Next Article in Journal
In Silico Studies on GCP-Lys-OMe as a Potential 14-3-3σ Homodimer Stabilizer
Next Article in Special Issue
2-Butoxytetrahydrofuran and Palmitic Acid from Holothuria scabra Enhance C. elegans Lifespan and Healthspan via DAF-16/FOXO and SKN-1/NRF2 Signaling Pathways
Previous Article in Journal
Chromatographic Techniques and Pharmacological Analysis as a Quality Control Strategy for Serjania triquetra a Traditional Medicinal Plant
Previous Article in Special Issue
Genus Lepisanthes: Unravelling Its Botany, Traditional Uses, Phytochemistry, and Pharmacological Properties
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Pharmaceuticals
Volume 15
Issue 10
10.3390/ph15101291
pharmaceuticals-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

Pimarane Diterpenes from Fungi

by
Ke Ye
and
Hong-lian Ai
*
School of Pharmaceutical Sciences, South-Central MinZu University, Wuhan 430074, China
*
Author to whom correspondence should be addressed.
Pharmaceuticals 2022, 15(10), 1291; https://doi.org/10.3390/ph15101291
Submission received: 20 September 2022 / Revised: 13 October 2022 / Accepted: 18 October 2022 / Published: 20 October 2022
(This article belongs to the Special Issue Discovery, Metabolism and Potential Bio-Activities of Natural Products in Traditional Medicine)
Browse Figures
Review Reports Versions Notes

Abstract

:
Pimarane diterpenes are a kind of tricyclic diterpene, generally isolated from plant and fungi. In nature, fungi distribute widely and there are nearly two to three million species. They provide many secondary metabolites, including pimarane diterpenes, with novel skeletons and bioactivities. These natural products from fungi have the potential to be developed into clinical medicines. Herein, the structures and bioactivities of 197 pimarane diterpenes are summarized and the biosynthesis and pharmacological researches of pimarane diterpenes are introduced. This review may be useful improving the understanding of pimarane diterpenes from fungi.

1. Introduction

“Terpene” originated from “turpentine” in Latin which means “resin of pine tree”. Terpenes, also called terpenoids, are one of the largest groups of bioactive natural products that have been identified. To date, hundreds of terpene skeletons have been described, and they exhibit surprising structural diversity [1]. In addition, they are derived from five carbon molecules, dimethylally diphosphate (DMAPP) and isopentenyl diphosphate (IPP). These two compounds are a pair of isomers, and their condensation is responsible for different hydrocarbon lengths [2]. According to the number of isoprene (C5) units, terpenes are classified into several types: monoterpenes (C10), sesquiterpenes (C15), diterpenes (C20), sesterterpenes (C25), triterpenes (C30), and even tetraterpenes (C40) [3].
Diterpenes are a varied class of natural products originating from the C20 precursor geranylgeranyl diphosphate (GGPP), and approximately 12,000 compounds have been reported [4]. Pimarane diterpenes, a kind of tricyclic diterpene, are generally obtained from plants and fungi but seldom from other biological resources [5]. On the basis of differences in stereochemistry, pimarane diterpnes are classified into pimarane, isopimrane, ent-pimarane and ent-isopimrane (“ent” means enantiomer) (Figure 1). Because of their bioactivities and potential applications in agriculture [6] and medicine [7], more attention has been given to pimarane diterpenes.
Fungi, as one of the sources of pimarane diterpenes, are a rich source of natural products. With a wide distribution, fungi exist in terrestrial environments, fresh water, and marine habitats, and there are approximately two to three million species of fungi in nature [8]. The species diversity of fungi results in the structural diversity of bioactive natural products, including pimarane diterpenes.
Reviews about diterpenes have been previously published in 2006, 2010, 2015, and 2018 [5], and they mainly focus on diterpenes from plants and marine organisms.
This review summarized the structures and bioactivities of pimarane diterpenes mainly collected from fungi, including marine-derived fungi, and introduced the biosynthesis of pimarane diterpenes. These pimarane diterpenes were described as the classes which were described above. The review will increase our understanding of the amazing chemistry and bioactivity of pimarane diterpenes from fungi.

2. Pimarane

From the endophytic fungus Talaromyces scorteus, which was derived from sea-anemone, talascortenes C–G (1–5) (Figure 2) were isolated. These compounds were further evaluated for antimicrobial activities. Compounds 1–4 exhibited inhibitory activity against Escherichia coli, with minimum inhibitory concentration (MIC) values of 8, 16, 1, and 8 μg/mL, respectively. Comparing the structures of compounds 2 and 3, the methylation of the hydroxyl group at C-14 probably increased the antimicrobial activity [9]. Botryopimrane A (6) was isolated from the marine-derived fungus Botryotinia fuckeliana. Its Δ9,11 double bond is unique in the pimarane skeleton [10]. From the fungus Bipolaris sp., 1β-hydroxy momilactone A (7) was isolated and identified. However, it showed no antimicrobial potential [11].
Euypenoids A–C (8–10) (Figure 2) were obtained from the fungus Eutypella sp. Compounds 8 and 10 possess a rearranged skeleton, and compound 9 contains an oxime group at C-11. Furthermore, they were evaluated for antiproliferation activity, and compound 9 showed potential immunosuppressive activity [12]. Epigenetic modification is a strong method to activate silent gene clusters in fungi. By using this method, the majority of biosynthetic genes can be overexpressed. Libertellenones R (11) and S (12) (Figure 2) were purified from another strain of Eutypella sp. [13]. Calcarisporic acid E–J (13–18) (Figure 2), exhibiting no cytotoxicity, were isolated from the fungus Calcarisporium arbuscula, which lacks the histone deacetylase gene [14].

