Next Article in Journal
Post-Harvest Processing Methods Have Critical Roles in the Contents of Active Ingredients of Scutellaria baicalensis Georgi
Next Article in Special Issue
Phytochemical Profiling, Isolation, and Pharmacological Applications of Bioactive Compounds from Insects of the Family Blattidae Together with Related Drug Development
Previous Article in Journal
Investigating the Function of Human Jumping Translocation Breakpoint Protein (hJTB) and Its Interacting Partners through In-Solution Proteomics of MCF7 Cells
Previous Article in Special Issue
Amino-Acid-Conjugated Natural Compounds: Aims, Designs and Results
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 27
Issue 23
10.3390/molecules27238303
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

A Review of Diterpenes from Marine-Derived Fungi: 2009–2021

by
Peng Qiu
1,2,3,†,
Jinmei Xia
2,†,
Haitao Zhang
1,3,*,
Donghai Lin
4,* and
Zongze Shao
2,*
1
Marine Biomedical Research Institution, Guangdong Medical University, Zhanjiang 524023, China
2
Key Laboratory of Marine Biogenetic Resources, Third Institute of Oceanography, Ministry of Natural Resources, Xiamen 361005, China
3
Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang 524023, China
4
Key Laboratory for Chemical Biology of Fujian Province, MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2022, 27(23), 8303; https://doi.org/10.3390/molecules27238303
Submission received: 9 November 2022 / Revised: 20 November 2022 / Accepted: 23 November 2022 / Published: 28 November 2022
(This article belongs to the Special Issue Research Progress and Applications of Natural Products)
Browse Figures
Versions Notes

Abstract

:
Marine-derived fungi are important sources of novel compounds and pharmacologically active metabolites. As an important class of natural products, diterpenes show various biological activities, such as antiviral, antibacterial, anti-inflammatory, antimalarial, and cytotoxic activities. Developments of equipment for the deep-sea sample collection allow discoveries of more marine-derived fungi with increasing diversity, and much progress has been made in the identification of diterpenes with novel structures and bioactivities from marine fungi in the past decade. The present review article summarized the chemical structures, producing organisms and biological activities of 237 diterpenes which were isolated from various marine-derived fungi over the period from 2009 to 2021. This review is beneficial for the exploration of marine-derived fungi as promising sources of bioactive diterpenes.

1. Introduction

As the largest part of the Earth’s surface area, the ocean contains resources worthy of in-depth exploration. Marine-derived fungi, which are rich sources of secondary metabolites, have great potential for the discovery of bioactive compounds. The number of new compounds derived from marine fungi is increasing every year, from 287 in 2012 [1] to 724 in 2019 [2]. The contribution of marine fungi in marine-derived compounds is also increasing, from 27.7% in 2012 to 48.6% in 2019 [3,4,5,6,7,8] (Figure 1).
The marine fungi-derived compounds are of very diverse types, which include alkaloids [9], terpenes [10], polyketones [11], peptides [12], etc. As a major class of secondary metabolites of marine fungi, terpenes show many excellent activities [13]. Diterpenes are a group of terpenes with various bioactivities and rich structural diversity [10].
There are quite a few review articles on the isolation, structure elucidation, and biological activities of diterpenes. Hanson James R. has been publishing reviews of new diterpenoids discovered every year since 1984 [14] and the latest report was published in 2009 [15]. After that, Hanson began to limit the scope of the reviews to terrestrial diterpenoids and the first report was published in 2011 [16]. His serial review articles were then published almost every year and the latest one was published in 2019 [17]. These review articles offer important information for newly found diterpenoids of terrestrial origin. In contrast, no such systematic and up-to-date review articles are available for marine-derived diterpenes.
In recent years, more and more research articles have reported works on the discovery of new diterpenes from marine-derived fungi. Expectedly, a review of these works will help to better understand recent discoveries and advances in this field. Herein, we summarize the structures and activities of newly discovered diterpenes derived from marine fungi in the past 13 years from 2009 to 2021.

2. Characteristics of Diterpenes from Marine-Derived Fungi

From 2009 to 2021, 237 new diterpenes were isolated from 47 strains of marine fungi that belong to 15 genera (Actinomadura, Arthrinium, Aspergillus, Botryotinia, Curvularia, Eupenicillium, Eutypella, Epicoccum, Micromonospora, Mucor, Neosartorya, Penicillium, Stachybotrys, Talaromyces, and Trichoderma). The pie chart in Figure 2A shows the distribution of the genera of the fungi covered in the 59 articles that reported newly discovered diterpenes. In these articles, Penicillium (25%), Aspergillus (20%), and Trichoderma (19%) are the most frequently studied genus. A total of 38 articles reported diterpenes from fungi of these three genera. Regarding the number of compounds, Botryotinia (34%), Penicillium (19%), and Aspergillus (16%) are the most productive, producing 80, 45, and 38 of new diterpenes, respectively (Figure 2B).
Of the 237 new compounds, 68 compounds were reported to possess various bioactivities (Table 1). A total of 70 pieces of activity data are available since both compounds 38 and 202 were reported to possess two kinds of bioactivities. Cytotoxic activity is the most reported bioactivity, with 25 of 70 compounds (compounds with more than one kind of activity were also counted more than once) (36%, Figure 3) being active. Antibacterial activity (20%), inhibition of enzymes (14%), antiviral activity (7%), and inhibition of the germination of seeds (7%) were the next, with the number of active compounds being 14, 10, 5, and 5, respectively.

3. Isolation, Structures, and Bioactivities of Marine Fungi-Derived Diterpenes

3.1. Actinomadura

Only one new diterpene was reported to be produced by the genus Actinomadura since 2009 (1, Figure 4). Compound JBIR-65 (1) was obtained from the sponge-derived fungus Actinomadura sp. SpB081030SC-15 [49]. This is the first report of a diterpene isolated from the genus Actinomadura. This work found that compound JBIR-65 possessed an ability to protect neuronal hybridoma N18-RE-105 cells from L-glutamate toxicity with an EC50 value of 31 µM (Table 1).

3.2. Arthrinium

Eight new diterpenes were reported for the genus Arthrinium (2–9, Figure 4). Five diterpenoids, arthritis A–D (2–5) and myrocin D (6) were isolated from the sponge-derived fungus Arthrinium sp. [50]. The bioactivity test revealed that myrocin D (6) had antitumor activity, it inhibited vascular endothelial growth factor A (VEGF-A)-dependent endothelial cell sprouting with an IC50 value of 2.6 µM, while the IC50 value for the positive control, sunitinib, was 0.12 µM.
In addition, in another fungus, Arthrinium sacchari, which was isolated from the sponge surface, researchers obtained three new diterpenes: myrocin D (7), libertellenone E (8), and libertellenone F (9) [55]. Antitumoral potentials of compounds 7–9 were tested in an in vitro angiogenesis assay against human umbilical vascular endothelial cell (HUVEC) sprouting induced by VEGF-A, but no positive result was obtained.
It is worth noticing that both compounds 6 and 7 were named myrocin D. They were identified from different strains of Arthrinium by different researchers. The coincidence may be explained by the close timing of submission and acceptance of the two articles, which were published in different journals [50,55].

