, Naik CG, D`Souza L (2012) Isolation and characterization of antibacterial compound from a mangrove-endophytic fungus, Penicillium chrysogenum MTCC 5108. Indian J Microbiol 52:617–623

  11. Ding Y, Wet JRD, Cavalcoli J, Li S, Greshock TJ, Miller KA, Finefield JM, Sunderhaus JD, McAfoos TJ, Tsukamoto S, Williams RM, Sherman DH (2010) Genome-based characterization of two prenylation steps in the assembly of the stephacidin and notoamide anticancer agents in a marine-derived Aspergillus sp. J Am Chem Soc 132:12733–12740

  12. Du L, Yang X, Zhu T, Wang F, Xiao X, Park H, Gu Q (2009a) Diketopiperazine alkaloids from a deep ocean sediment derived fungus Penicillium sp. Chem Pharm Bull 57:873–876

  13. Du L, Li D, Zhu T, Cai S, Wang F, Xiao X, Gu Q (2009b) New alkaloids and diterpenes from a deep ocean sediment derived fungus Penicillium sp. Tetrahedron 65:1033–1039

  14. Du L, Feng T, Zhao B, Li D, Cai S, Zhu T, Wang F, Xiao X, Gu Q (2010) Alkaloids from a deep ocean sediment-derived fungus Penicillium sp. and their antitumor activities. J Antibiot 63:165

  15. Du FY, Li XM, Li CS, Shang Z, Wang BG (2012) Cristatumins A-D, new indole alkaloids from the marine-derived endophytic fungus Eurotium cristatum EN-220. Bioorg Med Chem Lett 22:4650–4653

  16. Du FY, Li X, Li XM, Zhu LW, Wang BG (2017) Indolediketopiperazine alkaloids from Eurotium cristatum EN-220, an endophytic fungus isolated from the marine alga Sargassum thunbergii. Mar Drugs 15:24

  17. Fenical W, Jensen PR (1993) Marine microorganisms: a new biomedical resource. Pharmaceutical and bioactive natural products. Springer, Boston, pp 419–457

  18. Gao H, Liu W, Zhu T, Mo X, Mandi A, Kurtan T, Li J, Ai J, Gu Q, Li D (2012) Diketopiperazine alkaloids from a mangrove rhizosphere soil derived fungus Aspergillus effuses H1-1. Org Biomol Chem 10:9501–9506

  19. Gao H, Zhu T, Li D, Gu Q, Liu W (2013) Prenylated indole diketopiperazine alkaloids from a mangrove rhizosphere soil derived fungus Aspergillus effuses H1-1. Arch Pharm Res 36:952–956

  20. Gomes NM, Dethoup T, Singburaudom N, Gales L, Silva AMS, Kijjoa A (2012) Eurocristatine, a new diketopiperazine dimer from the marine sponge-associated fungus Eurotium cristatum. Phytochem Lett 5:717–720

  21. He F, Sun YL, Liu KS, Zhang XY, Qian PY, Wang YF, Qi SH (2012) Indole alkaloids from marine-derived fungus Aspergillus sydowii SCSIO 00305. J Antibiot 65:109

  22. He F, Han Z, Peng J, Qian PY, Qi SH (2013) Antifouling indole alkaloids from two marine derived fungi. Nat Prod Commun 8:329–332

  23. Höller U (1999) Isolation, biological activity and secondary metabolite investigations of marine-derived fungi and selected host sponges. Doctoral dissertation, Universität Carolo-Wilhelmina

  24. Huang RM, Yi XX, Zhou YZ, Su XD, Peng Y, Gao CH (2014) An update on 2,5-diketopiperazines from marine organisms. Mar Drugs 12:6213–6235

  25. Imhoff J (2016) Natural products from marine fungi—Still an underrepresented resource. Mar Drugs 14:19

  26. Jia B, Ma YM, Chen D, Chen P, Hu Y (2018) Studies on structure and biological activity of indole diketopiperazine alkaloids. Prog Chem 30:1067–1081