3. Isopimarane

Isopimaranes account for the majority of the pimarane diterpenes. In a bioassay-guided study, hymatoxin A–E (19–23) (Figure 3) were isolated from the pathogenic fungus Hypoxylon mammatum. They exhibited phytotoxic activity [15]. Hymatoxin K (24) and L (25) (Figure 3) were also obtained from H. mamatum, and are phytotoxins [16]. Diaporthein A (26) and B (27) (Figure 3), with antimycobacterial activity, were obtained from the fungus Diaporthe sp. The MIC value against Mycobaterium tuberculosis of compound 27 was 3.1 μg/mL [17]. Diporthein C (28) (Figure 3) was isolated from the fungus Penicillium sclerotiorum [18]. Compound 27 was also obtained from the mangrove endophytic fungus Leptosphaerulina sp. [19]. From the marine fungus Cryptosphaeria eunomi, deoxydiportherin A (29) (Figure 3) was purified and obtained [20]. Eutypellones A (30) and B (31) (Figure 3) were isolated from the endophytic fungus Eutypella sp. Compounds 30 and 31 showed weak cytotoxic activities [21].
Apsergilone A–C (32–34) (Figure 4) and compound 27, isolated from the marine fungus Epicoccum sp., were evaluated for their cytotoxic activity. Compounds 27 and 32 displayed strong cytotoxic activity against KB cell line with half maximum inhibitory concentration (IC50) values of 3.51 and 3.68 μg/mL respectively and against KBv200 cell with IC50 values of 2.34 and 6.52 μg/mL respectively. Compound 33 showed moderate cytotoxic activity against KB and KBv200 cell lines with IC50 values of 20.74 and 14.17 μg/mL, respectively. Compound 34 showed weaker or no activities [22]. Wentinoids A–F (35–40) (Figure 4), along with compound 34, were isolated from Aspergillus wentii. After being assayed for human-, and aqua-pathogenic bacteria and several plant-pathogenic fungi, the results showed that compound 35 exhibited selective activities against Fusarium graminearum, Botryosphaeria dotheidea, Fusarium oxysporum, and Phytophthora parasitica, with MIC values of 1, 4, 4, and 8 μg/mL, respectively [23]. From the same strain, Asprethers A–E (41–45) (Figure 4) were obtained and assayed for their cytotoxicity and showed cytotoxicity against the A549 cell line, with the IC50 values of 20, 16, 19, 17, and 20 μM, respectively. Compound 41 possessed better activities against T-47D cell line than others, and compound 42 was more effective than others against HEK293 and SMMC-7721 cell lines [24]. From another Algicolous strain A. wentii, Aspewentins A–C (46–48) (Figure 4) were isolated. They were assayed for inhibitory activity against several marine planktons. The data suggested that aspewentin A (46) was active against Chattonella marina and Heterosigma akashiwo, with half-lethal concentration (LC50) values of 0.81 and 2.88 μM, respectively, compound 47 was effective against Artemia salina, with LC50 value of 6.36 μM, and compound 48 was more active against Alexandrium sp., with LC50 value of 8.73 μM [25]. From another sediment-derived fungus A. wentii, Aspewntins D–H (49–53) (Figure 4) were isolated. They were evaluated for human pathogenic bacteria, aquatic pathogens, and plant-pathogenic fungi. The results indicated that compounds 49 and 51–53 showed inhibitory activity against the pathogens Edwardsiella tarda, Micrococcus luteus, Pseudomonas aeruginosa, Vibrio harveyi, and V. parahemolyticus, each with MIC values of 4.0 μg/mL, and compounds 49 and 52 showed inhibitory activity against the plant pathogen Fusarium graminearum, with MIC values of 2.0 and 4.0 μg/mL, respectively [26].
Libertellenones A–D (54–57) (Figure 5) were isolated from the fungus Libertella sp., which was incubated with marine bacteria. Compound 57 displayed potent cytotoxicity, with IC50 values of 0.76 μM, but compounds 54–56 showed less cytotoxic activities, with IC50 values of 15, 15, and 53 μM, respectively [27]. Libertellenone E (58) and libertellenone F (59) (Figure 5) were isolated from Arthrinium sacchari, along with compound 56, which exhibited less inhibitory activities against proliferation of HUVEC and HUACE cell lines after bioactivity evaluation [28]. Libertellenone G (60) and H (61) (Figure 5) were isolated from the Arctic fungus Eutypella sp. According to further evaluation of their cytotoxicity and antibacterial activities, compound 60 displayed some antibacterial activities against Escherichia coli, Bacillus subtilis, and Staphylococcus aureus and compound 61 showed slight cytotoxicity against several tumour cell lines, with IC50 values from 3.31 to 44.1 μM [29]. Libertellenone G (62) (Figure 5), with the same name as compound 60, and Libertellenone L (63) (Figure 5) from the fungus Apiospora montagnei [30]. From the culture of Phomopsis sp., libertellenone J (64) and libertellenone K (65) (Figure 5) were isolated. Compound 64 exhibited outstanding anti-inflammatory activities [31].
Libertellenone M (66) and N (67) (Figure 6) were isolated from Eutypella sp. Compound 67 displayed cytotoxicity against K562 cells, with an IC50 value of 7.67 μM, and moderate cytotoxic activities against HeLa, MCF-7, and SW1990 cell lines [32]. By a discovery approach based on a combination of bioassay-guided and dereplication, the compound 68 (Figure 6), also called libertellenone M, was obtained from Stilbella fimetaria. It showed cytotoxicity against patient-derived glioblastoma stem-like cells, with IC50 values of 18 μM, and weak cytotoxicity against several other cancer cell lines [33]. Libertellenones O−Q (69–71) (Figure 6) were isolated from the Arctic fungus Eutypella sp. They were assayed for their cytotoxic activities against HeLa, MCF-7, HCT-116, PANC-1, and SW1990 cell lines and showed great activities [13].
Scopararanes A (72) and B (73) (Figure 7) were isolated from the endophytic fungus Eutypella sccparia [34]. Scopararanes C–G (74–78) (Figure 7) were obtained from the marine-derived fungus E. scoparia, along with compounds 26, 27, 29, 73, and isopimara-8(14),15-diene (81) (Figure 7). Compounds 74 and 75 showed moderate cytotoxicity against the tumor cell line MCF-7 with IC50 values of 35.9 μM and 25.6 μM, respectively [35]. Scopararanes H (79) and I (80) (Figure 7) were isolated from the culture of the marine-derived fungus Eutypella sp. compound 80 showed moderate inhibitory activities against different tumour cell lines, with IC50 values ranging from 13.6 to 83.9 μM [36].
Myrocin A (82) (Figure 8) was isolated from the marine fungus Apiospora montagnei [37]. Myrocin B (83) (Figure 8), obtained from the fungus Myrothecium verrucaria, showed antimicrobial activities against Gram-positive and fungi, such as Bacillus subtilis, Aspergillus niger and Candida albicans with MIC values of 12.5, 50, and 25 μg/mL, respectively [38]. Myrocin C (84) (Figure 8), from Myrothecium sp., displayed antimicrobial activities against B. subtilis, A. niger and C. albicans, which were weaker than those of compound 83 [39]. Myrocin D (85) (Figure 8) was isolated from the marine fungus Arthrinium sacchari [28]. Myrocin E (86) (Figure 8) were obtained from the fungus Phomopsis sp. [31]. Myrocin F (87) (Figure 8) was isolated from Stilbella fimetaria. It showed moderate cytotoxicity against glioblastoma stem-like cells [33].
Sphaeropsidin A (88) and B (89) (Figure 9) were isolated from the phytopathogenic fungus Sphaeropsis sapinea. Sphaeropsidin C (90) (Figure 9) was purified from another phytopathogenic fungus Diplodia mutila. Both fungi were able to cause the disease of Italian cypress, and according to the bioactivity tests, these compounds were reported to be phytotoxins. However, when evaluated for their antimicrobial activities, they showed moderate inhibitory activities against several fungi [40,41]. Sphaeropsidin D (91) and E (92) (Figure 9) were obtained from the same phytopathogenic fungus S. sapinea. The activity of compound 91 was stronger than that of compound 88 [42].
Taichunins A–D (93–96) (Figure 10) were isolated from Aspergillus taichungensis. The plausible formation explained how the novel structure of compound 93 was produced. Compound 93 displayed cytotoxicity against HeLa cell line with an IC50 value of 4.5 μM [43]. From the same strain, A. taichungensis. Taichunins E–T (97–112), along with 1β, 7α-dihydroxysandaracopimar-8(14), 15-diene19 (113) (Figure 10), were obtained. Compound 99, 103, and 106 were shown to suppress the receptor activator of nuclear factor-κB ligand-induced formation of multinuclear osteoclasts at 5 μM, and 99 displayed 92% inhibition at a concentration of 0.2 μM in RAW264 cells [44]. Apsergiloid D (114) (Figure 10) was isolated from Aspergillus sp. [45].
From the fungus Xylaria sp., xylarenolide (115) (Figure 11) was obatained [46]. From the wood-decay fungus X. allantoidea., xylallantins A–C (116–118), along with compounds 24, 25 and 115, were isolated [47]. From the fungicolous fungus X. longipes, Xylarilongipins A (119) and B (120) (Figure 11) both with an unusual bicyclo [2.2.2] octane structure, and compound 26, were obtained. Compound 119 exhibited moderate concanavalin A-induced T lymphocytes and lipopolysaccharide-induced B lymphocytes with IC50 values of 13.6 and 22.4 μM, respectively [48]. From the same strain, xylarinorditerpene A–R (121–138) (Figure 12) were purified and obtained. Compound 122–125, 129, 134, 137 and 138 were able to inhibit the proliferation of T and B lymphocytes and showed immnosuppressive activity [49]. From the solid culture of the fungus X. longipes, Xylongoic acids A–C (139–141) (Figure 12) were obtained [50]. From another fungus Xylaria sp., which was wood-decay, a hymatoxin-like isopimarane (142) (Figure 13) and compound 24 were obtained [51]. From the endophytic fungus Xylaria sp., three isopimarane diterpenes, 14α,16-epoxy-18-norisopimar-7-en-4α-ol (143), 16-O-sulfo-18-norisopimar-7-en-4α,16-diol (144) and, 9-deoxy-hymatoxin A (145) (Figure 13), were obtained. The antifungal assays displayed their moderate antifungal activity [52].
By the same method, the fungus Calcarisporium arbuscula also produced Calcarisporic acid K (146) and L (147) (Figure 14) with no bioactivity [14]. Inonotolides A–C (148–150) (Figure 14), from the fungus Inonotus sinensis, were isolated [53]. 9α-hydroxy-l, 8(14), 15-isopimaratriene-3, 7, 1l-trione (151) and 9α-hydroxy-l, 8(14), 15-isopimaratriene-3, 11-dione (152) (Figure 14), two insect toxins, were isolated from cultures of the fungi Hormononema dermatioides and Phyllosticta sp. [54].
Some isopimarane diterpenes would become diterpene glycosides by enzymatic catalysis. From the fruiting body of Xylaria polymorpha. 16-α-D-mannopyranosyloxyisopimar-7-en-19-oic acid (153), 15-hydroxy-16-α-D-mannopyranosyloxyisopimar-7-en-19-oic acid (154), and 16-α-D-glucopyranosyloxyisopimar-7-en-19-oic acid (155) (Figure 15) were obtained, but they showed weak inhibitory activities against tumour cell lines [55]. Six isopimrane diterpene glycodides (156–161) (Figure 15) were isolated from the endophytic fungus Paraconiothyrium sp. Compounds 157 and 158 showed moderate cytotoxicities against the human promyelocytic leukaemia cell line HL60 with IC50 values of 6.7 and 9.8 μM, respectively [56]. Hypoxylonoids A–G (162–168), together with five analogues (169–173) (Figure 16), were isolated from the fungus Xylaria hypoxylon [57]. Virescenosides O (174), P (175), and Q (176) (Figure 17) were isolated from a marine strain of Acremonium striatisporum. They exhibited cytotoxic activity against tumour cells of Ehrlich carcinoma [58].