3.3. Aspergillus

From 2009 to 2021, 12 articles reported the discovery of 38 new diterpenes (10–47, Figure 5) from marine Aspergillus, accounting for over one-fifth of the total articles. Aspergillus of marine origin is an important source of active compounds. More than 170 of 232 compounds isolated from marine Aspergillus from 2006 to 2016 showed cytotoxic and antimicrobial activities [56].
Li et al. isolated the fungus Aspergillus wentii SD-310 from deep-sea sediments. Further investigation of its products led to the isolation of 18 new diterpenes (10–27), including two new tetranorlabdane diterpenes, asperolides D (10) and E (11) [33]. Compound 10 had moderate inhibitory activities against Edwardsiella tarda, with an MIC value of 16 µg/mL (Table 1). Chloramphenicol and ampicillin were used as positive controls, with MIC values being 8.0 and 2.0 µg/mL, respectively.
The 18 new compounds also include nine 20-nor-isopimarane diterpenoids, aspewentins D−L (12–20), and a new methylated derivative, aspewentin M (21) [34,42]. The pimarane diterpenes were reported to have a wide range of biological activities including antimicrobial, antifungal, antiviral, phytotoxic, phytoalexin, cytotoxic, and antispasmodic effects [57]. An activity test showed that compound 12 and compounds 14–16 have inhibitory activities against aquatic pathogens Edwardsiella tarda, Micrococcus luteus, Pseudomonas aeruginosa, Vibrio harveyi, and V. parahemolyticus, each with an MIC value of 4.0 µg/mL. Compounds 12 and 16 showed inhibitory activities against the plant pathogen Fusarium graminearum, with MIC values of 2.0 and 4.0 µg/mL, respectively. Notably, these two compounds were more potent than the positive control, amphotericin B (MIC of 8.0 µg/mL). Compounds 17 and 18 showed inhibitory effects against zoonotic pathogenic bacteria between human and aquatic animals such as Escherichia coli, Edwardsiella tarda, Vibrio harveyi, and V. parahaemolyticus. Compound 21, which may prove useful as an antifungal agent, exhibited potent antimicrobial activities against some plant pathogenic fungi, such as Fusarium graminearum.
Another 6 of the 18 new compounds produced by the strain Aspergillus wentii SD-310 were isopimarane diterpenoids, wentinoids A–F (22–27) [57]. This is the first report on the isolation of isopimarane diterpenoids from the species Aspergillus wentii. The antibacterial activities of these compounds were evaluated. Compound 22 had inhibitory effects on Fusarium. oxysporum f. sp. lycopersici, Phytophthora parasitica, Fusarium graminearum, and Botryosphaeria dothidea, with MIC values of 4.0, 8.0, 1.0, and 4.0 µg/mL, respectively, which were comparable to that of the positive control, amphotericin B (MIC values being 1.0, 2.0, 1.0, and 2.0 µg/mL, respectively) [57].
Indole diterpenoids are an important group of diterpenoids with diverse bioactivities [58]. The mining of the metabolites of the sponge-derived fungus Aspergillus candidus HDN15-152 resulted in the isolation and identification of four new indole diterpenoids, ascandinines A–D (28–31) [18]. Compounds 29–31 are diterpenes with rare 6/5/5/6/6/6/6 fused ring systems. Compound 30 displayed an anti-influenza virus A (H1N1) activity with an IC50 value of 26 µM (ribavirin as the positive control, IC50 = 31 µM), while compound 31 showed cytotoxicity against HL-60 cells with an IC50 value of 7.8 µM (Table 1) [18].
Sun et al. obtained three new norditerpenoids, asperolides A–C (32–34), from a brown algal-derived fungus Aspergillus wentii EN-48 [59].
New diterpenes were also found from the fermentation of the fungus Aspergillus wentii na-3, which was isolated from the surface of Sargassum alagl [51]. A chemical epigenetic manipulation strategy was used to turn on the silent metabolic pathways. A histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), was added to the medium, and three new norditerpenes (35–37) were obtained [51].
In addition, the inhibitory effects of compounds 35–36 on the growth of one marine zooplankton (Artemia salina) and three marine phytoplankton species (Chattonella marina, Heterosigma akashiwo, and Alexandrium sp.) were evaluated. The results showed that compound 36 inhibited the growth of Artemia salina with an LC50 of 6.36 µM, and compound 35 was active against Chattonella marina and Heterosigma akashiwo, with LC50 values of 0.81 and 2.88 µM, respectively.
Sun et al. isolated two indole diterpenes, (2R, 4bR, 6aS, 12bS, 12cS, 14aS)-4b-Deoxy-β-aflatrem (38), and (2R, 4bS), 6aS, 12bS, 12cR)-9-Isopentenylpaxilline D (39), from the Penaeus vannamei-derived fungus Aspergillus flavus OUCMDZ-2205 [19]. Compounds 38 and 39 were cytotoxic to the A-549 cell cycle in the S phase with IC50 values of 10 µM. Besides, compound 38 had an inhibitory effect on the kinase PKC-β with an IC50 value of 15.6 µM, which was effective in attenuating vascular complications of diabetes.
Two new indole diterpenes derivatives asporyzins A–B (40–41), one new indole diterpenes asporyzin C (42), and three known related indole diterpenes were isolated from the red algae-derived fungus Aspergillus oryzae. These three new compounds did not show antibacterial activity against Escherichia coli and antifungal activity against plant pathogens Colletotrichum lagenarium and Fusarium oxysporum [60].
Zhang et al. isolated two indole diterpenes, 19-hydroxypenitrem A (43) and 19-hydroxypenitrem E (44), from a red alga-derived fungus Aspergillus nidulans EN-330 [61]. In the assay for antibacterial activity against pathogens Edwardsiella tarda, Vibrio anguillarum, Escherichia coli, and Staphylococcus aureus, compound 43 showed activities with MIC values of 16, 32, 16, and 16 µg/mL, respectively, comparing with 16, 0.5, 2, and 2 µg/mL of the positive control, chloramphenicol [35]. Compound 44 lacks a chlorine atom compared with compound 43 and is much less active, indicating that the Cl substitution on C-6 might enhance the antimicrobial activity and the cytotoxic activity against brine shrimp (Artemia salina L.) larvae, which was consistent with previous studies [61].
Marwa Elsbaey et al. isolated two new oxoindolo diterpenes, anthcolorin G (45) and anthcolorin H (46), from a mangrove-derived fungus Aspergillus versicolor [20]. Their biological activities were evaluated on HeLa cells, and only compound 46 showed activity with an IC50 value of 43.7 µM.
Zhang et al. isolated a new indole diterpene, (3R, 9S, 12R, 13S, 17S, 18S)-2-carbonyl3-hydroxylemeniveol (47) from a marine fungus Aspergillus versicolor ZZ761 [36]. The biological activity test using Escherichia coli and Candida albicans showed MIC values of 20.6 and 22.8 µM, respectively.

3.4. Botryotinia

Botryotinia has previously been studied more as a plant pathogenic fungus than as a natural product producer [62]. The investigation of a marine Botryotinia strain, Botryotinia fuckeliana MCCC 3A00494, led to the isolation of 80 new diterpenes (48–127, Figure 6).
Botryotinia fuckeliana MCCC 3A00494 was isolated from the deep sea at −5572 m. A new pimarane diterpenoid with a Δ9(11) double bond, botryopimarene A (48), which was rarely discovered in the pimarane family, was obtained from its fermentation [63].
Another 71 new diterpenes A1–A71 (49–119), all belonging to aphidicolin congeners, were also obtained from the same strain [21]. Compounds 102–106 and 107–113 are novel 6/6/5/6/5 pentacyclic aphidicolanes featuring tetrahydrofuran and dihydrofuran rings, respectively. In addition, compounds 114–119 are rare noraphidicolins. Significantly, aphidicolin A8 (56) showed good activities against T24 and HL-60 cells, with IC50 values of 2.5 and 6.1 µM, respectively. Thus, compound 56 can serve as a potent cytotoxic lead compound.
The potential of the strain MCCC 3A00494 in producing diverse diterpenes was more than that. Further investigation of its products led to the isolation of eight more new diterpenes. They represent three new carbon skeletons with 6/6/5/5 (120), 6/6/5/6 (121–125), and 6/6/6/5 (126–127) tetracyclic scaffolds. In terms of biological activity, compound 120 showed anti-allergic activity with an IC50 value of 0.2 mM (loratadine as the positive control with an IC50 of 0.1 mM) [53].

3.5. Curvularia

Only one new diterpene was produced by the genus Curvulari since 2009 (128, Figure 7). An investigation of extracts from the coral-derived fungus Curvularia hawaiiensis TA26-15 afforded one new sordaricin tetracyclic diterpene, sordaricin B (128), together with two known analogs, moriniafungin and sordaricin [64]. Their antifungal, antibacterial, and antiviral activities were tested. Moriniafungin and sordaricin showed antifungal activities against Candida albicans ATCC10231 with MIC values of 24 and 18 µM, whereas sordaricin B (128) did not show observable biological activity.

3.6. Eupenicillium

Zheng et al. isolated three new indole diterpenes, penicilindoles A–C (129–131, Figure 7), from a mangrove-derived fungus Eupenicillium sp. HJ002 [22]. Cytotoxic activities of all compounds against human A-549, HeLa, and HepG2 cell lines were evaluated by the MTT method. Compound 129 displayed biological activities against human A-549 and HepG2 cell lines with IC50 values of 5.5 and 1.5 µM, respectively. These values for the positive control, adriamycin, were 0.002 and 0.1 µM, whereas for 5-fluoracil, 36.8 and 76.9 µM, respectively.

3.7. Eutypella

Seven diterpene compounds were produced by the genus Eutypella since 2009 (132–138, Figure 7). Sun et al. isolated five new oxygenated pimarane diterpenes from a marine sediment-derived fungus Eutypella scoparia FS26, which were named scopararanes C–G (132–136). The biological activities of these compounds were evaluated on three human cell lines, including SF-268 (human glioma cell line), MCF-7 (human breast adenocarcinoma cell line), and NCI-H460 (human non-small cell lung cancer cell line) [65]. The results showed that compounds 132 and 133 exhibited weak cytotoxicity against the MCF-7 cell line with IC50 values of 35.9 and 25.6 µM, respectively.
Liu et al. isolated two new pimarane-type diterpenes, named scopararanes H–I (137–138), from a marine sediment-derived fungus Eutypella sp. FS46, which was collected at a depth of −292 m [24]. Compound 138 showed moderate inhibitory activities against NCI-H460 and SF-268 cell lines with IC50 values of 13.59 and 25.31 µg/mL, respectively.

3.8. Epicoccum

The genus Epicoccum generated four diterpenes (139–142, Figure 7). Xia et al. isolated three new pimarane-type diterpenes, compounds 139–141, from a marine-derived fungus Epicoccum sp. HS-1. All isolated compounds were tested for cytotoxicity against KB (human epidermis carcinoma cell line) and KBv200 (a classic multidrug-resistant cell line) cells [25]. Compounds 139 and 140 inhibited the growth of KB cells with IC50 values of 3.51 and 20.74 µg/mL, and the growth of KBv200 cells with IC50 values of 2.34 and 14.47 µg/mL, respectively. As the positive control, cisplatin showed cytotoxic activities against KB and KBv200 cell lines with IC50 values of 0.96 and 0.76 µM, respectively.
Xia et al. also isolated another new isopimarane diterpene from the same strain, naming it isopimarane diterpene (142) [43]. In the bioactivity assay, compound 142 exhibited α-glucosidase inhibitory activity with an IC50 value of 4.6 µM. Isopimarane diterpenes were reported to have biological activities such as antiviral, cytotoxic, etc. This is the first report on the α-glucosidase inhibition activity of isopimarane diterpenes. Compound 142 might be applied for the treatment of type 2 diabetes.

3.9. Micromonospora

The genus Micromonospora produced three new diterpene compounds (143–145, Figure 7). Mullowney et al. isolated a novel Δ8,9-pimarane diterpene, named isopimara-2-one-3-ol-8,15-diene (143), from a sediment-derived fungus Micromonospora sp. [66].
Micromonospora sp. WMMC-218 is a fungus derived from the marine ascidian Symlegma brakenhielmi. LC-MS-based metabolomics was used and showed that the secondary metabolite profile of the strain is unique. Further investigation of the fermentation led to the isolation of two new halimane-type diterpenoid micromonohalimanes A (144) and B (145) [37]. This is the first time that halimane-type diterpenes isolated from the genus Micromonospora. In terms of activity, compound 145 displayed an inhibitory effect on the methicillin-resistant Staphylococcus aureus with an MIC value of 40 µg/mL, compared with the MIC value of 1 µg/mL for the positive control, vancomycin.