  27. Jiang CS, Guo YW (2011) Epipolythiodioxopiperazines from fungi: chemistry and bioactivities. Mini-Rev Med Chem 11:728–745

  28. Kamauchi H, Kinoshita K, Sugita T, Koyam K (2016) Conditional changes enhanced production of bioactive metabolites of marine derived fungus Eurotium rubrum. Bioorg Med Chem Lett 26:4911–4914

  29. Kato H, Yoshida T, Tokue T, Nojiri Y, Hirota H, Ohta T, Williams RM, Tsukamoto S (2007) Notoamides A-D: prenylated indole alkaloids isolated from a marine-derived fungus, Aspergillus sp. Angew Chem Int Edit 46:2254–2256

  30. Kohlmeyer J (1974) On the definition and taxonomy of higher marine fungi. Veröff Inst Meeresforsch Bremenh Suppl 5:263–286

  31. Lee SU, Asami Y, Lee D, Jang JH, Ahn JS, Oh H (2011) Protuboxepins A and B and protubonines A and B from the marine-derived fungus Aspergillus sp. SF-5044. J Nat Prod 74:1284–1287

  32. Li DL, Li XM, Li TG, Duang HY, Wang BG (2008) Dioxopiperazine alkaloids produced by the marine mangrove derived endophytic fungus Eurotium rubrum. Helv Chim Acta 91:1888–1893

  33. Li GY, Yang T, Luo YG, Chen XZ, Fang DM, Zhang GL (2009) Brevianamide J, a new indole alkaloid dimer from fungus Aspergillus versicolor. Org Lett 11:3714–3717

  34. Li DL, Li XM, Proksch P, Wang BG (2010) 7-O-Methylvariecolortide A, a new spirocyclic diketopiperazine alkaloid from a marine mangrove derived endophytic fungus, Eurotium rubrum. Nat Prod Commun 5:1583–1586

  35. Li Y, Sun KL, Wang Y, Fu P, Liu PP, Wang C, Zhu WM (2013) A cytotoxic pyrrolidinoindoline diketopiperazine dimer from the algal fungus Eurotium herbariorum HT-2. Chin Chem Lett 24:1049–1052

  36. Liu J, Gu B, Yang L, Yang F, Lin H (2018) New anti-inflammatory cyclopeptides from a sponge-derived fungus Aspergillus violaceofuscus. Front Chem 6:226

  37. Liu W, Wang L, Wang B, Xu Y, Zhu G, Lan M, Zhu W, Sun K (2019) Diketopiperazine and diphenylether derivatives from marine algae-derived Aspergillus versicolor OUCMDZ-2738 by epigenetic activation. Mar Drugs 17:6

  38. Ma YM, Liang XA, Kong Y, Jia B (2016) Structural diversity and biological activities of indole diketopiperazine alkaloids from fungi. J Agr Food Chem 64:6659–6671

  39. May Zin WW, Buttachon S, Dethoup T, Fernandes C, Cravo S, Pinto MMM, Gales L, Pereira JA, Silva AMS, Nazim S, Kijjoa A (2016) New cyclotetrapeptides and a new diketopiperzine derivative from the marine sponge-associated fungus Neosartorya glabra KUFA 0702. Mar Drugs 14:136

  40. Miao FP, Li XD, Liu XH, Cichewicz RH, Ji NY (2012) Secondary metabolites from an algicolous Aspergillus versicolor strain. Mar Drugs 10:131–139

  41. Ortiz A, Sansinenea E (2017) Cyclic dipeptides: secondary metabolites isolated from different microorganisms with diverse biological activities. Curr Med Chem 24:2773–2780

  42. Paz Z, Komon-Zelazowska M, Druzhinina IS, Aveskamp MM, Shnaiderman A, Aluma Y, Carmeli S, Ilan M, Yarden O (2010) Diversity and potential antifungal properties of fungi associated with a Mediterranean sponge. Fungal Divers 42:17–26