4. ent-Pimarane and ent-Isopimarane

Chenopodolin (177) (Figure 18) with phytotoxic activity, from the fungal pathogen Phoma chenopodiicola, was isolated. It resulted in necrotic lesions on Mercurialis annua, Cirsium arvense, and Setaria viride at a concentration of 2 mg/mL [59]. From the same strain, chenopodolin B (178) (Figure 18) was obtained. Assayed for leaf puncture against nonhost weeds, Compound 178 exhibited phytotoxicity [60]. Diplopimarane (179) (Figure 18) was obtained from the oak pathogen Diplodia quercivora. It exhibited a several kinds of activities, such as impressive phytotoxicity on nonhost plants, zootoxicity against Artemia salina, and some antifungal activity against plant pathogens [61]. From the arctic fungus Eutypella sp., eutypellenones A (180) and B (181) (Figure 18) were isolated, which showed anti-inflammatory activity and cytotoxicity against several cell lines. A plausible biosynthesis pathway was proposed [13]. Isogeopyxin B (182) (Figure 18) were isolated from a plant-endophytic fungus Geopyxis sp., which showed no cytotoxicity against several human tumour cell lines [62]. ent-Pimara-8(14), 15-diene (183) (Figure 18) were isolated and purified from the engineered fungus Aspergillus nidulans. Its antioxidant activity was reported first in [63].
Microbiological transformation was carried out to identify the bioactive compounds. By using this method, compounds 184, 185 and 186 (Figure 19) were isolated from Glomerella cingulate and Mucor rouxii. Both fungi were incubated with ent-8(14),15-pimaradien-19-ol (187) (Figure 19) which displayed very promising antibacterial activity against the main pathogens responsible for dental caries. In addition, compounds 184, 185, and 186 exhibited great antibacterial activity [64]. By using the same strategy, 19-hydroxy-13-epi-ent-pimara-9(11),15-diene (188) and 13-epi-ent-pimara-9 (11),15-diene-19-oic acid (189) (Figure 19) were incubated with the fungus Gibberella fujikuroi, respectively. Compounds 190–193 (Figure 19) were isolated from the fungus fed with the former, and compounds 194–197 (Figure 19) were obtained from the fungus incubated with the latter [65].

5. Pharmacology

Previous studies have displayed the structural diversity and broad bioactivities of four types of pimarane diterpenes. Bioactivities or potent bioactive properties are essential for natural products, which means it is possible for them to be developed into clinical medicine. In-depth studies are important to determine mechanism of action, which contributes to determing the molecular target and underlying mechanism and provides a new direction for the development of medicine. Herein, several studies on the pharmacological mechanism of pimarane dipternes are summarized.
Libertellenone H (61), isopimarane-type, showed effective cytotoxicity against several tumour cell lines, with IC50 values from 3.31 to 44.1 μM [29]. In addition, it has anticancer activity and was able to inhibit cell proliferation and pro-apoptosis in the human pancreatic cancer cell lines PANC-1 and SW1990. It induced reactive oxygen species (ROS) accumulation that resulted in apoptosis as antioxidant N-acetylcysteine and antioxidant enzyme superoxide dismutase antagonized its inhibitory activity. The thioredoxin system consists of thioredox (Trx), thioreductase (TrxR), and NADPH. This is an essential antioxidant system in defending against oxidative stress and maintaining cellular redox homeostasis by eliminating reductant ROS [66]. The mechanism of action was that compound 61 was combined with the cysteine residue of Trx1 and selenocysteine of TrxR by a Michael addition, which was responsible for a decrease in the cellular level of glutathione and activation of the downstream apoptosis signal regulating kinase 1 (ASK1)/c-Jun N-terminal kinases (JNK) signaling pathway, ensuring apoptosis. In brief, compound 61 inhibited the Trx system and triggered ROS-mediated apoptosis in human pancreatic cancer cell lines [67].
Libertellenone J (64) exhibited great anti-inflammatory activity against LPS-activated RAW264.7 macrophages, and reduced the production of several inflammatory mediators, including NO, IL-1β, IL-6, and TNF-α with IC50 values of 2.2–10.2 μM. Being evaluated for its effect on the mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways, it inhibited p38, ERK, and JNK phosphorylation in a dose-dependently manner and obviously decreased the phosphorylation of IKKα/β, the p65 subunit of NF-κB, and IκBα with no influence on their protein expression. However, the expression of MAPK was not completely inhibited. The results of western blotting and immunofluorescence further showed that the nuclear localization of p65, the target, was inhibited by compound 64. The high selective index value indicated that compound 64 had potent selective immunosuppressive activity and can be used as a lead structure compound for immunosuppressants [31].
Compared with compound 64, Libertellenone M (68) showed relatively different anti-inflammatory activity both in vitro and in vivo. It also suppressed the nuclear localization of p65, a subunit of NF-κB, which did not result in a decrease in IL-6, and TNF-α expression, but led to the inhibition of IL-1β and IL-18. Immunoprecipitation and immunofluorescence analysis suggested that the presence of compound 68 blocked the assembly of NLRP3 inflammasome. This inflammasome is a multimeric protein complex that initiates the release of the proinflammatory cytokines IL-1β and IL-18, which are involved in diverse kinds of inflammatory diseases [68]. Compound 68 reduced the cleavage of pro-caspase-1 in a concentration-dependent manner in LPS-activated BMDMs in vitro and in colon tissues from the treated mice in vivo. Although compound 68 seemed to barely interfere with the upstream signaling pathway of the NLRP3 inflammasome, it was able to inhibit the assemble and further activation of the NLRP3 inflammasome, which led to the reduction of IL-1β and IL-18 [69]. This is the difference between the anti-inflammatory mechanism of compound 64 and 68.
Taichunin G (99), K (104), and N (107) were evaluated for their inhibitory activities against nuclear factor-κB ligand (RANKL) induced osteoclastogenesis and cytotoxicity in RAW264 cells. Osteoporotic fractures, related to osteoclasts, are life-threatening to elderly people [70]. In contrast to the monocyte/macrophage lineage, osteoclasts are stimulated by receptor activator of RANKL. And RANKL initiates some downstream signaling pathway (e.g., the NF-κB and MPAK signaling pathways), which leads to the expression of osteoclast-specific genes, including genes encoding tartrate-resistant acid phosphate (TRAP) and enzymes participating in cell fusion. These changes result in the development of mature osteoclasts. The results suggested that Taichunin G (99), K (104), and N (107) obviously reduced TRAP activity and the number of multinucleated osteoclasts, suggesting that these compounds inhibited osteoclast differentiation at 5 μM, and their effects were shown to be dose dependent. Compound 99 exhibited 92% inhibition at a concentration of 0.2 μM [44].
These studies on the pharmacological mechanism of pimarane diterpenes provide potent lead compounds for the development of clinical medicines.