3.10. Mucor irregularis

The genus Mucor yielded six diterpenes (146–151, Figure 7), which are all indole diterpenes. They were discovered by Gao et al. and were named rhizovarins A–F (146–151). The producing strain Mucor irregularis QEN-189 was isolated from mangroves. Among these compounds, rhizovarins A–C, with the unique 4/6/6/8/5/6/6/6/6 nine-ring structure and a rare acetal, have the most complex structure among the indole diterpenes reported before 2016 [26].
Activities of compounds 146–151 were assessed on human A-549 and HL-60 cancer cell lines. Compounds 146, 147, and 151 showed biological activities against the A-549 cancer cell line with IC50 values of 11.5, 6.3, and 9.2 µM, respectively, compared with 0.30 µM of adriamycin as the positive control. Compounds 146 and 147 were active against the HL-60 cancer cell line with IC50 values of 9.6 and 5.0 µM, respectively, compared with 0.067 µM of adriamycin.

3.11. Neosartorya

Only one diterpene was produced by the genus Neosartorya since 2009 (152, Figure 8). The new compound, a meroditerpene, sartorypyrone C (152), was obtained from a rare sponge-derived fungus Neosartorya paulistensis. The antibacterial activity of sartorypyrone C against four reference strains (Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa) was tested, but no significant activity was observed [67].

3.12. Penicillium

As an important source of bioactive secondary metabolites, Penicillium produced many diterpenes with novel structures [10]. From 2009 to 2021, 15 articles reported the discovery of 45 new diterpenes (153–197, Figure 8) from marine Penicillium.
Six new diterpenes, named conidiogenones B–G (153–158), were obtained from a deep-sea sediment-derived fungus Penicillium sp. F23-2 [27]. Their cytotoxic activities were evaluated on HL-60, A-549, BEL-7402, and MOLT-4 cell lines. To the A-549 cell line, compounds 153 and 157 showed weak cytotoxicity with IC50 values of 40.3 and 42.2 µM, respectively, while compounds 155, 156, and 158 displayed much stronger cytotoxicity with IC50 values of 9.3, 15.1, and 8.3 µM, respectively. To the HL-60 cell line, compounds 153 and 157 showed weak cytotoxicity with IC50 values of 28.2 and 17.8 µM, respectively, while compounds 155, 156, and 158 exhibited much stronger cytotoxicity with IC50 values of 5.3, 8.5, and 1.1 µM, respectively. Compound 154 showed ultra-high activity against the HL-60 cell line with an IC50 value of 0.038 µM. In addition, it also displayed ultra-high activity against the BEL-7402 cell line with an IC50 value of 0.97 µM, while compounds 155, 157, and 158 showed moderate to weak activities against the same cell line with IC50 values of 11.7, 17.1, and 43.2 µM, respectively. Only compounds 155, 157, and 158 showed biological activities against the MOLT-4 cell line with IC50 values of 21.1, 25.8, and 4.7 µM, respectively.
By activity tracing, Gao et al. isolated two unusual diterpenes cyclopiasconidiogenones H and I (159 and 160) from a red alga-derived fungus Penicillium chrysogenum QEN-24S [68]. However, the two compounds did not show biological activity in the antimicrobial test.
Six novel indole diterpenoids (161–166) were obtained from a mangrove-derived fungus Penicillium camemberti OUCMDZ-1492 [47]. Among them, compounds 161–163 and 165 exhibited weak activities against the H1N1 virus, with IC50 values of 28.3, 38.9, 32.2, and 73.3 µM, respectively.
A novel spirotetracyclic diterpene with a 5/5/5/5 spiro-carbon skeleton structure, named spirograterpene A (167), was obtained from the deep-sea fungus Penicillium granulatum MCCC 3A00475 [23]. Spirograterpene A showed anti-allergic effects on immunoglobulin E (IgE)-mediated rat mast RBL-2H3 cells. Its inhibition rate was 18% at 20 µg/mL. This data of loratadine serving as a positive control was 35% at the same concentration.
Three new indole diterpenes, 22-hydroxylshearinine F (168), 6-hydroxylaspalinine (169), and 7-O-acetylemindole SB (170), were obtained from a sea-anemone-derived fungus, Penicillium sp. AS-79 [38]. Among them, compound 169 was active against the aquatic pathogen Vibrio parahaemolyticus with an MIC of 64.0 µg/mL, compared with 0.5 µg/mL for the positive control chloromycetin.
Moreover, three new cyclopiane diterpenes (161–173) were isolated from a deep-sea fungus Penicillium commune MCCC 3A00940. They all contain a rigid 6/5/5/5 fused tetracyclic ring framework, which is rare in nature [69].
Cheng et al. also isolated three cyclopiane diterpenes (174–176) from a deep-sea sediment-derived fungus Penicillium sp. YPGA11 [70]. The compound conidiogenol D (175) showed weak cytotoxic activity against five esophageal cancer cell lines (EC109, KYSE70, EC9706, KYSE30, and KYSE450) with IC50 values ranging from 25 to 55 µM.
Furthermore, 15 indole diterpenes (177–191) were successively obtained from the Penicillium sp. KFD28, a fungus derived from bivalve mollusk [28,44,45,71]. Compound 178 represents the first indole diterpenoid with a unique pyridine-containing heptacyclic ring system. Compound 181 is an indole diterpenoid with a unique 6/5/5/6/6/5/5 heptacyclic system. Compound 183 contains an additional oxygen atom between C-21 and C-22 compared to paxilline, and thus, forms an unusual 6/5/5/6/6/7 hexacyclic ring system bearing a 1,3-dioxepane ring, which is rarely encountered in natural products. Compounds 177, 178, 181, 182, 184, 185, and 190 showed potent inhibitory activities against protein tyrosine phosphatase (PTP1B) with IC50 values of 1.7, 2.4, 14, 27, 23, 31.5, and 9.5 µM, respectively, compared with 1.6 µM for the positive control, Na3VO4. Compound 189 had a weak activity against HeLa cells with an IC50 value of 36.3 µM, whereas the value for the positive control, cisplatin, was 8.6 µM.
An indole diterpene, named penicindopene A (192), was obtained from the fungus Penicillium sp. YPCMAC1, collected at a depth of −4500 m in the western Pacific Ocean [29]. This is the first report of indole diterpenes containing a 3-hydroxy-2-indolone moiety. Penicindopene A also showed moderate cytotoxic activities against A-549 and HeLa cell lines with IC50 values of 15.2 and 20.5 µM, respectively.
In addition, Penicillium thomii YPGA3, Penicillium sp. YPGA11, and Penicillium sp. YPCMAC1 were all derived from the deep-sea water at a depth of −4500 m in the Yap Trench (West Pacific Ocean). A rare 19-nor labdane-type diterpenoid, named penitholabene (193), was isolated from Penicillium thomii YPGA3 [46]. This represents the first 19-nor labdane-type diterpenoid found in nature. It showed an inhibitory effect against α-glucosidase with an IC50 value of 282 µM, being more active than the positive control, acarbose (1330 µM).
A new pimarane diterpene, named diaporthein C (194), was obtained from a sea slug gut-derived fungus, Penicillium sclerotiorum GZU-XW03-2 [72]. This is the third pimarane diterpene identified with a Δ8(9) double bond.
Three unreported cyclopiane diterpenes (195–197) were obtained from the deep-sea sediment fungus Penicillium sp. TJ403-2 [73]. The anti-inflammatory activities of these compounds were evaluated. Compound 195 could significantly reduce LPS-induced NO production with an IC50 value of 2.19 mM, which was only one-third of that of the positive control, indomethacin.

3.13. Stachybotrys

Three new diterpenes were generated by the genus Stachybotrys (198–200, Figure 9). These compounds, named stachatranones A–C (198–200), are all of the dolabelllane-type. They were isolated from a coral-derived fungus Stachybotrys chartarum TJ403-SS6 [39]. Stachatranone B exhibited an inhibitory effect on Acinetobacter baumannii with an MIC value of 16 µg/mL, compared with 2 and 8 µg/mL for the positive controls, amikacin and vancomycin, respectively. Stachatranone B also showed an inhibitory effect on Enterococcus faecalis with an MIC value of 32 µg/mL, compared with 0.5 µg/mL for vancomycin.

3.14. Talaromyces

Only one new diterpene was produced by the genus Talaromyces (201, Figure 9). The compound, roussoellol C (201), was obtained from the fungus Talaromyces purpurogenus PP-414 isolated from a beach in Qinhuangdao, Hebei Province [74]. It was cytotoxic to MCF-7 cells with an IC50 of 6.5 µM.