  43. Peng J, Zhang XY, Tu ZC, Xu XY, Qi SH (2013) Alkaloids from the deep-sea-derived fungus Aspergillus westerdijkiae DFFSCS013. J Nat Prod 76:983–987

  44. Peng J, Gao H, Li J, Ai J, Geng M, Zhang G, Zhu T, Gu Q, Li D (2014) Prenylated indole diketopiperazines from the marine-derived fungus Aspergillus versicolor. J Org Chem 79:7895–7904

  45. Quang TH, Lee DS, Sohn JH, Kim YC, Oh H (2013) New deoxyisoaustamide derivative from the marine-derived fungus Penicillium sp. JF-72. B Korean Chem Soc 34:3109–3112

  46. Rateb ME, Ebel R (2011) Secondary metabolites of fungi from marine habitats. Nat Prod Rep 28:290–344

  47. Saleem M, Ali MS, Hussain S, Asharaf M, Lee YS (2007) Marine natural products of fungal origin. Nat Prod Rep 24:1142–1152

  48. Song F, Liu X, Guo H, Ren B, Chen C, Piggott AM, Yu K, Gao H, Wang Q, Liu M, Liu X, Dai H, Zhang L, Capon RJ (2012) Brevianamides with antitubercular potential from a marine-derived isolate of Aspergillus versicolor. Org Lett 14:4770–4773

  49. Tsukamoto S, Kato H, Samizo M, Nojiri Y, Onuki H, Hirota H, Ohta T (2008) Notoamides F − K, prenylated indole alkaloids isolated from a marine-derived Aspergillus sp. J Nat Prod 71:2064–2067

  50. Tsukamoto S, Kato H, Greshock TJ, Hirota H, Ohta T, Williams RM (2009a) Isolation of notoamide E, a key precursor in the biosynthesis of prenylated indole alkaloids in a marine-derived fungus, Aspergillus sp. J Am Chem Soc 131:3834–3835

  51. Tsukamoto S, Kawabata T, Kato H, Greshock TJ, Hirota H, Ohta T, Williams RM (2009b) Isolation of antipodal (−)-versicolamide B and notoamides L − N from a marine-derived Aspergillus sp. Org Lett 11:1297–1300

  52. Tsukamoto S, Umaoka H, Yoshikawa K, Ikeda T, Hirota H (2010) Notoamide O, a structurally unprecedented prenylated indole alkaloid, and notoamides P − R from a marine-derived fungus, Aspergillus sp. J Nat Prod 73:1438–1440

  53. Usami Y, Yamaguchi J, Numata A (2004) Gliocladins A-C and glioperazine; cytotoxic dioxo-or trioxopiperazine metabolites from a Gliocladium sp. separated from a sea hare. Heterocycles 63:1123–1129

  54. Wakefield J, Hassan HM, Jaspars M, Ebel R, Rateb ME (2017) Dual induction of new microbial secondary metabolites by fungal bacterial co-cultivation. Front Microbiol 8:1284

  55. Wang F, Fang Y, Zhu T, Zhang M, Lin A, Gu Q, Zhu W (2008) Seven new prenylated indole diketopiperazine alkaloids from holothurian-derived fungus Aspergillus fumigatus. Tetrahedron 64:7986–7991

  56. Wang FZ, Huang Z, Shi XF, Chen YC, Zhang WM, Tian XP, Li J, Zhang S (2012a) Cytotoxic indole diketopiperazines from the deep sea-derived fungus Acrostalagmus luteoalbus SCSIO F457. Bioorg Med Chem Lett 22:7265–7267

  57. Wang Y, Li ZL, Bai J, Zhang LM, Wu X, Zhang L, Pei YH, Jing YK, Hua HM (2012b) 2, 5-Diketopiperazines from the marine-derived fungus Aspergillus fumigatus YK-7. Chem Biodivers 9:385–393

  58. Wang KT, Xu MY, Liu W, Li HJ, Xu J, Yang DP, Lan WJ, Wang LY (2016) Two additional new compounds from the marine-derived fungus Pseudallescheria ellipsoidea F42-3. Molecules 21:442