6. Biosynthesis

The biogenesis of pimarane diterpenes was previously assumed to be generate from iso-GGPP. The process involves the dissociation of pyrophosphate anion to produce the (+)-copalyl cation. The remaining acylic allylic cation undergoes a 1,3-sigmatropic hydrogen shift, resulting in a monocyclic carbenium ion. This would isomerize to the ionic precursor of the pimarane skeleton (Figure 20) [3]. However, with further research on the biosynthesis of terpenes and the development of synthetic biology, it is acknowledged that hydrocarbons with different lengths experience a dephosphorylation and cyclization cascade to yield complex terpene scaffolds. These reactions are catalyzed by enzymes, named terpene synthases, which are also referred to as terpene cyclases [1,71].
Terpene synthases, according to the substrate activation mechanism, are generally sorted into two main classes: class Ⅰ terpene synthases and class Ⅱ terpene synthases. The former, also called ionization-dependent terpene synthase, utilizes trinuclear metal clusters to cause the dissociation of the diphosphate group of the substrate to produce the carbocation intermediate and then catalyzes the cyclization reaction, while the latter, also named ionization-dependent terpene synthases, depends on an acid (an aspartic acid side chain) to protonate the terminal C–C double bond to yield the carbocation intermediate [71,72].
Among diterpene synthases, there is the third class of synthases, bifunctional synthases. They have both class Ⅰ and class Ⅱ active sites and can tandemly catalyze two cyclization reactions with different mechanisms [71,72,73]. The crystal structure of abietadiene synthase was the first to prove the existence of bifunctional diterpene synthases [74], and many bacteria producing gibberellins prove the rationality of bifunctional diterpene synthases, though in the bacteria it is two separate enzymes that catalyze the biosynthesis of gibberellins [75].
To date, some bifunctional diterpene synthases have been not only found in many plants, but also in fungi. Except for the conserved motifs, there is little similarity between the sequences of diterpene synthase from fungi and from plants. Homology modelling indicates that the domain organization of fungal bifunctional synthases is the same as that of plants [1]. Although there have been few reports about the biosynthesis of pimarane diterpenes from fungi, researches on the (iso)pimaradiene synthases from plants [76,77] and other tricyclic diterpene synthases [78,79,80] from fungi or plants are helpful for proposing a plausible biosynthesis mechanism of pimarane diterpenes.
In fungi, ent-pimara-8(14), 15-diene synthase from Aspergillus nidulans has been identified as a bifunctional diterpene synthase [81]. This synthase would be an example to propose how ent-pimara-8(14), 15-diene is generated from GGPP by the catalysis of bifunctional diterpene synthase. The first step is the class Ⅱ cyclization reaction of GGPP, which generates ent-copalyl diphosphate. Consequently, the second step catalyzed is the class Ⅰ cyclization reaction, which initiates ionization of ent-copalyl diphosphate and cyclization to produce the ent-pimarenyl cation. The process is terminated by proton elimination to yield ent-pimara-8(14), 15-diene (Figure 21).
Research on the structural and chemical biology of terpene synthase are impressive and profound. There have been tremendous important developments in the biosynthesis of terpenes. However, there was no report of the crystal structure of pimarane diterpene synthases, which means there is much potential to further explore fungal terpene synthases. More studies will be carried out to illuminate the versatility and utility of fungal pimarane terpenoid synthase structure and function.

7. Conclusions

The structures, bioactivities and biosynthesis of pimarane diterpenes from fungi were summarized in this review (Table 1). Except for the general tricyclic diterpene structure of pimarane diterpene, many compounds possess various structures, such as lactones, hemiacetal, epoxy, cyclopropyl, decarbonization, and other common changes (substitution, hydroxylation, acetylation, rearrangement, and ring expansion). These are catalyzed by the cryptic enzymes in fungi. Diverse structures imply multiple potential bioactivities, such as phytotoxicity, cytotoxicity, anti-inflammatory activity, and antibacterial activity. However, their potential medicinal applications require further development.
Natural products from fungi are a treasure for drug discoveries and developments. In fact, the acknowledgement of natural products is not sufficient. Some natural products, such as pimarane diterpenes, account for a minority of the products and need systematic review, which will be beneficial for drug discovery and enrich the applications of natural products. In addition, with the technology developed, the genomes of the fungi can be conveniently obtained. By the synthetic biology method, which is an approach based on heterologous biosynthesis and genome mining, the information of biosynthetic gene clusters and cryptic enzymes can be deciphered and some natural products with excellent bioactivities will be biosynthesised efficiently. By constructing high-yield cell factories, the industrial production of natural products with medicine potentiality, such as pimarane diterpenes, will be realized. Some fungal pimarane diterpenes are biologically active with diverse scaffolds and further research is required for their medicinal application. In the future, on the basis of synthetic biology and fungal natural products, drugs originating from fungal pimarane diterpenes will appear in our sights.

Author Contributions

K.Y. and H.-l.A. conceptualized the review. K.Y. wrote the review with the help of H.-l.A. H.-l.A. reviewed the text and structure the review. All authors have read and agreed to the published version of the manuscript.