3.15. Trichoderma

Marine-derived fungi of the Trichoderma genus have produced many structurally novel natural products with diverse bioactivities [75]. From 2009 to 2021, 11 articles reported the discovery of 27 new diterpenes (202–228, Figure 9) from marine Trichoderma.
A new harziane dieterpene harzianone (202) was isolated from a seaweed endophytic fungus Trichoderma longibrachiatum [40]. It displayed antibacterial effects on Escherichia coli and Staphylococcus aureus at 30 µg/disk (inhibitory diameters of 8.3 and 7.0 mm, respectively), while chloramphenicol as the positive control showed inhibitory diameters of 22 mm at 20 µg/disc. In addition, harzianone showed 82.6% of lethality in brine shrimp (Artemia salina L.) larvae at 100 µg/mL.
Xie et al. detected unusual signals in the 13C NMR spectra recorded on the fractions of the fungus Trichoderma erinaceum [76], and thereafter identified a new diterpene trichodermaerin (203) in the subsequent fermentation and isolation.
A novel diterpene trichocitrin (204) was isolated from the culture of the fungus Trichoderma citrinoviride cf-27 isolated from the seaweed surface. This represents both the first report of the isolation of a fusicoccane diterpene from Trichoderma, and the first discovery of a furan-bearing fusicoccane diterpene. At 20 µg/disk, trichocitrin formed an 8.0 mm inhibition zone against Escherichia coli [41]. Later, a fungus, Trichoderma asperellum cf44-2, was isolated from the alga collected in the same batch. Additionally, an unreported diterpene, named 11-hydroxy-9-harzien-3-one (205), was isolated from the fermentation of this fungus [77].
Two harziane diterpenoids (206–207) were isolated from a mangrove-derived fungus, Trichoderma sp. Xy24 [31]. Compound 206 exhibited low cytotoxic activities against the HeLa and MCF-7 cell lines with IC50 values of 30.1 and 30.7 mM, respectively.
Six new diterpenes, trichodermanins C–H (208–213), with a rare fused 6/5/6/6 ring system, were isolated from a sponge-derived fungus Trichoderma harzianum OUPS-111D-4 [32,78]. Trichodermanin C had significant cytotoxic activities against P388, HL-60, and L1210 cell lines with IC50 values of 7.9, 6.8, and 7.6 µM, respectively, compared with 6.1, 5.1, and 4.5 µM for the positive control, 5-fluorouraci. Compound 211 showed weak cytotoxic activities against these cell lines with IC50 values exceeding 40 µM.
Two new diterpenes, named 3R-hydroxy-9R,10R-dihydroharzianone (214), and 11R-methoxy-5,9,13-proharzitrien-3-ol (215), were isolated from the fungus Trichoderma harzianum X-5 derived from the surface of a brown alga Laminaria japonica [52]. Among them, compound 215 has a bicyclic skeleton that is rarely reported. The growth-inhibitory effects of these two compounds were tested on four phytoplankton species, Chattonella marina, Heterosigma akashiwo, Karlodinium veneficum, and Prorocentrum donghaiense. Compound 214 had inhibitory activity against Chattonella marina with an IC50 value of 7.0 µg/mL. Compound 215 displayed an excellent inhibitory effect on the growth of all four kinds of phytoplankton, with IC50 values of 1.2, 1.3, 3.2, and 4.3 µg/mL, respectively, compared with 0.46, 0.98, 0.89, and 1.9 µM for the positive control, K2Cr2O7.
Five new diterpenes, named harzianones A–D (216–219) and harziane (220), were isolated from a soft coral-derived fungus, Trichoderma harzianum XS 20,090,075 [48]. Compounds 216–220 were extremely phytotoxic, inhibiting the germination of amaranth and lettuce seeds at a concentration of 200 ppm. This is the first time that phytotoxic compounds were isolated from Trichoderma.
Three new harziane derivatives 3S-hydroxy-9R,10R-dihydroharzianone, 3S-hydroxytrichodermaerin, and methyl 3S-hydroxy-10,11-seco-harzianate (221–223) were isolated from an algicolous fungus, Trichoderma asperelloides RR-dl-6-11 [79]. This is the first work reporting secondary metabolites of Trichoderma asperelloides. The compounds were tested for inhibitory activity against four marine bacteria Vibrio anguillarum, V. harveyi, V. parahemolyticus, and V. splendidus. At 100 µg/disc, compounds 221–223 did not show any observable inhibitory effect against any of the tested marine bacteria.
Five new harziane-type diterpenes named harzianols K–O (224–228) were obtained from a deep-sea sediment-derived fungus, Trichoderma sp. SCSIOW21 [54]. Compound 225 had a strong anti-inflammatory effect. It showed a NO inhibition rate of 81.8% at 100 µM.

3.16. Others

In addition to the 15 genera mentioned above, there are also some marine fungi whose taxonomic status has not been determined, but their secondary metabolites have been obtained and studied. Nine new diterpenoids were reported to be produced by unidentified marine fungi (229–237, Figure 10). They were named phomactin I (229), 13-epi-phomactin I (230), phomactin J (231), phomactins K–M (232–234), and phomactins N−P (235–237). They were isolated by Masahiro Ishino et al. from a fungus of unknown red algal origin [80,81,82]. HUVECs, NHDF (normal human dermal fibroblasts) cells, and HeLa cells were used to test the cytotoxicity of these compounds. However, they did not show any observable cytotoxic effect.

4. Conclusions

This review provides a comprehensive overview of the structures and activities of 237 new diterpenes discovered from 47 strains of marine-derived fungi from 2009 to 2021. The articles reporting Penicillium, Aspergillus, and Trichoderma accounted for the majority (64%) of all the relevant publications. The numbers of diterpenes isolated from the four genera Botryotinia (80), Penicillium (45), Aspergillus (38), and Trichoderma (27) are the top four. It is noteworthy that 80 new diterpenes were isolated from a single strain of the genus Botryotinia, 71 of which are aphidicolin congeners. After aphidicolanes, indole-type diterpenes (46) are the most numerous diterpenes, followed by pimarane-type (29), harziane-type (16), and cyclopiane-type (9) diterpenes. Among the bioactive compounds, the compounds with cytotoxic activity were the most, accounting for 36%, followed by compounds with antibacterial effects, accounting for 20%. The compound with the most notable cytotoxicity is conidiogenone C (154), which showed cytotoxic activities in HL-60 and BEL-7402 cell lines, with IC50 values of 0.038 and 0.97 µM, respectively. The compound with the most promising antimicrobial activity is aspewentin D (12). It showed inhibitory activity against Edwardsiella tarda and Vibrio harveyi with MIC values of 2.0 and 4.0 µg/mL, respectively. These marine-derived diterpenes show rich structural diversities and bioactivities. The reported compounds partially uncovered the untapped potential of marine fungi as diterpene producers.

Author Contributions

Conceptualization, J.X. and P.Q.; formal analysis, P.Q.; writing—original draft preparation, P.Q. and J.X.; writing—review and editing, J.X., D.L. and Z.S.; visualization, P.Q.; supervision, J.X., H.Z. and Z.S.; funding acquisition, J.X., D.L. and Z.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Natural Science Foundation of China (41906104), the Scientific Research Foundation of the Third Institute of Oceanography MNR (2022007, 2019021), the COMRA program (DY135-B-01), and the Open Funding Project of the Key Laboratory of Systems Bioengineering (Ministry of Education) (2022001, 2022002).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

HDAC, Histone deacetylase; HUVEC, Human umbilical vascular endothelial cells; LC-MS, Liquid chromatography-mass spectrometry; NHDF, Normal human dermal fibroblasts; NMR, Nuclear magnetic resonance; PKC, Protein kinase C; RBL, Rat basophilic leukemia; SAHA, Suberoylanilide hydroxamic acid; VEGF-A, Vascular endothelial growth factor A.