  59. Xu J, Hu Q, Ding W, Wang P, Di Y (2018) New asymmetrical bispyrrolidinoindoline diketopiperazines from the marine fungus Aspergillus sp. DX4H. Nat Prod Res 32:815–820

  60. Yamada T, Iwamoto C, Yamagaki N, Yamanouchi T, Minoura K, Yamori T, Uehara Y, Andoh T, Umenmura K, Numata A (2002) Leptosins M-N1, cytotoxic metabolites from a Leptosphaeria species separated from a marine alga. Structure determination and biological activities. Tetrahedron 58:479–487

  61. Yamada T, Iwamoto C, Yamagaki N, Yamanouchi T, Minoura K, Hagishita S, Numata A (2004) Leptosins O-S, cytotoxic metabolites of a strain of Leptosphaeria sp. isolated from a marine alga. Heterocycles 63:641–653

  62. Yan HJ, Li XM, Li CS, Wang BG (2012) Alkaloid and anthraquinone derivatives produced by the marine-derived endophytic fungus Eurotium rubrum. Helv Chim Acta 95:163–168

  63. Yu L, Ding W, Wang Q, Ma Z, Xu X, Zhao X, Chen Z (2017) Induction of cryptic bioactive 2, 5-diketopiperazines in fungus Penicillium sp. DT-F29 by microbial co-culture. Tetrahedron 73:907–914

  64. Zhang M, Wang WL, Fang YC, Zhu TJ, Gu QQ, Zhu WM (2008) Cytotoxic alkaloids and antibiotic nordammarane triterpenoids from the marine-derived fungus Aspergillus sydowi. J Nat Prod 71:985–989

  65. Zhang Y, Mu J, Feng Y, Zhang J, Gu PJ, Wang Y, Ma LF, Zhu YH (2009) Broad-spectrum antimicrobial epiphytic and endophytic fungi from marine organisms: isolation, bioassay and taxonomy. Mar Drugs 7:97–112

  66. Zhong WM, Wang JF, Shi XF, Wei XY, Chen YC, Zeng Q, Xiang Y, Chen XY, Tian XP, Xiao ZH, Zhang WM, Wang FZ, Zhang S (2018a) Eurotiumins A-E, five new alkaloids from the marine-derived fungus Eurotium sp. SCSIO F452. Mar Drugs 16:136

  67. Zhong W, Wang J, Wei X, Chen Y, Fu T, Xiang Y, Huang X, Tian X, Xiao Z, Zhang W, Zhang S, Long L, Wang F (2018b) Variecolortins A-C, three pairs of spirocyclic diketopiperazine enantiomers from the marine-derived fungus Eurotium sp. SCSIO F452. Org Lett 20:4593–4596

  68. Zhou LN, Zhu TJ, Cai SX, Gu QQ, Li DH (2010) Three new indole-containing diketopiperazine alkaloids from a deep-ocean sediment derived fungus Penicillium griseofulvum. Helv Chim Acta 93:1758–1763

  69. Zhuravleva OI, Afiyatullov SS, Denisenko VA, Ermakova SP, Slinkina NN, Dmitrenok PS, Kim NN (2012) Secondary metabolites from a marine-derived fungus Aspergillus carneus Blochwitz. Phytochemistry 80:123–131

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This work was financially supported by the National Natural Science Foundation of China (NSFC Grant Nos. 81673351 and 31330009).

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B-GW provided the idea and revised the manuscript. JC contributed in preparing the manuscript.

Correspondence to Bin-Gui Wang.

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Cao, J., Wang, B. Chemical diversity and biological function of indolediketopiperazines from marine-derived fungi. Mar Life Sci Technol 2, 31–40 (2020). https://doi.org/10.1007/s42995-019-00023-0

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  • Indolediketopiperazines
  • Marine-derived fungi
  • Natural products
  • Chemical diversity
  • Biological function