Funding

This work was financially supported by the National Natural Science Foundation of China (32000011) and the Fund of State Key Laboratory of Phytochemistry and Plant Resources in West China (P2022-KF03).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data sharing not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Quin, M.B.; Flynn, C.M.; Schmidt-Dannert, C. Traversing the fungal terpenome. Nat. Prod. Rep. 2014, 31, 1449–1473. [Google Scholar] [CrossRef] [Green Version]
  2. Putter, K.M.; van Deenen, N.; Unland, K.; Prufer, D.; Schulze Gronover, C. Isoprenoid biosynthesis in dandelion latex is enhanced by the overexpression of three key enzymes involved in the mevalonate pathway. BMC Plant Biol. 2017, 17, 88. [Google Scholar] [CrossRef] [PubMed]
  3. Breitmaier, E. Terpenes: Importance, General Structure, and Biosynthesis. In Terpenes: Flavors, Fragrances, Pharmaca, Pheromones, 1st ed.; Weily-VCH: Weinheim, German, 2006; pp. 1–9. [Google Scholar]
  4. Zi, J.; Mafu, S.; Peters, R.J. To gibberellins and beyond! Surveying the evolution of (di)terpenoid metabolism. Annu. Rev. Plant Biol. 2014, 65, 259–286. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Reveglia, P.; Cimmino, A.; Masi, M.; Nocera, P.; Berova, N.; Ellestad, G.; Evidente, A. Pimarane diterpenes: Natural source, stereochemical configuration, and biological activity. Chirality 2018, 30, 1115–1134. [Google Scholar] [CrossRef] [PubMed]
  6. Cimmino, A.; Masi, M.; Evidente, M.; Superchi, S.; Evidente, A. Fungal phytotoxins with potential herbicidal activity: Chemical and biological characterization. Nat. Prod. Rep. 2015, 32, 1629–1653. [Google Scholar] [CrossRef] [PubMed]
  7. Evidente, A.; Kornienko, A.; Cimmino, A.; Andolfi, A.; Lefranc, F.; Mathieu, V.; Kiss, R. Fungal metabolites with anticancer activity. Nat. Prod. Rep. 2014, 31, 617–627. [Google Scholar] [CrossRef]
  8. Hawksworth, D.L.; Lucking, R. Fungal Diversity Revisited: 2.2 to 3.8 Million Species. MicroBiol. Spectr. 2017, 5, 1–17. [Google Scholar] [CrossRef]
  9. Meng, L.H.; Li, X.M.; Zhang, F.Z.; Wang, Y.N.; Wang, B.G. Talascortenes A-G, Highly Oxygenated Diterpenoid Acids from the Sea-Anemone-Derived Endozoic Fungus Talaromyces scorteus AS-242. J. Nat. Prod. 2020, 83, 2528–2536. [Google Scholar] [CrossRef]
  10. 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]
  11. Shen, L.; Liu, M.; He, Y.; Al Anbari, W.H.; Li, H.; Lin, S.; Chai, C.; Wang, J.; Hu, Z.; Zhang, Y. Novel Antimicrobial Compounds as Ophiobolin-Type Sesterterpenes and Pimarane-Type Diterpene from Bipolaris Species TJ403-B1. Front. MicroBiol. 2020, 11, 856. [Google Scholar] [CrossRef]
  12. Zhang, L.Q.; Chen, X.C.; Chen, Z.Q.; Wang, G.M.; Zhu, S.G.; Yang, Y.F.; Chen, K.X.; Liu, X.Y.; Li, Y.M. Eutypenoids A-C: Novel Pimarane Diterpenoids from the Arctic Fungus Eutypella sp. D-1. Mar. Drugs 2016, 14, 44. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Yu, H.B.; Wang, X.L.; Zhang, Y.X.; Xu, W.H.; Zhang, J.P.; Zhou, X.Y.; Lu, X.L.; Liu, X.Y.; Jiao, B.H. Libertellenones O-S and Eutypellenones A and B, Pimarane Diterpene Derivatives from the Arctic Fungus Eutypella sp. D-1. J. Nat. Prod. 2018, 81, 1553–1560. [Google Scholar] [CrossRef] [PubMed]
  14. Bai, J.; Mu, R.; Dou, M.; Yan, D.; Liu, B.; Wei, Q.; Wan, J.; Tang, Y.; Hu, Y. Epigenetic modification in histone deacetylase deletion strain of Calcarisporium arbuscula leads to diverse diterpenoids. Acta Pharm. Sin. B 2018, 8, 687–697. [Google Scholar] [CrossRef]
  15. Borgschulte, K.; Rebuffat, S.; Trowitzsch-Kienast, W.; Schomburg, D.; Pinon, J.; Bodo, B. Isolation and structure elucidation of hymatoxins B-E and other phytotoxins from Hypoxylon mammatum fungal pathogen of leuce poplars. Tetrahedron 1991, 47, 8351–8360. [Google Scholar] [CrossRef]
  16. Jossang, A.; Mbeminack, B.; Pinon, J.; Bodo, B. Hymatoxins K and L, Novel Phytotoxins from Hypoxylon mammatum, Fungal Pathogen of Aspens. Nat. Prod. Lett. 1995, 6, 37–42. [Google Scholar] [CrossRef]
  17. Dettrakul, S.; Kittakoop, P.; Isaka, M.; Nopichai, S.; Suyarnsestakorn, C.; Tanticharoen, M.; Thebtaranonth, Y. Antimycobacterial pimarane diterpenes from the Fungus Diaporthe sp. Bioorganic Med. Chem. Lett. 2003, 13, 1253–1255. [Google Scholar] [CrossRef]
  18. 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]
  19. Cui, H.; Liu, Y.; Ding, M.; Zhang, Z.; Liu, H.; Huang, X.; She, Z. New pyranonaphthazarin and 2-naphthoic acid derivatives from the mangrove endophytic fungus Leptosphaerulina sp. SKS032. PhytoChem. Lett. 2017, 20, 214–217. [Google Scholar] [CrossRef]
  20. Yoshida, S.; Kito, K.; Ooi, T.; Kanoh, K.; Shizuri, Y.; Kusumi, T. Four Pimarane Diterpenes from Marine Fungus: Chloroform Incorporated in Crystal Lattice for Absolute Configuration Analysis by X-ray. Chem. Lett. 2007, 36, 1386–1387. [Google Scholar] [CrossRef]
  21. Isaka, M.; Palasarn, S.; Prathumpai, W.; Laksanacharoen, P. Pimarane Diterpenes from the Endophytic Fungus Eutypella sp. BCC 13199. Chem. Pharm. Bull. 2011, 59, 1157–1159. [Google Scholar] [CrossRef]
  22. 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]
  23. 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]
  24. Li, X.; Li, X.-M.; Li, X.-D.; Xu, G.-M.; Liu, Y.; Wang, B.-G. 20-Nor-isopimarane cycloethers from the deep-sea sediment-derived fungus Aspergillus wentii SD-310. RSC Adv. 2016, 6, 75981–75987. [Google Scholar] [CrossRef]
  25. 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]
  26. 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]
  27. Oh, D.C.; Jensen, P.R.; Kauffman, C.A.; Fenical, W. Libertellenones A-D: Induction of cytotoxic diterpenoid biosynthesis by marine microbial competition. Bioorg. Med. Chem. 2005, 13, 5267–5273. [Google Scholar] [CrossRef]
  28. 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]
  29. Lu, X.-L.; Liu, J.-T.; Liu, X.-Y.; Gao, Y.; Zhang, J.; Jiao, B.-H.; Zheng, H. Pimarane diterpenes from the Arctic fungus Eutypella sp. D-1. J. Antibiot. 2014, 67, 171–174. [Google Scholar] [CrossRef]
  30. Wang, H.; Umeokoli, B.O.; Eze, P.; Heering, C.; Janiak, C.; Müller, W.E.G.; Orfali, R.S.; Hartmann, R.; Dai, H.; Lin, W.; et al. Secondary metabolites of the lichen-associated fungus Apiospora montagnei. Tetrahedron Lett. 2017, 58, 1702–1705. [Google Scholar] [CrossRef]
  31. Wei, W.; Gao, J.; Shen, Y.; Chu, Y.L.; Xu, Q.; Tan, R.X. Immunosuppressive Diterpenes from Phomopsis sp. S12. Eur. J. Org. Chem. 2014, 2014, 5728–5734. [Google Scholar] [CrossRef]
  32. Wang, X.; Sun, K.; Wang, B. Bioactive Pimarane Diterpenes from the Arctic Fungus Eutypella sp. D-1. Chem. Biodivers. 2018, 15, e1700501. [Google Scholar] [CrossRef]
  33. Kildgaard, S.; Subko, K.; Phillips, E.; Goidts, V.; de la Cruz, M.; Díaz, C.; Gotfredsen, C.H.; Andersen, B.; Frisvad, J.C.; Nielsen, K.F.; et al. A Dereplication and Bioguided Discovery Approach to Reveal New Compounds from a Marine-Derived Fungus Stilbella fimetaria. Mar. Drugs 2017, 15, 253. [Google Scholar] [CrossRef] [Green Version]