References

  1. Blunt, J.W.; Copp, B.R.; Keyzers, R.A.; Munro, M.H.; Prinsep, M.R. Marine natural products. Nat. Prod. Rep. 2014, 31, 160–258. Available online: https://www.ncbi.nlm.nih.gov/pubmed/24389707 (accessed on 9 November 2022). [PubMed] [Green Version]
  2. Carroll, A.R.; Copp, B.R.; Davis, R.A.; Keyzers, R.A.; Prinsep, M.R. Marine natural products. Nat. Prod. Rep. 2021, 38, 362–413. Available online: https://www.ncbi.nlm.nih.gov/pubmed/33570537 (accessed on 9 November 2022). [PubMed]
  3. Blunt, J.W.; Copp, B.R.; Keyzers, R.A.; Munro, M.H.G.; Prinsep, M.R. Marine natural products. Nat. Prod. Rep. 2017, 34, 235–294. Available online: https://www.ncbi.nlm.nih.gov/pubmed/28290569 (accessed on 9 November 2022).
  4. Blunt, J.W.; Carroll, A.R.; Copp, B.R.; Davis, R.A.; Keyzers, R.A.; Prinsep, M.R. Marine natural products. Nat. Prod. Rep. 2018, 35, 8–53. Available online: https://www.ncbi.nlm.nih.gov/pubmed/29335692 (accessed on 9 November 2022). [PubMed] [Green Version]
  5. Carroll, A.R.; Copp, B.R.; Davis, R.A.; Keyzers, R.A.; Prinsep, M.R. Marine natural products. Nat. Prod. Rep. 2019, 36, 122–173. Available online: https://www.ncbi.nlm.nih.gov/pubmed/30663727 (accessed on 9 November 2022). [PubMed] [Green Version]
  6. Carroll, A.R.; Copp, B.R.; Davis, R.A.; Keyzers, R.A.; Prinsep, M.R. Marine natural products. Nat. Prod. Rep. 2020, 37, 175–223. Available online: https://www.ncbi.nlm.nih.gov/pubmed/32025684 (accessed on 9 November 2022). [CrossRef] [PubMed]
  7. Blunt, J.W.; Copp, B.R.; Keyzers, R.A.; Munro, M.H.; Prinsep, M.R. Marine natural products. Nat. Prod. Rep. 2015, 32, 116–211. Available online: https://www.ncbi.nlm.nih.gov/pubmed/25620233 (accessed on 9 November 2022).
  8. Blunt, J.W.; Copp, B.R.; Keyzers, R.A.; Munro, M.H.; Prinsep, M.R. Marine natural products. Nat. Prod. Rep. 2016, 33, 382–431. Available online: https://www.ncbi.nlm.nih.gov/pubmed/26837534 (accessed on 9 November 2022).
  9. Willems, T.; De Mol, M.L.; De Bruycker, A.; De Maeseneire, S.L.; Soetaert, W.K. Alkaloids from Marine Fungi: Promising Antimicrobials. Antibiotics 2020, 9, 340. [Google Scholar] [CrossRef]
  10. Jiang, M.; Wu, Z.; Guo, H.; Liu, L.; Chen, S. A Review of Terpenes from Marine-Derived Fungi: 2015–2019. Mar. Drugs 2020, 18, 321. [Google Scholar] [CrossRef]
  11. Shabana, S.; Lakshmi, K.R.; Satya, A.K. An Updated Review of Secondary Metabolites from Marine Fungi. Mini Rev. Med. Chem. 2021, 21, 602–642. [Google Scholar] [CrossRef]
  12. Youssef, F.S.; Ashour, M.L.; Singab, A.N.B.; Wink, M. A Comprehensive Review of Bioactive Peptides from Marine Fungi and Their Biological Significance. Mar. Drugs 2019, 17, 559. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Huang, M.; Lu, J.J.; Huang, M.Q.; Bao, J.L.; Chen, X.P.; Wang, Y.T. Terpenoids: Natural products for cancer therapy. Expert Opin. Investig. Drugs 2012, 21, 1801–1818. [Google Scholar] [CrossRef] [PubMed]
  14. Hanson, J.R. Diterpenoids. Nat. Prod. Rep. 1986, 3, 307–322. [Google Scholar] [CrossRef] [PubMed]
  15. Hanson, J.R. Diterpenoids. Nat. Prod. Rep. 2009, 26, 1156–1171. Available online: https://www.ncbi.nlm.nih.gov/pubmed/19693413 (accessed on 9 November 2022).
  16. Hanson, J.R. Diterpenoids of terrestrial origin. Nat. Prod. Rep. 2011, 28, 1755–1772. Available online: https://www.ncbi.nlm.nih.gov/pubmed/21713271 (accessed on 9 November 2022). [PubMed]
  17. Hanson, J.R.; Nichols, T.; Mukhrish, Y.; Bagley, M.C. Diterpenoids of terrestrial origin. Nat. Prod. Rep. 2019, 36, 1499–1512. Available online: https://www.ncbi.nlm.nih.gov/pubmed/31417997 (accessed on 9 November 2022). [CrossRef] [PubMed]
  18. Takagi, M.; Motohashi, K.; Khan, S.T.; Hashimoto, J.; Shin-Ya, K. JBIR-65, a new diterpene, isolated from a sponge-derived Actinomadura sp. SpB081030SC-15. J. Antibiot. 2010, 63, 401–403. [Google Scholar] [CrossRef] [Green Version]
  19. Zhou, G.; Sun, C.; Hou, X.; Che, Q.; Zhang, G.; Gu, Q.; Liu, C.; Zhu, T.; Li, D. Ascandinines A-D, indole diterpenoids, from the sponge-derived fungus Aspergillus candidus HDN15-152. J. Org. Chem. 2021, 86, 2431–2436. [Google Scholar] [CrossRef]
  20. Sun, K.; Li, Y.; Guo, L.; Wang, Y.; Liu, P.; Zhu, W. Indole diterpenoids and isocoumarin from the fungus, Aspergillus flavus, isolated from the prawn, Penaeus vannamei. Mar. Drugs 2014, 12, 3970–3981. [Google Scholar] [CrossRef] [Green Version]
  21. Elsbaey, M.; Tanaka, C.; Miyamoto, T. New secondary metabolites from the mangrove endophytic fungus Aspergillus versicolor. Phytochem. Lett. 2019, 32, 70–76. [Google Scholar] [CrossRef]
  22. Niu, S.; Xia, J.M.; Li, Z.; Yang, L.H.; Yi, Z.W.; Xie, C.L.; Peng, G.; Luo, Z.H.; Shao, Z.; Yang, X.W. Aphidicolin chemistry of the deep-sea-derived fungus Botryotinia fuckeliana MCCC 3A00494. J. Nat. Prod. 2019, 82, 2307–2331. [Google Scholar] [CrossRef] [PubMed]
  23. Zheng, C.J.; Bai, M.; Zhou, X.M.; Huang, G.L.; Shao, T.M.; Luo, Y.P.; Niu, Z.G.; Niu, Y.Y.; Chen, G.Y.; Han, C.R. Penicilindoles A-C, cytotoxic indole diterpenes from the mangrove-derived fungus Eupenicillium sp. HJ002. J. Nat. Prod. 2018, 81, 1045–1049. [Google Scholar] [CrossRef]
  24. Niu, S.; Fan, Z.W.; Xie, C.L.; Liu, Q.; Luo, Z.H.; Liu, G.; Yang, X.W. Spirograterpene A, a tetracyclic spiro-diterpene with a fused 5/5/5/5 ring system from the deep-sea-derived fungus Penicillium granulatum MCCC 3A00475. J. Nat. Prod. 2017, 80, 2174–2177. [Google Scholar] [CrossRef]
  25. Liu, H.; Zhang, L.; Chen, Y.; Li, S.; Tan, G.; Sun, Z.; Pan, Q.; Ye, W.; Li, H.; Zhang, W. Cytotoxic pimarane-type diterpenes from the marine sediment-derived fungus Eutypella sp. FS46. Nat. Prod. Res. 2017, 31, 404–410. [Google Scholar] [CrossRef] [PubMed]
  26. Xia, X.; Zhang, J.; Zhang, Y.; Wei, F.; Liu, X.; Jia, A.; Liu, C.; Li, W.; She, Z.; Lin, Y. Pimarane diterpenes from the fungus Epicoccum sp. HS-1 associated with Apostichopus japonicus. Bioorg. Med. Chem. Lett. 2012, 22, 3017–3019. [Google Scholar] [CrossRef] [PubMed]
  27. Gao, S.S.; Li, X.M.; Williams, K.; Proksch, P.; Ji, N.Y.; Wang, B.G. Rhizovarins A-F, indole-diterpenes from the mangrove-derived endophytic fungus Mucor irregularis QEN-189. J. Nat. Prod. 2016, 79, 2066–2074. [Google Scholar] [CrossRef]
  28. Du, L.; Li, D.; Zhu, T.; Cai, S.; Wang, F.; Xiao, X.; Gu, Q. New alkaloids and diterpenes from a deep ocean sediment derived fungus Penicillium sp. Tetrahedron 2009, 65, 1033–1039. [Google Scholar] [CrossRef]
  29. Dai, L.T.; Yang, L.; Kong, F.D.; Ma, Q.Y.; Xie, Q.Y.; Dai, H.F.; Yu, Z.F.; Zhao, Y.X. Cytotoxic indole-diterpenoids from the marine-derived fungus Penicillium sp. KFD28. Mar. Drugs 2021, 19, 613. [Google Scholar] [CrossRef]
  30. Liu, L.; Xu, W.; Li, S.; Chen, M.; Cheng, Y.; Yuan, W.; Cheng, Z.; Li, Q. Penicindopene A, a new indole diterpene from the deep-sea fungus Penicillium sp. YPCMAC1. Nat. Prod. Res. 2019, 33, 2988–2994. [Google Scholar] [CrossRef]
  31. Zhao, W.Y.; Yi, J.; Chang, Y.B.; Sun, C.P.; Ma, X.C. Recent studies on terpenoids in Aspergillus fungi: Chemical diversity, biosynthesis, and bioactivity. Phytochemistry 2022, 193, 113011. [Google Scholar] [CrossRef] [PubMed]
  32. Zhang, M.; Liu, J.-M.; Zhao, J.-L.; Li, N.; Chen, R.-D.; Xie, K.-B.; Zhang, W.-J.; Feng, K.-P.; Yan, Z.; Wang, N.; et al. Two new diterpenoids from the endophytic fungus Trichoderma sp. Xy24 isolated from mangrove plant Xylocarpus granatum. Chin. Chem. Lett. 2016, 27, 957–960. [Google Scholar] [CrossRef]
  33. Yamada, T.; Suzue, M.; Arai, T.; Kikuchi, T.; Tanaka, R. Trichodermanins C-E, new diterpenes with a fused 6-5-6-6 ring system produced by a marine sponge-derived fungus. Mar. Drugs 2017, 15, 169. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Li, X.D.; Li, X.; Li, X.M.; Xu, G.M.; Zhang, P.; Meng, L.H.; Wang, B.G. Tetranorlabdane diterpenoids from the deep sea sediment-derived fungus Aspergillus wentii SD-310. Planta Med. 2016, 82, 877–881. [Google Scholar] [CrossRef] [PubMed]
  35. Li, X.D.; Li, X.M.; Li, X.; Xu, G.M.; Liu, Y.; Wang, B.G. Aspewentins D-H, 20-nor-isopimarane derivatives from the deep sea sediment-derived fungus Aspergillus wentii SD-310. J. Nat. Prod. 2016, 79, 1347–1353. [Google Scholar] [CrossRef]
  36. Zhang, P.; Li, X.-M.; Li, X.; Wang, B.-G. New indole-diterpenoids from the algal-associated fungus Aspergillus nidulans. Phytochem. Lett. 2015, 12, 182–185. [Google Scholar] [CrossRef]
  37. Zhang, D.; Yi, W.; Ge, H.; Zhang, Z.; Wu, B. A new antimicrobial indoloditerpene from a marine-sourced fungus Aspergillus versicolor ZZ761. Nat. Prod. Res. 2021, 35, 3114–3119. [Google Scholar] [CrossRef]