  34. Pongcharoen, W.; Rukachaisirikul, V.; Phongpaichit, S.; Rungjindamai, N.; Sakayaroj, J. Pimarane Diterpene and Cytochalasin Derivatives from the Endophytic Fungus Eutypella scoparia PSU-D44. J. Nat. Prod. 2006, 69, 856–858. [Google Scholar] [CrossRef]
  35. 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] [Green Version]
  36. 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]
  37. Klemke, C.; Kehraus, S.; Wright, A.D.; König, G.M. New secondary metabolites from the marine endophytic fungus Apiospora montagnei. J. Nat. Prod. 2004, 67, 1058–1063. [Google Scholar] [CrossRef]
  38. Hsu, Y.-H.; Nakagawa, M.; Hirota, A.; Shima, S.; Nakayama, M. Structure of Myrocin B, a New Diterpene Antibiotic Produced by Myrothecium verrucaria. Agric. Biol. Chem. 1988, 52, 1305–1307. [Google Scholar] [CrossRef] [Green Version]
  39. Hsu, Y.H.; Hirota, A.; Shima, S.; Nakagawa, M.; Nozaki, H.; Tada, T.; Nakayama, M. Structure of Myrocin C, a New Diterpene Antibiotic Produced by a Strain of Myrothecium sp. Agric. Biol. Chem. 1987, 51, 3455–3457. [Google Scholar] [CrossRef]
  40. Evidente, A.; Sparapano, L.; Motta, A.; Giordano, F.; Fierro, O.; Frisullo, S. A phytotoxic pimarane diterpene of Sphaeropsis sapinea f. sp. Cupressi, the pathogen of a canker disease of cypress. PhytoChemistry 1996, 42, 1541–1546. [Google Scholar] [CrossRef]
  41. Evidente, A.; Sparapano, L.; Fierro, O.; Bruno, G.; Giordano, F.; Motta, A. Sphaeropsidins B and C, phytotoxic pimarane diterpenes from Sphaeropsis sapinea f. sp. Cupressi and Diplodia mutila. PhytoChemistry 1997, 45, 705–713. [Google Scholar] [CrossRef]
  42. Evidente, A.; Sparapano, L.; Bruno, G.; Motta, A. Sphaeropsidins D and E, two other pimarane diterpenes, produced in vitro by the plant pathogenic fungus Sphaeropsis sapinea f. sp. cupressi. PhytoChemistry 2002, 59, 817–823. [Google Scholar] [CrossRef]
  43. Kato, H.; Sebe, M.; Nagaki, M.; Eguchi, K.; Kagiyama, I.; Hitora, Y.; Frisvad, J.C.; Williams, R.M.; Tsukamoto, S. Taichunins A–D, Norditerpenes from Aspergillus taichungensis (IBT 19404). J. Nat. Prod. 2019, 82, 1377–1381. [Google Scholar] [CrossRef]
  44. El-Desoky, A.H.H.; Inada, N.; Maeyama, Y.; Kato, H.; Hitora, Y.; Sebe, M.; Nagaki, M.; Kai, A.; Eguchi, K.; Inazumi, T.; et al. Taichunins E-T, Isopimarane Diterpenes and a 20-nor-Isopimarane, from Aspergillus taichungensis (IBT 19404): Structures and Inhibitory Effects on RANKL-Induced Formation of Multinuclear Osteoclasts. J. Nat. Prod. 2021, 84, 2475–2485. [Google Scholar] [CrossRef]
  45. Guo, Z.K.; Yan, T.; Guo, Y.; Song, Y.C.; Jiao, R.H.; Tan, R.X.; Ge, H.M. p-Terphenyl and Diterpenoid Metabolites from Endophytic Aspergillus sp. YXf3. J. Nat. Prod. 2012, 75, 15–21. [Google Scholar] [CrossRef]
  46. Li, Y.-Y.; Hu, Z.-Y.; Lu, C.-H.; Shen, Y.-M. Four New Terpenoids from Xylaria sp. 101. Helv. Chim. Acta 2010, 93, 796–802. [Google Scholar] [CrossRef]
  47. Isaka, M.; Yangchum, A.; Supothina, S.; Chanthaket, R.; Srikitikulchai, P. Isopimaranes and eremophilanes from the wood-decay fungus Xylaria allantoidea BCC 23163. PhytoChem. Lett. 2014, 8, 59–64. [Google Scholar] [CrossRef]
  48. Chen, H.-P.; Li, J.; Zhao, Z.-Z.; Li, X.; Liu, S.-L.; Wang, Q.-Y.; Liu, J.-K. Diterpenes with bicyclo [2.2.2]octane moieties from the fungicolous fungus Xylaria longipes HFG101811. Org. Biomol. Chem. 2020, 18, 2410–2415. [Google Scholar] [CrossRef]
  49. Chen, H.-P.; Zhao, Z.-Z.; Cheng, G.-G.; Zhao, K.; Han, K.-Y.; Zhou, L.; Feng, T.; Li, Z.-H.; Liu, J.-K. Immunosuppressive Nor-isopimarane Diterpenes from Cultures of the Fungicolous Fungus Xylaria longipes HFG1018. J. Nat. Prod. 2020, 83, 401–412. [Google Scholar] [CrossRef]
  50. Wang, Q.-Y.; Chen, H.-P.; Liu, J.-K. Isopimarane diterpenes from the rice fermentation of the fungicolous fungus Xylaria longipes HFG1018. PhytoChem. Lett. 2021, 45, 100–104. [Google Scholar] [CrossRef]
  51. Isaka, M.; Srisanoh, U.; Sappan, M.; Kongthong, S.; Srikitikulchai, P. Eremophilane and eudesmane sesquiterpenoids and a pimarane diterpenoid from the wood-decay fungus Xylaria sp. BCC 5484. PhytoChem. Lett. 2012, 5, 78–82. [Google Scholar] [CrossRef]
  52. Wu, S.H.; He, J.; Li, X.N.; Huang, R.; Song, F.; Chen, Y.W.; Miao, C.P. Guaiane sesquiterpenes and isopimarane diterpenes from an endophytic fungus Xylaria sp. PhytoChemistry 2014, 105, 197–204. [Google Scholar] [CrossRef] [PubMed]
  53. Ding, J.H.; Li, Z.H.; Feng, T.; Liu, J.K. Inonotolides A-C, isopimarane diterpenoid lactones from Inonotus sinensis. Fitoterapia 2018, 127, 410–412. [Google Scholar] [CrossRef] [PubMed]
  54. Findlay, J.A.; Li, G.; Penner, P.E.; Miller, J.D. Novel Diterpenoid Insect Toxins from a Conifer Endophyte. J. Nat. Prod. 1995, 58, 197–200. [Google Scholar] [CrossRef]
  55. Shiono, Y.; Motoki, S.; Koseki, T.; Murayama, T.; Tojima, M.; Kimura, K. Isopimarane diterpene glycosides, apoptosis inducers, obtained from fruiting bodies of the ascomycete Xylaria polymorpha. PhytoChemistry 2009, 70, 935–939. [Google Scholar] [CrossRef] [PubMed]
  56. Shiono, Y.; Kikuchi, M.; Koseki, T.; Murayama, T.; Kwon, E.; Aburai, N.; Kimura, K. Isopimarane diterpene glycosides, isolated from endophytic fungus Paraconiothyrium sp. MY-42. PhytoChemistry 2011, 72, 1400–1405. [Google Scholar] [CrossRef] [PubMed]
  57. Zhou, P.; Zheng, M.; Li, X.-N.; Wei, M.; Zhang, M.; Li, Q.; Zang, Y.; Sun, W.; Wang, J.; Zhu, H.; et al. Hypoxylonoids A−G: Isopimarane diterpene glycosides from Xylaria hypoxylon. PhytoChemistry 2021, 182, 112613. [Google Scholar] [CrossRef]
  58. Afiyatullov, S.S.; Kalinovsky, A.I.; Kuznetsova, T.A.; Isakov, V.V.; Pivkin, M.V.; Dmitrenok, P.S.; Elyakov, G.B. New Diterpene Glycosides of the Fungus Acremonium striatisporum Isolated from a Sea Cucumber. J. Nat. Prod. 2002, 65, 641–644. [Google Scholar] [CrossRef] [PubMed]
  59. Cimmino, A.; Andolfi, A.; Zonno, M.C.; Avolio, F.; Santini, A.; Tuzi, A.; Berestetskyi, A.; Vurro, M.; Evidente, A. Chenopodolin: A phytotoxic unrearranged ent-pimaradiene diterpene produced by Phoma chenopodicola, a fungal pathogen for Chenopodium album biocontrol. J. Nat. Prod. 2013, 76, 1291–1297. [Google Scholar] [CrossRef]
  60. Evidente, M.; Cimmino, A.; Zonno, M.C.; Masi, M.; Berestetskyi, A.; Santoro, E.; Superchi, S.; Vurro, M.; Evidente, A. Phytotoxins produced by Phoma chenopodiicola, a fungal pathogen of Chenopodium album. PhytoChemistry 2015, 117, 482–488. [Google Scholar] [CrossRef]
  61. Andolfi, A.; Maddau, L.; Basso, S.; Linaldeddu, B.T.; Cimmino, A.; Scanu, B.; Deidda, A.; Tuzi, A.; Evidente, A. Diplopimarane, a 20-nor-ent-Pimarane Produced by the Oak Pathogen Diplodia quercivora. J. Nat. Prod. 2014, 77, 2352–2360. [Google Scholar] [CrossRef]
  62. Xia, J.-N.; Hu, K.; Su, X.-Z.; Tang, J.-W.; Li, X.-N.; Sun, H.-D.; Puno, P.-T. Discovery of ent-kaurane diterpenoids, characteristic metabolites of Isodon species, from an endophytic fungal strain Geopyxis sp. XY93 inhabiting Isodon parvifolia. Fitoterapia 2022, 158, 105160. [Google Scholar] [CrossRef] [PubMed]
  63. Bromann, K.; Viljanen, K.; Moreira, V.M.; Yli-Kauhaluoma, J.T.; Ruohonen, L.; Nakari-Setälä, T. Isolation and purification of ent-pimara-8(14),15-diene from engineered Aspergillus nidulans by accelerated solvent extraction combined with HPLC. Anal. Methods 2014, 6, 1227–1234. [Google Scholar] [CrossRef] [Green Version]
  64. Severiano, M.E.; Simao, M.R.; Porto, T.S.; Martins, C.H.; Veneziani, R.C.; Furtado, N.A.; Arakawa, N.S.; Said, S.; Oliveira, D.C.; Cunha, W.R.; et al. Anticariogenic Properties of ent-Pimarane Diterpenes Obtained by Microbial Transformation. Molecules 2010, 15, 8553–8566. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Fraga, B.M.; Guillermo, R.; Hernández, M.G.; Chamy, M.C.; Garbarino, J.A. Biotransformation of Two ent-Pimara-9(11),15-diene Derivatives by Gibberella fujikuroi. J. Nat. Prod. 2009, 72, 87–91. [Google Scholar] [CrossRef] [PubMed]
  66. Lu, J.; Holmgren, A. The thioredoxin antioxidant system. Free. Radic. Biol. Med. 2014, 66, 75–87. [Google Scholar] [CrossRef]
  67. Zhang, W.; Zhu, Y.; Yu, H.; Liu, X.; Jiao, B.; Lu, X. Libertellenone H, a Natural Pimarane Diterpenoid, Inhibits Thioredoxin System and Induces ROS-Mediated Apoptosis in Human Pancreatic Cancer Cells. Molecules 2021, 26, 315. [Google Scholar] [CrossRef]
  68. Yang, Y.; Yu, G. The analysis of social resource mobilization on new media: A case study of Chinese environmental protection documentary Under the Dome. Telemat. Inform. 2019, 37, 128–136. [Google Scholar] [CrossRef]
  69. Fan, M.; Xiang, G.; Chen, J.; Gao, J.; Xue, W.; Wang, Y.; Li, W.; Zhou, L.; Jiao, R.; Shen, Y.; et al. Libertellenone M, a diterpene derived from an endophytic fungus Phomopsis sp. S12, protects against DSS-induced colitis via inhibiting both nuclear translocation of NF-κB and NLRP3 inflammasome activation. Int. Immunopharmacol. 2020, 80, 106144. [Google Scholar] [CrossRef]
  70. Rachner, T.D.; Khosla, S.; Hofbauer, L.C. Osteoporosis: Now and the future. Lancet 2011, 377, 1276–1287. [Google Scholar] [CrossRef] [Green Version]
  71. Christianson, D.W. Structural and Chemical Biology of Terpenoid Cyclases. Chem. Rev. 2017, 117, 11570–11648. [Google Scholar] [CrossRef]
  72. Oldfield, E.; Lin, F.Y. Terpene biosynthesis: Modularity rules. Angew. Chem. Int. Ed. Engl. 2012, 51, 1124–1137. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Faylo, J.L.; Ronnebaum, T.A.; Christianson, D.W. Assembly-Line Catalysis in Bifunctional Terpene Synthases. Acc. Chem. Res. 2021, 54, 3780–3791. [Google Scholar] [CrossRef]
  74. Zhou, K.; Gao, Y.; Hoy, J.A.; Mann, F.M.; Honzatko, R.B.; Peters, R.J. Insights into Diterpene Cyclization from Structure of Bifunctional Abietadiene Synthase from Abies grandis. J. Biol. Chem. 2012, 287, 6840–6850. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Morrone, D.; Chambers, J.; Lowry, L.; Kim, G.; Anterola, A.; Bender, K.; Peters, R.J. Gibberellin biosynthesis in bacteria: Separate ent-copalyl diphosphate and ent-kaurene synthases in Bradyrhizobium japonicum. FEBS Lett. 2009, 583, 475–480. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Hall, D.E.; Zerbe, P.; Jancsik, S.; Quesada, A.L.; Dullat, H.; Madilao, L.L.; Yuen, M.; Bohlmann, J. Evolution of conifer diterpene synthases: Diterpene resin acid biosynthesis in lodgepole pine and jack pine involves monofunctional and bifunctional diterpene synthases. Plant Physiol. 2013, 161, 600–616. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Toyomasu, T. Recent Advances Regarding Diterpene Cyclase Genes in Higher Plants and Fungi. Biosci. Biotechnol. Biochem. 2008, 72, 1168–1175. [Google Scholar] [CrossRef] [Green Version]
  78. Peters, R.J.; Carter, O.A.; Zhang, Y.; Matthews, B.W.; Croteau, R.B. Bifunctional Abietadiene Synthase: Mutual Structural Dependence of the Active Sites for Protonation-Initiated and Ionization-Initiated Cyclizations. Biochemistry 2003, 42, 2700–2707. [Google Scholar] [CrossRef]
  79. Ravn, M.M.; Peters, R.J.; Coates, R.M.; Croteau, R. Mechanism of Abietadiene Synthase Catalysis:  Stereochemistry and Stabilization of the Cryptic Pimarenyl Carbocation Intermediates. J. Am. Chem. Soc. 2002, 124, 6998–7006. [Google Scholar] [CrossRef]
  80. Liu, W.; Feng, X.; Zheng, Y.; Huang, C.-H.; Nakano, C.; Hoshino, T.; Bogue, S.; Ko, T.P.; Chen, C.-C.; Cui, Y.; et al. Structure, function and inhibition of ent-kaurene synthase from Bradyrhizobium japonicum. Sci. Rep. 2014, 4, 6214. [Google Scholar] [CrossRef] [Green Version]
  81. Bromann, K.; Toivari, M.; Viljanen, K.; Vuoristo, A.; Ruohonen, L.; Nakari-Setala, T. Identification and characterization of a novel diterpene gene cluster in Aspergillus nidulans. PLoS ONE 2012, 7, e35450. [Google Scholar]
Pharmaceuticals 15 01291 g001 550
Figure 1. Structures of four kinds of pimarane diterpenes.
Figure 1. Structures of four kinds of pimarane diterpenes.
Pharmaceuticals 15 01291 g001
Pharmaceuticals 15 01291 g002 550
Figure 2. Structures of compounds 1–18.
Figure 2. Structures of compounds 1–18.
Pharmaceuticals 15 01291 g002
Pharmaceuticals 15 01291 g003 550
Figure 3. Structures of compounds 19–31.
Figure 3. Structures of compounds 19–31.
Pharmaceuticals 15 01291 g003
Pharmaceuticals 15 01291 g004 550
Figure 4. Structures of compounds 32–53.
Figure 4. Structures of compounds 32–53.
Pharmaceuticals 15 01291 g004
Pharmaceuticals 15 01291 g005 550
Figure 5. Structures of compounds 54–65.
Figure 5. Structures of compounds 54–65.
Pharmaceuticals 15 01291 g005
Pharmaceuticals 15 01291 g006 550
Figure 6. Structures of compounds 66–71.
Figure 6. Structures of compounds 66–71.
Pharmaceuticals 15 01291 g006
Pharmaceuticals 15 01291 g007 550
Figure 7. Structures of compounds 72–81.
Figure 7. Structures of compounds 72–81.
Pharmaceuticals 15 01291 g007
Pharmaceuticals 15 01291 g008 550
Figure 8. Structures of compounds 82–87.
Figure 8. Structures of compounds 82–87.
Pharmaceuticals 15 01291 g008
Pharmaceuticals 15 01291 g009 550
Figure 9. Structures of compounds 88–92.
Figure 9. Structures of compounds 88–92.
Pharmaceuticals 15 01291 g009
Pharmaceuticals 15 01291 g010 550
Figure 10. Structures of compounds 93–114.
Figure 10. Structures of compounds 93–114.
Pharmaceuticals 15 01291 g010
Pharmaceuticals 15 01291 g011 550
Figure 11. Structures of compounds 115–120.
Figure 11. Structures of compounds 115–120.
Pharmaceuticals 15 01291 g011
Pharmaceuticals 15 01291 g012 550
Figure 12. Structures of compounds 121–141.
Figure 12. Structures of compounds 121–141.
Pharmaceuticals 15 01291 g012
Pharmaceuticals 15 01291 g013 550
Figure 13. Structures of compounds 142–145.
Figure 13. Structures of compounds 142–145.
Pharmaceuticals 15 01291 g013
Pharmaceuticals 15 01291 g014 550
Figure 14. Structures of compounds 146–152.
Figure 14. Structures of compounds 146–152.
Pharmaceuticals 15 01291 g014
Pharmaceuticals 15 01291 g015 550
Figure 15. Structures of compounds 153–161.