  38. Zhang, Y.; Adnani, N.; Braun, D.R.; Ellis, G.A.; Barns, K.J.; Parker-Nance, S.; Guzei, I.A.; Bugni, T.S. Micromonohalimanes A and B: Antibacterial halimane-type diterpenoids from a marine Micromonospora species. J. Nat. Prod. 2016, 79, 2968–2972. [Google Scholar] [CrossRef] [Green Version]
  39. Hu, X.Y.; Meng, L.H.; Li, X.; Yang, S.Q.; Li, X.M.; Wang, B.G. Three new indole diterpenoids from the sea-anemone-derived fungus Penicillium sp. AS-79. Mar. Drugs 2017, 15, 137. [Google Scholar] [CrossRef] [Green Version]
  40. Yang, B.; He, Y.; Lin, S.; Zhang, J.; Li, H.; Wang, J.; Hu, Z.; Zhang, Y. Antimicrobial dolabellanes and atranones from a marine-derived strain of the toxigenic fungus Stachybotrys chartarum. J. Nat. Prod. 2019, 82, 1923–1929. [Google Scholar] [CrossRef]
  41. Miao, F.P.; Liang, X.R.; Yin, X.L.; Wang, G.; Ji, N.Y. Absolute configurations of unique harziane diterpenes from Trichoderma species. Org. Lett. 2012, 14, 3815–3817. [Google Scholar] [CrossRef] [PubMed]
  42. Liang, X.R.; Miao, F.P.; Song, Y.P.; Guo, Z.Y.; Ji, N.Y. Trichocitrin, a new fusicoccane diterpene from the marine brown alga-endophytic fungus Trichoderma citrinoviride cf-27. Nat. Prod. Res. 2016, 30, 1605–1610. [Google Scholar] [CrossRef]
  43. Li, X.D.; Li, X.; Li, X.M.; Xu, G.M.; Liu, Y.; Wang, B.G. 20-nor-isopimarane epimers produced by Aspergillus wentii SD-310, a fungal strain obtained from deep sea sediment. Mar. Drugs 2018, 16, 440. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Xia, X.; Qi, J.; Liu, Y.; Jia, A.; Zhang, Y.; Liu, C.; Gao, C.; She, Z. Bioactive isopimarane diterpenes from the fungus, Epicoccum sp. HS-1, associated with Apostichopus japonicus. Mar. Drugs 2015, 13, 1124–1132. [Google Scholar] [CrossRef]
  45. Kong, F.D.; Fan, P.; Zhou, L.M.; Ma, Q.Y.; Xie, Q.Y.; Zheng, H.Z.; Zheng, Z.H.; Zhang, R.S.; Yuan, J.Z.; Dai, H.F.; et al. Penerpenes A-D, four indole terpenoids with potent protein tyrosine phosphatase iInhibitory activity from the marine-derived fungus Penicillium sp. KFD28. Org. Lett. 2019, 21, 4864–4867. [Google Scholar] [CrossRef] [PubMed]
  46. Zhou, L.M.; Kong, F.D.; Fan, P.; Ma, Q.Y.; Xie, Q.Y.; Li, J.H.; Zheng, H.Z.; Zheng, Z.H.; Yuan, J.Z.; Dai, H.F.; et al. Indole-diterpenoids with protein tyrosine phosphatase inhibitory activities from the marine-derived fungus Penicillium sp. KFD28. J. Nat. Prod. 2019, 82, 2638–2644. [Google Scholar] [CrossRef]
  47. Li, Y.; Liu, W.; Han, S.; Zhang, J.; Xu, W.; Li, Q.; Cheng, Z. Penitholabene, a rare 19-nor labdane-type diterpenoid from the deep-sea-derived fungus Penicillium thomii YPGA3. Fitoterapia 2020, 146, 104691. [Google Scholar] [CrossRef]
  48. Fan, Y.; Wang, Y.; Liu, P.; Fu, P.; Zhu, T.; Wang, W.; Zhu, W. Indole-diterpenoids with anti-H1N1 activity from the aciduric fungus Penicillium camemberti OUCMDZ-1492. J. Nat. Prod. 2013, 76, 1328–1336. [Google Scholar] [CrossRef]
  49. Zhao, D.L.; Yang, L.J.; Shi, T.; Wang, C.Y.; Shao, C.L.; Wang, C.Y. Potent phytotoxic harziane diterpenes from a soft coral-derived strain of the fungus Trichoderma harzianum XS-20090075. Sci. Rep. 2019, 9, 13345. [Google Scholar] [CrossRef] [Green Version]
  50. Ebada, S.S.; Schulz, B.; Wray, V.; Totzke, F.; Kubbutat, M.H.; Muller, W.E.; Hamacher, A.; Kassack, M.U.; Lin, W.; Proksch, P. Arthrinins A-D: Novel diterpenoids and further constituents from the sponge derived fungus Arthrinium sp. Bioorg. Med. Chem. 2011, 19, 4644–4651. [Google Scholar] [CrossRef]
  51. Miao, F.P.; Liang, X.R.; Liu, X.H.; Ji, N.Y. Aspewentins A-C, norditerpenes from a cryptic pathway in an algicolous strain of Aspergillus wentii. J. Nat. Prod. 2014, 77, 429–432. [Google Scholar] [CrossRef] [PubMed]
  52. Song, Y.P.; Fang, S.T.; Miao, F.P.; Yin, X.L.; Ji, N.Y. Diterpenes and sesquiterpenes from the marine algicolous fungus Trichoderma harzianum X-5. J. Nat. Prod. 2018, 81, 2553–2559. [Google Scholar] [CrossRef] [PubMed]
  53. Niu, S.; Xie, C.L.; Xia, J.M.; Liu, Q.M.; Peng, G.; Liu, G.M.; Yang, X.W. Botryotins A-H, tetracyclic diterpenoids representing three carbon skeletons from a deep-sea-derived Botryotinia fuckeliana. Org. Lett. 2020, 22, 580–583. [Google Scholar] [CrossRef] [PubMed]
  54. Li, H.; Liu, X.; Li, X.; Hu, Z.; Wang, L. Novel harziane diterpenes from deep-sea sediment fungus Trichoderma sp. SCSIOW21 and their potential anti-inflammatory effects. Mar. Drugs 2021, 19, 689. [Google Scholar] [CrossRef]
  55. Tsukada, M.; Fukai, M.; Miki, K.; Shiraishi, T.; Suzuki, T.; Nishio, K.; Sugita, T.; Ishino, M.; Kinoshita, K.; Takahashi, K.; et al. Chemical constituents of a marine fungus, Arthrinium sacchari. J. Nat. Prod. 2011, 74, 1645–1649. [Google Scholar] [CrossRef]
  56. Wang, K.W.; Ding, P. New bioactive metabolites from the marine-derived fungi Aspergillus. Mini Rev. Med. Chem. 2018, 18, 1072–1094. [Google Scholar] [CrossRef]
  57. Li, X.; Li, X.-D.; Li, X.-M.; Xu, G.-M.; Liu, Y.; Wang, B.-G. Wentinoids A–F, six new isopimarane diterpenoids from Aspergillus wentii SD-310, a deep-sea sediment derived fungus. RSC Adv. 2017, 7, 4387–4394. [Google Scholar] [CrossRef] [Green Version]
  58. Saha, P.; Rahman, F.I.; Hussain, F.; Rahman, S.M.A.; Rahman, M.M. Antimicrobial Diterpenes: Recent Development from Natural Sources. Front. Pharmacol. 2021, 12, 820312. [Google Scholar] [CrossRef]
  59. Sun, H.F.; Li, X.M.; Meng, L.; Cui, C.M.; Gao, S.S.; Li, C.S.; Huang, C.G.; Wang, B.G. Asperolides A-C, tetranorlabdane diterpenoids from the marine alga-derived endophytic fungus Aspergillus wentii EN-48. J. Nat. Prod. 2012, 75, 148–152. [Google Scholar] [CrossRef]
  60. Qiao, M.F.; Ji, N.Y.; Liu, X.H.; Li, K.; Zhu, Q.M.; Xue, Q.Z. Indoloditerpenes from an algicolous isolate of Aspergillus oryzae. Bioorg. Med. Chem. Lett. 2010, 20, 5677–5680. [Google Scholar] [CrossRef]
  61. González, M.C.; Lull, C.; Moya, P.; Ayala, I.; Primo, J.; Primo Yúfera, E. Insecticidal activity of penitrems, including penitrem G, a new member of the family isolated from Penicillium crustosum. J. Agric. Food. Chem. 2003, 51, 2156–2160. [Google Scholar] [CrossRef] [PubMed]
  62. De Miccolis Angelini, R.M.; Rotolo, C.; Masiello, M.; Gerin, D.; Pollastro, S.; Faretra, F. Occurrence of fungicide resistance in populations of Botryotinia fuckeliana (Botrytis cinerea) on table grape and strawberry in southern Italy. Pest Manag. Sci. 2014, 70, 1785–1796. [Google Scholar] [CrossRef] [PubMed]
  63. Niu, S.; Peng, G.; Xia, J.M.; Xie, C.L.; Li, Z.; Yang, X.W. A new pimarane diterpenoid from the Botryotinia fuckeliana fungus isolated from deep-sea water. Chem. Biodivers. 2019, 16, e1900519. [Google Scholar] [CrossRef]
  64. Zhang, M.Q.; Xu, K.X.; Xue, Y.; Cao, F.; Yang, L.J.; Hou, X.M.; Wang, C.Y.; Shao, C.L. Sordarin diterpene glycosides with an unusual 1,3-Dioxolan-4-one ring from the zoanthid-derived fungus Curvularia hawaiiensis TA26-15. J. Nat. Prod. 2019, 82, 2477–2482. [Google Scholar] [CrossRef]
  65. Sun, L.; Li, D.; Tao, M.; Chen, Y.; Dan, F.; Zhang, W. Scopararanes C-G: New oxygenated pimarane diterpenes from the marine sediment-derived fungus Eutypella scoparia FS26. Mar. Drugs 2012, 10, 539–550. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Mullowney, M.W.; Ó hAinmhire, E.; Tanouye, U.; Burdette, J.E.; Pham, V.C.; Murphy, B.T. A pimarane diterpene and cytotoxic angucyclines from a marine-derived Micromonospora sp. in Vietnam’s east sea. Mar. Drugs 2015, 13, 5815–5827. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  67. Gomes, N.M.; Bessa, L.J.; Buttachon, S.; Costa, P.M.; Buaruang, J.; Dethoup, T.; Silva, A.M.; Kijjoa, A. Antibacterial and antibiofilm activities of tryptoquivalines and meroditerpenes isolated from the marine-derived fungi Neosartorya paulistensis, N. laciniosa, N. tsunodae, and the soil fungi N. fischeri and N. siamensis. Mar. Drugs 2014, 12, 822–839. [Google Scholar] [CrossRef] [Green Version]
  68. Gao, S.S.; Li, X.M.; Zhang, Y.; Li, C.S.; Wang, B.G. Conidiogenones H and I, two new diterpenes of cyclopiane class from a marine-derived endophytic fungus Penicillium chrysogenum QEN-24S. Chem. Biodivers. 2011, 8, 1748–1753. [Google Scholar] [CrossRef]
  69. Niu, S.; Fan, Z.; Tang, X.; Liu, Q.; Shao, Z.; Liu, G.; Yang, X.-W. Cyclopiane-type diterpenes from the deep-sea-derived fungus Penicillium commune MCCC 3A00940. Tetrahedron Lett. 2018, 59, 375–378. [Google Scholar] [CrossRef]
  70. Cheng, Z.; Li, Y.; Xu, W.; Liu, W.; Liu, L.; Zhu, D.; Kang, Y.; Luo, Z.; Li, Q. Three new cyclopiane-type diterpenes from a deep-sea derived fungus Penicillium sp. YPGA11 and their effects against human esophageal carcinoma cells. Bioorg. Chem. 2019, 91, 103129. [Google Scholar] [CrossRef]
  71. Chen, M.Y.; Xie, Q.Y.; Kong, F.D.; Ma, Q.Y.; Zhou, L.M.; Yuan, J.Z.; Dai, H.F.; Wu, Y.G.; Zhao, Y.X. Two new indole-diterpenoids from the marine-derived fungus Penicillium sp. KFD28. J. Asian Nat. Prod. Res. 2021, 23, 1030–1036. [Google Scholar] [CrossRef]
  72. Zhao, M.; Ruan, Q.; Pan, W.; Tang, Y.; Zhao, Z.; Cui, H. New polyketides and diterpenoid derivatives from the fungus Penicillium sclerotiorum GZU-XW03-2 and their anti-inflammatory activity. Fitoterapia 2020, 143, 104561. [Google Scholar] [CrossRef] [PubMed]
  73. Li, F.; Sun, W.; Zhang, S.; Gao, W.; Lin, S.; Yang, B.; Chai, C.; Li, H.; Wang, J.; Hu, Z.; et al. New cyclopiane diterpenes with anti-inflammatory activity from the sea sediment-derived fungus Penicillium sp. TJ403-2. Chin. Chem. Lett. 2020, 31, 197–201. [Google Scholar] [CrossRef]
  74. Wang, W.; Wan, X.; Liu, J.; Wang, J.; Zhu, H.; Chen, C.; Zhang, Y. Two new terpenoids from Talaromyces purpurogenus. Mar. Drugs 2018, 16, 150. [Google Scholar] [CrossRef] [PubMed]
  75. Su, D.; Ding, L.; He, S. Marine-derived Trichoderma species as a promising source of bioactive secondary metabolites. Mini Rev. Med. Chem. 2018, 18, 1702–1713. [Google Scholar] [CrossRef]
  76. Xie, Z.-L.; Li, H.-J.; Wang, L.-Y.; Liang, W.-L.; Liu, W.; Lan, W.-J. Trichodermaerin, a new diterpenoid lactone from the marine fungus Trichoderma erinaceum associated with the sea star Acanthaster planci. Nat. Prod. Commun. 2013, 8, 67–68. [Google Scholar] [CrossRef] [Green Version]
  77. Song, Y.P.; Liu, X.H.; Shi, Z.Z.; Miao, F.P.; Fang, S.T.; Ji, N.Y. Bisabolane, cyclonerane, and harziane derivatives from the marine-alga-endophytic fungus Trichoderma asperellum cf44-2. Phytochemistry 2018, 152, 45–52. [Google Scholar] [CrossRef]
  78. Yamada, T.; Fujii, A.; Kikuchi, T. New diterpenes with a fused 6-5-6-6 ring system isolated from the marine sponge-derived fungus Trichoderma harzianum. Mar. Drugs 2019, 17, 480. [Google Scholar] [CrossRef] [Green Version]
  79. Zou, J.X.; Song, Y.P.; Zeng, Z.Q.; Ji, N.Y. Proharziane and harziane derivatives from the marine algicolous fungus Trichoderma asperelloides RR-dl-6-11. J. Nat. Prod. 2021, 84, 1414–1419. [Google Scholar] [CrossRef]
  80. Ishino, M.; Kiyomichi, N.; Takatori, K.; Sugita, T.; Shiro, M.; Kinoshita, K.; Takahashi, K.; Koyama, K. Phomactin I, 13-epi-phomactin I, and phomactin J, three novel diterpenes from a marine-derived fungus. Tetrahedron 2010, 66, 2594–2597. [Google Scholar] [CrossRef]
  81. Ishino, M.; Kinoshita, K.; Takahashi, K.; Sugita, T.; Shiro, M.; Hasegawa, K.; Koyama, K. Phomactins K–M, three novel phomactin-type diterpenes from a marine-derived fungus. Tetrahedron 2012, 68, 8572–8576. [Google Scholar] [CrossRef]
  82. Ishino, M.; Kamauchi, H.; Takatori, K.; Kinoshita, K.; Sugita, T.; Koyama, K. Three novel phomactin-type diterpenes from a marine-derived fungus. Tetrahedron Lett. 2016, 57, 4341–4344. [Google Scholar] [CrossRef]
Molecules 27 08303 g001 550
Figure 1. Numbers of new compounds from marine and marine-derived fungi from 2012 to 2019, data adapted from the serial review articles of Blunt et al. ([1,2,3,4,5,6,7,8]).
Figure 1. Numbers of new compounds from marine and marine-derived fungi from 2012 to 2019, data adapted from the serial review articles of Blunt et al. ([1,2,3,4,5,6,7,8]).
Molecules 27 08303 g001
Molecules 27 08303 g002a 550Molecules 27 08303 g002b 550
Figure 2. Distribution of the number of papers reporting marine fungi-derived diterpenes (A) and the number of diterpenes (B) by fungal genus.
Figure 2. Distribution of the number of papers reporting marine fungi-derived diterpenes (A) and the number of diterpenes (B) by fungal genus.
Molecules 27 08303 g002aMolecules 27 08303 g002b
Molecules 27 08303 g003 550
Figure 3. Percentages of different kinds of activities compared to the whole occurrence of activities of bioactive diterpenes derived from marine fungi.
Figure 3. Percentages of different kinds of activities compared to the whole occurrence of activities of bioactive diterpenes derived from marine fungi.
Molecules 27 08303 g003
Molecules 27 08303 g004 550
Figure 4. Chemical structures of diterpenes (1 from Actinomadura sp., 2–9 from Arthrinium sp.).
Figure 4. Chemical structures of diterpenes (1 from Actinomadura sp., 2–9 from Arthrinium sp.).
Molecules 27 08303 g004
Molecules 27 08303 g005a 550Molecules 27 08303 g005b 550
Figure 5. Chemical structures of diterpenes (10–47 from Aspergillus sp.).
Figure 5. Chemical structures of diterpenes (10–47 from Aspergillus sp.).
Molecules 27 08303 g005aMolecules 27 08303 g005b
Molecules 27 08303 g006a 550Molecules 27 08303 g006b 550Molecules 27 08303 g006c 550
Figure 6. Chemical structures of diterpenes (48–127 from Botryotinia sp.).
Figure 6. Chemical structures of diterpenes (48–127 from Botryotinia sp.).
Molecules 27 08303 g006aMolecules 27 08303 g006bMolecules 27 08303 g006c
Molecules 27 08303 g007a 550Molecules 27 08303 g007b 550
Figure 7. Chemical structures of diterpenes (128 from Curvularia sp., 129–131 from Eupenicillium sp., 132–138 from Eutypella sp., 139–142 from Epicoccum sp.,143–145 from Micromonospora sp., and 146–151 from Mucor sp.).
Figure 7. Chemical structures of diterpenes (128 from Curvularia sp., 129–131 from Eupenicillium sp., 132–138 from Eutypella sp., 139–142 from Epicoccum sp.,143–145 from Micromonospora sp., and 146–151 from Mucor sp.).
Molecules 27 08303 g007aMolecules 27 08303 g007b
Molecules 27 08303 g008a 550Molecules 27 08303 g008b 550Molecules 27 08303 g008c 550
Figure 8. Chemical structures of diterpenes (152 from Neosartorya sp., 153–197 from Penicillium sp.).
Figure 8. Chemical structures of diterpenes (152 from Neosartorya sp., 153–197 from Penicillium sp.).
Molecules 27 08303 g008aMolecules 27 08303 g008bMolecules 27 08303 g008c
Molecules 27 08303 g009a 550Molecules 27 08303 g009b 550
Figure 9. Chemical structures of diterpenes (198–200 from Stachybotrys sp., 201 from Talaromyces sp., 202–228 from Trichoderma sp.).
Figure 9. Chemical structures of diterpenes (198–200 from Stachybotrys sp., 201 from Talaromyces sp., 202–228 from Trichoderma sp.).
Molecules 27 08303 g009aMolecules 27 08303 g009b
Molecules 27 08303 g010 550
Figure 10. Chemical structures of diterpenes (229–237 from unidentified fungus).
Figure 10. Chemical structures of diterpenes (229–237 from unidentified fungus).
Molecules 27 08303 g010
Table
Table 1. Marine fungi-derived compounds with various bioactivities.
Table 1. Marine fungi-derived compounds with various bioactivities.
Compound NumberCompound NameProducing OrganismActivityReference
Cytotoxicity to cancer cell lines
31Ascandinine DAspergillus candidus HDN15-152Cytotoxicity against HL-60 cells with an IC50 value of 7.8 µM[18]
38(2R,4bR,6aS,12bS,12cS,14aS)-4b-Deoxy-β-aflatremAspergillus flavus OUCMDZ-2205Activity to A-549 cell cycle in the S phase with an IC50 value of 10 µM[19]
39(2R,4bS,6aS,12bS,12cR)-9-Isopentenylpaxilline DAspergillus flavus OUCMDZ-2205Activity to A-549 cell cycle in the S phase with an IC50 value of 10 µM[19]
46Anthcolorin HAspergillus versicolorActivity to Hela cells with an IC50 value of 43.7 µM[20]
56Aphidicolin A8Botryotinia fuckeliana MCCC 3A00494Activity to T24 and HL-60 cells with IC50 values of 2.5 and 6.1 µM, respectively[21]
129Penicilindole AEupenicillium sp. HJ002Activity to A-549 and HepG2 cell lines with IC50 values of 5.5 and 1.5 µM, respectively[22]
132Scopararane CEutypella scoparia FS26Cytotoxicity against the MCF-7 cell line with an IC50 value of 35.9 µM[23]
133Scopararane DEutypella scoparia FS26Cytotoxicity against the MCF-7 cell line with an IC50 value of 25.6 µM[23]
138Scopararane IEutypella sp. FS46Inhibitory activities against NCI-H460 and SF-268 cell lines with IC50 values of 13.59 and 25.31 µg/mL, respectively[24]
139Aspergilone AEpicoccum sp. HS-1Inhibits the growth of human epidermis carcinoma cell line and multidrug-resistant cell line expressing high levels of P-gp with IC50 values of 3.51 and 2.34 µg/mL, respectively[25]
140Aspergilone B 1Epicoccum sp. HS-1Inhibits the growth of human epidermis carcinoma cell line and multidrug-resistant cell line expressing high levels of P-gp with IC50 values of 20.74 and 14.47 µg/mL, respectively[25]
146Rhizovarin AMucor irregularis QEN-189Activity against A-549 and HL-60 cancer cell lines with IC50 values of 11.5 and 9.6 µM, respectively[26]
147Rhizovarin BMucor irregularis QEN-189Activity against A-549 and HL-60 cancer cell lines with IC50 values of 6.3 and 5.0 µM, respectively[26]
151Rhizovarin FMucor irregularis QEN-189Activity against the A-549 cancer cell line with an IC50 value of 9.2 µM[26]
153Conidiogenone BPenicillium sp. F23-2Cytotoxicity to A-549 and HL-60 cell lines with IC50 values of 40.3 and 28.2 µM, respectively[27]
154Conidiogenone CPenicillium sp. F23-2Activity to HL-60 and BEL-7402 cell lines with IC50 values of 0.038 and 0.97 µM, respectively[27]
155Conidiogenone DPenicillium sp. F23-2Activity to A-549, HL-60, BEL-7402, and MOLT-4 cell lines with IC50 values of 9.3, 5.3, 11.7, and 21.1 µM, respectively[27]
156Conidiogenone EPenicillium sp. F23-2Activity to A-549 and HL-60 cell lines with IC50 values of 15.1 and 8.5 µM, respectively[27]
157Cnidiogenone FPenicillium sp. F23-2Activity to A-549, HL-60, BEL-7402, and MOLT-4 cell lines with IC50 values of 42.2, 17.8, 17.1, and 25.8 µM, respectively[27]
158Conidiogenone GPenicillium sp. F23-2Activity to A-549, HL-60, BEL-7402, and MOLT-4 cell lines with IC50 values of 8.3, 1.1, 43.2, and 4.7 µM, respectively[27]
189Penerpene MPenicillium sp. KFD28Activity against HeLa cells with an IC50 value of 36.3 µM[28]
192Penicindopene APenicillium sp. YPCMAC1Cytotoxicity against A-549 and HeLa cell lines with IC50 values of 15.2 and 20.5 µM, respectively[29]
201Roussoellol CTalaromyces purpurogenus PP-414Cytotoxic to MCF-7 cells with an IC50 value of 6.5 µM[30]
206(9R,10R)-dihydro-harzianoneTrichoderma sp. Xy24Activity against HeLa and MCF-7 cell lines with IC50 values of 30.1 and 30.7 µM, respectively[31]
208Trichodermanin CTrichoderma harzianum OUPS-111D-4Cytotoxic activity against P388, HL-60, and L1210 cell lines with IC50 values of 7.9, 6.8, and 7.6 µM, respectively[32]
Antimicrobial activity
10Asperolide DAspergillus wentii SD-310Inhibits Edwardsiella tarda with an MIC value of 16 µg/mL[33]
12Aspewentin DAspergillus wentii SD-310Activity against Fusarium graminearum and Micrococcus luteus, with MIC values of 2.0 and 4.0 µg/mL, respectively[34]
14Aspewentin FAspergillus wentii SD-310Inhibitory activity against Edwardsiella tarda and Vibrio harveyi with MIC values of 4.0 and 8.0 µg/mL, respectively[34]
15Aspewentin GAspergillus wentii SD-310Inhibitory activity against Vibrio harveyi with an MIC value of 4.0 µg/mL[34]
16Aspewentin HAspergillus wentii SD-310Activity against Pseudomonas aeruginosa and Fusarium graminearum with MIC values of 4.0 and 4.0 µg/mL, respectively[34]
4319-hydroxypenitrem AAspergillus nidulans EN-330Activity against pathogens Edwardsiella tarda, Vibrio anguillarum, Escherichia coli, and Staphylococcus aureus with MIC values of 16, 32, 16, and 16 µg/mL, respectively[35]
47(3R,9S,12R,13S,17S,18S)-2-carbonyl-3-hydroxylemeniveolAspergillus versicolor ZZ761Antimicrobial activity against Escherichia coli and Candida albicans with MIC values of 20.6 and 22.8 µM, respectively[36]
145Micromonohalimane BMicromonospora sp.Inhibitory effect on methicillin-resistant Staphylococcus aureus with an MIC value of 40 µg/mL[37]
1696-hydroxylpaspalininePenicillium sp. AS-79Activity against the aquatic pathogen Vibrio parahaemolyticus with an MIC value of 64.0 µg/mL[38]
199Stachatranone BStachybotrys chartarum TJ403-SS6Activity against Acinetobacter baumannii and Enterococcus faecalis with MIC values of 16 and 32 µg/mL[39]
202HarzianoneTrichoderma longibrachiatumEffect on Escherichia coli and Staphylococcus aureus at 30 µg/disk (with inhibitory diameters of 8.3 and 7.0 mm, respectively)[40]
204TrichocitrinTrichoderma citrinoviride cf-27Inhibit Escherichia coli with an inhibitory diameter of 8.0 mm at 20 µg/disk[41]
17–18Aspewentins I–JAspergillus wentii SD-310Inhibitory activity against Edwardsiella tarda, Vibrio harveyi, and V. parahemolyticus, each with an MIC value of 8.0 µg/mL[42]
Inhibition of enzymes
38(2R,4bR,6aS,12bS,12cS,14aS)-4b-Deoxy-β-aflatremAspergillus flavus OUCMDZ-2205Inhibitory effect on the kinase PKC-β with an IC50 value of 15.6 µM[19]
142Isopimarane diterpeneEpicoccum sp. HS-1Inhibits α-glucosidase with an IC50 value of 4.6 µM[43]
177–178Penerpenes A–BPenicillium sp. KFD28Inhibitory activity against protein tyrosine phosphatase (PTP1B) with IC50 values of 1.7 and 2.4 µM, respectively[44]
181–182Penerpenes E–FPenicillium sp. KFD28Inhibitory activity against PTP1B with an IC50 value of 14 and 27 µM, respectively[45]
184–185Penerpenes H–IPenicillium sp. KFD28Inhibitory activity against PTP1B with an IC50 value of 23 and 31.5 µM, respectively[45]
190Penerpene NPenicillium sp. KFD28Inhibitory activity against PTP1B with an IC50 value of 9.5 µM[28]
193PenitholabenePenicillium thomii YPGA3Inhibitory effect against α-glucosidase with an IC50 value of 282 µM[46]
Antivirus
30Ascandinine CAspergillus candidus HDN15-152Anti-influenza virus A (H1N1) activity with an IC50 value of 26 µM[18]
1613-deoxo-4b-deoxypaxillinePenicillium camemberti OUCMDZ-1492Activity against the H1N1 virus with an IC50 value of 28.3 µM[47]
1624a-demethylpaspaline-4a-carboxylic acidPenicillium camemberti OUCMDZ-1492Activity against the H1N1 virus with an IC50 value of 38.9 µM[47]
1634a-demethylpaspaline-3,4,4a-triolPenicillium camemberti OUCMDZ-1492Activity against the H1N1 virus with an IC50 value of 32.2 µM[47]
1659,10-diisopentenylpaxillinePenicillium camemberti OUCMDZ-1492Activity against the H1N1 virus with an IC50 value of 73.3 µM[47]
Inhibition of the germination of seeds
216−219Harzianones A−DTrichoderma harzianum XS 20090075Inhibits the germination of amaranth and lettuce seeds at a concentration of 200 ppm[48]
220HarzianeTrichoderma harzianum XS 20090075Inhibiting the germination of amaranth and lettuce seeds at a concentration of 200 ppm[48]
Others
1JBIR-65Actinomadura sp. SpB081030SC-15Protects neuronal hybridoma N18-RE-105 cells with an EC50 value of 31 µM[49]
5Arthrinin DArthrinium sp.Inhibits VEGF-A (vascular endothelial growth factor A)-dependent endothelial cell sprouting with an IC50 of 2.6 µM[50]
6Myrocin DArthrinium sp.Inhibits VEGF-A-dependent endothelial cell sprouting with an IC50 of 3.7 µM[50]
35Aspewentin AAspergillus wentii na-3Active against Chattonella marina and Heterosigma akashiwo, with LC50 values of 0.81 and 2.88 µM, respectively[51]
2143R-hydroxy-9R,10R-dihydroharzianoneTrichoderma harzianum X-5Activity against Chattonella marina with an IC50 value of 7.0 µg/mL[52]
21511R-methoxy-5,9,13-proharzitrien-3-olTrichoderma harzianum X-5Inhibitory effect on the growth of four kinds of phytoplankton Chattonella marina, Heterosigma akashiwo, Karlodinium veneficum, and Prorocentrum donghaiense with IC50 values of 1.2, 1.3, 3.2, and 4.3 µg/mL, respectively[52]
36Aspewentin BAspergillus wentii na-3Inhibits the growth of Artemia salina with an LC50 value of 6.36 µM[51]
120Botryotin ABotryotinia fuckeliana MCCC 3A00494Anti-allergic activity with an IC50 value of 0.2 mM[53]
167Spirograterpene APenicillium granulatum MCCC 3A00475Anti-allergic effect on immunoglobulin E (IgE)-mediated rat mast RBL-2H3 cells with 18% inhibition at 20 µg/mL[23]
202HarzianoneTrichoderma longibrachiatum82.6% of lethality to brine shrimp (Artemia salina L.) larvae at 100 µg/mL[40]
225Harzianol LTrichoderma sp. SCSIOW21Anti-inflammatory effect with 81.8% NO inhibition at 100 µM[54]
1 Compounds 139−141 were reported as compounds 1−3 in the reference [25], where only compound 139 (numbered as compound 1 in the reference) was named as aspergilone A, while the names for compounds 140 and 141 (numbered as compounds 2 and 3, respectively, in the reference) were not provided. The name aspergilone B was used to represent compound 140 in this article.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Qiu, P.; Xia, J.; Zhang, H.; Lin, D.; Shao, Z. A Review of Diterpenes from Marine-Derived Fungi: 2009–2021. Molecules 2022, 27, 8303. https://doi.org/10.3390/molecules27238303

AMA Style

Qiu P, Xia J, Zhang H, Lin D, Shao Z. A Review of Diterpenes from Marine-Derived Fungi: 2009–2021. Molecules. 2022; 27(23):8303. https://doi.org/10.3390/molecules27238303

Chicago/Turabian Style

Qiu, Peng, Jinmei Xia, Haitao Zhang, Donghai Lin, and Zongze Shao. 2022. "A Review of Diterpenes from Marine-Derived Fungi: 2009–2021" Molecules 27, no. 23: 8303. https://doi.org/10.3390/molecules27238303

Article Metrics

Back to TopTop