Figure 15. Structures of compounds 153–161.
Pharmaceuticals 15 01291 g015
Pharmaceuticals 15 01291 g016 550
Figure 16. Structures of compounds 162–173.
Figure 16. Structures of compounds 162–173.
Pharmaceuticals 15 01291 g016
Pharmaceuticals 15 01291 g017 550
Figure 17. Structures of compounds 174–176.
Figure 17. Structures of compounds 174–176.
Pharmaceuticals 15 01291 g017
Pharmaceuticals 15 01291 g018 550
Figure 18. Structures of compounds 177–183.
Figure 18. Structures of compounds 177–183.
Pharmaceuticals 15 01291 g018
Pharmaceuticals 15 01291 g019 550
Figure 19. Structures of compounds 184–197.
Figure 19. Structures of compounds 184–197.
Pharmaceuticals 15 01291 g019
Pharmaceuticals 15 01291 g020 550
Figure 20. Previous biosynthesis of pimarane diterpene skeletons.
Figure 20. Previous biosynthesis of pimarane diterpene skeletons.
Pharmaceuticals 15 01291 g020
Pharmaceuticals 15 01291 g021 550
Figure 21. Biosynthesis of ent-pimara-8(14), 15-diene.
Figure 21. Biosynthesis of ent-pimara-8(14), 15-diene.
Pharmaceuticals 15 01291 g021
Table
Table 1. Pimarane diterpens from fungi.
Table 1. Pimarane diterpens from fungi.
CompoundFungal SpeciesBioactivityReference
Talascortenes C–G (1–5)Talaromyces scorteusAntimicrobial
activity		[9]
Botryopimrane A (6)Botryotinia fuckeliana/[10]
1β-hydroxy momilactone A (7)Bipolaris sp./[11]
Euypenoids A–C (8–10)Eutypella sp.Immunosuppressive activity[12]
Libertellenones R–S (11–12)Eutypella sp./[13]
Calcarisporic acids E–J (13–18)Calcarisporium arbuscula/[14]
Hymatoxins A–E (19–23)Hypoxylon mammatumPhytotoxic activity[15]
Hymatoxins K (24) and L (25)Hypoxylon mammatum Xylaria allantoideaPhytotoxic activity[16,47]
Diaporthein A (26)Diaporthe sp.Antimycobacterial
activity		[17]
Diaporthein B (27)Diaporthe sp.
Leptosphaerulina sp. Epicoccum sp.		[17,19,22]
Diporthein C (28)Penicillium
sclerotiorum		/[18]
Deoxydiportherin A (29)Cryptosphaeria eunomi/[20]
Eutypellones A (30) and B (31)Eutypella sp.Cytotoxic activity[21]
Apsergilones A (32) and B (33)Epicoccum sp.Cytotoxic activity[22]
Apsergilone C (34)Epicoccum sp. and Aspergillus wentii[22,23]
Wentinoid A (35)Aspergillus wentiiAntimycobacterial
activity		[23]
Wentinoids B–F (36–40)/
Asprethers A–E (41–45)Aspergillus wentiiCytotoxic activity[24]
Aspewentins A–C (46–48)Aspergillus wentiiInhibitory activity against marine planktons[25]
Aspewentins D–H (49–53)Aspergillus wentiiAntimycobacterial
activity		[26]
Libertellenones A (54), B (55), and D (57)Libertella sp.cytotoxic activity[27]
Libertellenone C (56)Libertella sp. Arthrinium saccharicytotoxic activity and antiproliferative activity[27,28]
Libertellenones E (58) and F (59)Arthrinium sacchariAntiproliferation[28]
Libertellenone G (60)Eutypella sp.antibacterial activity[29]
Libertellenone H (61)Cytotoxic activity
Libertellenone G (62) and L (63)Apiospora montagnei/[30]
Libertellenone J (64)Phomopsis sp.anti-inflammatory activity[31]
Libertellenone K (65)/
Libertellenone M (66)Eutypella sp.Cytotoxic activity[32]
Libertellenone N (67)
Libertellenone M (68)Stilbella fimetariaCytotoxic activity[33]
Libertellenones O–P (69–71)Eutypella spCytotoxic activity[13]
Scopararanes A–B (72–73)Eutypella sccparia/[34]
Scopararanes C–E (74–76), and G (78)Eutypella sccpariaCytotoxic activity[35]
Scopararanes F (77)/
Scopararane H (79)Eutypella sp./[36]
Scopararane I (80)Cytotoxic activity
Myrocin A (82)Apiospora montagnei./[37]
Myrocin B (83)Myrothecium verrucariaantimicrobial activity[38]
Myrocin C (84)Myrothecium sp.antimicrobial activity[39]
Myrocin D (85)Arthrinium sacchari/[28]
Myrocin E (86)Phomopsis sp./[31]
Myrocin F (87)Stilbella fimetariaCytotoxic activity[33]
Sphaeropsidins A–B (88–89)Sphaeropsis sapineaphytotoxicity[40]
Sphaeropsidin C (90)Diplodia mutila[41]
Sphaeropsidin D (91)Sphaeropsis sapineaphytotoxicity[42]
Sphaeropsidin E (92)/
Taichunin A (93)Aspergillus taichungensisCytotoxic activity[43]
Taichunins B–D (94–96)/
Taichunins E (97), F (98), H–J (100–102), L–M (104–105), and O–T (107–112)Aspergillus taichungensis/[44]
Taichunin G (99)Inhibitory Effects on RANKL-Induced Formation of Multinuclear Osteoclasts
Taichunin K (103)
Taichunin N (106)
1β, 7α-dihydroxysandaracopimar-8(14), 15-diene19 (113)/
Apsergiloid D (114)Aspergillus sp./[45]
Xylarenolide (115)Xylaria sp.
Xylaria allantoidea		/[46,47]
Xylallantins A–C (116–118)Xylaria allantoidea/[47]
Xylarilongipin A (119)Xylaria longipesImmunosuppressive activity[48]
Xylarilongipin B (120)/
Xylarinorditerpenes A (121), F–H (126–128), J–M (130–133), O (135), and (136)Xylaria longipes/[49]
Xylarinorditerpenes B–E (122–125), I (129), N (134), Q (137), and R (138)Immunosuppressive activity
Xylongoic acids A–C (139–141)Xylaria longipes/[50]
Compound 142Xylaria sp./[51]
14α,16-epoxy-18-norisopimar-7-en-4α-ol (143), 16-O-sulfo-18-norisopimar-7-en-4α,16-diol (144), and 9-deoxy-hymatoxin A (145)Xylaria sp.Antifungal activity[52]
Calcarisporic acid K (146) and L (147)Calcarisporium arbuscula/[14]
Inonotolides A–C (148–150)Inonotus sinensis/[53]
9α-hydroxy-l, 8(14), 15-isopimaratriene-3, 7, 1l-trione (151) and 9α-hydroxy-l, 8(14), 15-isopimaratriene-3, 11-dione (152)Hormononema dermatioides
Phyllosticta sp.		insect toxicity[54]
16-α-D-mannopyranosyloxyisopimar-7-en-19-oic acid (153), 15-hydroxy-16-α-D-mannopyranosyloxyisopimar-7-en-19-oic acid (154), and 16-α-D-glucopyranosyloxyisopimar-7-en-19-oic acid (155)Xylaria polymorphainhibitory activity against tumour cell lines[55]
Compound 156 and 159–161Paraconiothyrium sp./[56]
Compound 157 and 158Cytotoxic activity
Hypoxylonoids A–G (162–168)Xylaria hypoxylon/[57]
Compound 169–173
Virescenosides O–Q (174–176)Acremonium striatisporumCytotoxic activity[58]
Chenopodolin (177)Phoma chenopodiicolaphytotoxic activity[59]
chenopodolin B (178)Phoma chenopodiicolaphytotoxic activity[60]
Diplopimarane (179)Diplodia quercivoraphytotoxic activity, zootoxicity, antifungal activity[61]
Eutypellenones A (180) and B (181)Eutypella sp.anti-inflammatory activity, cytotoxicity[13]
Isogeopyxin B (182)Geopyxis sp./[62]
ent-Pimara-8(14), 15-diene (183)Aspergillus nidulansantioxidant activity[63]
compounds 184, 185, and 186Glomerella cingulateMucor rouxiiantibacterial activity[64]
ent-8(14),15-pimaradien-19-ol (187)/
9-hydroxy-13-epi-ent-pimara-9(11),15-diene (188) and 13-epi-ent-pimara-9 (11),15-diene-19-oic acid (189)//[65]
Compounds 190–193Gibberella fujikuroi/
Compounds 194–197Gibberella fujikuroi/
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Ye, K.; Ai, H.-l. Pimarane Diterpenes from Fungi. Pharmaceuticals 2022, 15, 1291. https://doi.org/10.3390/ph15101291

AMA Style

Ye K, Ai H-l. Pimarane Diterpenes from Fungi. Pharmaceuticals. 2022; 15(10):1291. https://doi.org/10.3390/ph15101291

Chicago/Turabian Style

Ye, Ke, and Hong-lian Ai. 2022. "Pimarane Diterpenes from Fungi" Pharmaceuticals 15, no. 10: 1291. https://doi.org/10.3390/ph15101291

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop