Progress on Terpenoids With Biological Activities Produced by Plant Endophytic Fungi in China Between 2017 and 2019

Abstract

Plant endophytic fungi are an important part of plant microecosystems and a natural resource for human survival and development. Various bioactive natural products produced by plant endophytic fungi show promising prospects in biopharmacy, agricultural production, and industrial fermentation. Terpenoids, the most numerous and structurally diverse natural products from endophytic fungi, possess a broad range of biological activities and huge potential for drug development. It is critically significant for ecological and economic benefits to develop their activities. This paper utilized literature analysis to summarize 200 terpenoids with biological activities that are derived from plant endophytic fungi in China between 2017 and 2019. Among them, sesquiterpenoids were the most important kind of terpenoids, and Trichoderma and Aspergillus species were main terpenoid-producing plant endophytic fungi. Furthermore, these terpenoids displayed multifarious biological activities, including antimicrobial, antipathogenic, and anti-inflammatory activities, as well as cytotoxicity, antitumor agents, and enzyme inhibition.

Keywords

plant endophytic fungi terpenoids biological activities sesquiterpenoids

Endophytic fungi are organisms that live in healthy plants at a certain period of time, but do not cause significant infection in host plant tissues. Endophytes are an ecological concept rather than a taxonomic unit and are natural components of the plant microecosystem. Since Vogl¹ isolated the first endophytic fungi from ryegrass seeds in 1898, endophytic fungi have obtained more and more attention as a new microbial resource. In 1993, an endophytic fungus named Taxomyces andreanae which could produce taxol was isolated from the phloem of Taxus brevifalia Nutt by Strobel et al,² and aroused great interest from scholars worldwide. Both Petrini³ and Dreyfuss and Chapela⁴ estimated that there are at least 1 million species of endophytic fungi in nature that are considered an important component of biodiversity.^5,6 China contains abundant plant resources including a huge database of endophytic fungi. Chinese researchers have isolated an abundant variety of novel secondary metabolites from endophytic fungi. The discovery of and search for new active compounds from endophytic fungi have become hot topics around the world.

Endophytic fungi have been associated with plants for over 400 million years.⁷ They are ubiquitous and widely distributed in various terrestrial and aquatic plants, ie, mosses,⁸ ferns,⁹ grasses,^10,11 shrubs,¹² deciduous and coniferous trees,^13

-16 and lichens.^17
-19 Endophytic fungi and their host plants can co-evolve for a long time, and they have a mutually beneficial symbiosis.²⁰ Endophytic fungi have become an important source of structurally unique secondary metabolites such as terpenoids, polyketides, alkaloids, benzopyranones, benzoquinones, phenols, steroids, tetralones, and xanthones. Furthermore, they also show diverse potential bioactivities, ie, antifungal, antiviral, antibacterial, cytotoxic, and immunosuppressive activities, as well as wide potential for the exploration of novel therapies.

Terpenoids can also be regarded as a class of natural products linked in various ways by isoprene or isopentane. Terpenoids are widely distributed in nature and classified based on the isoprene rule, including hemiterpenoids, monoterpenoids, sesquiterpenoids, diterpenoids, sesterterpenoids, and triterpenoids. Several studies indicated that terpenoids have significant biological activity, and many terpenoids have been used clinically with great curative effects. Paclitaxel, a diterpene derivative, is isolated from the bark²¹ and endophytic fungus T. andreanae ²² of Taxus brevifolia. Paclitaxel has a positive therapeutic effect on a variety of cancers such as ovarian, breast, colon, rectal, bladder, and lung cancer, as well as on rheumatoid arthritis by inhibiting microtubules depolymerization and stabilizing microtubules, thereby affecting mitosis. Terpenoids are recognized as a diverse group of natural compounds possessing a broad range of biological activities and huge potential for drug development. Therefore, it is important to study novel and active terpenoids isolated from endophytic fungi.

This paper summarized the research progress on terpenoids and biological activities from plant endophytic fungi between 2017 and 2019 through literature analysis of studies reported by Chinese researchers. A total of 200 terpenoids were obtained from the plant endophytic fungi genera Aspergillus, Trichoderma, Penicillium, Bipolaris, Phomopsis, and Paraconiothyrium, including monoterpenoids 1 to 4, sesquiterpenoids 5 to 117, diterpenoids 118 to 131, sesterterpenoids 132 to 159, triterpenoids 160 to 170, and meroterpenoids 171 to 200. These terpenoids showed diverse biological activities such as antibacterial, antifungal, antipathogenic, cytotoxic, antitumor, and hyperglycemic activities, as well as latent hepatic protection, promotion of root growth, and quinone reductase-inducing activity. These studies proposed the future developmental direction of research on endophytic fungi and active substances and provided references for future research.

Results and Discussion

This review summarized the remarkable findings from characteristic terpenoids and biological activities of plant endophytic fungi over a 3-year period from 2017 to 2019. All relevant databases were searched for the keywords “endophytic fungi,” “plant endophytic fungi,” and “terpenoids.” By searching through foreign language databases like PubMed, SpringerLink, and ACS publication, as well as Chinese databases like CNKI and Wanfang Data, more than 600 Chinese and English articles in total were selected and about 46 references were cited in this paper.

Monoterpenoids

Monoterpenoids consist of a 10-carbon backbone (2 isoprene units) structure and can be divided into 3 subgroups: acyclic, monocyclic, and bicyclic. Three carene-type monoterpenoids, 2-carene-5,8-diol (1), 2-carene-8,10-diol (2), and 2-carene-8-acetamide (3), and 1 menthene-type monoterpenoid, 8-hydroxy-1,7-expoxy-2-menthene (4), were isolated from the endophytic fungus Periconia sp. F-31, which was separated from the medicinal plant Annona muricata, is distributed in the Hainan Province, China.²³ The structures of these monoterpenoids are displayed in Figure 1.

Figure 1

Chemical structures of monoterpenoids 1-4.

Sesquiterpenoids

Sesquiterpenoids are the most diverse group of terpenoids derived from 3 isoprene units and exist in a wide variety of forms. According to our literature analysis, this paper summarized 145 characteristic examples of sesquiterpenoids isolated from plant endophytic fungi between 2017 and 2019, including bisabolane, cadinane, cyclonerane, guaiane, hirsutane, tremulane, protoilludane, eudesmane, illudalane, eremophilane, drimane, sativene, trichothecene, and other different types. These sesquiterpenoids exhibited a variety of biological activities such as antibacterial, antifungal, antipathogenic, antitumor, and hyperglycemic activities, as well as latent hepatic protection effects, and promotion of root growth. Moreover, Aspergillus, Trichoderma, and Penicillium species were the most important sesquiterpenoid-producing endophytic fungi.

A total of 19 bisabolane-type sesquiterpenes (5-23) were isolated from plant endophytic fungi and are displayed in Figure 2. Interestingly, a majority of these bisabolane sesquiterpenoids have been isolated from Aspergillus species and some bisabolane-type sesquiterpenoids showed antitumor and hyperglycemic effects. Fumagillenes A and B (5-6) were isolated from a fermentation broth of Aspergillus fumigatus, a root endophyte of Ligusticum wallichii from Dujiangyan city in the suburb of Chengdu, China.²⁴ Compounds 5 and 6 exhibited moderate growth inhibition against MV4-11 and MDA-MB-231 cell lines.²⁴ Sesquiterpenoids 7 to 10, 4 phenolic bisabolanes, were isolated from a culture of the endophytic fungus Aspergillus flavus QQSG-3 which was obtained from a fresh branch of Kandelia obobata from Huizhou city in the province of Guangdong, China.^²⁵ Compounds 7 and 9 showed strong α-glucosidase inhibitory effects with IC₅₀ values in the range of 1.5 to 4.5 µM.²⁵ Aspergoterpenins B-D (11-13), 4 bisabolane sesquiterpenoid derivatives, were obtained from the endophytic fungus Aspergillus versicolor from the healthy leaves of Elaeocarpus decipiens Hemsl.²⁶ Two phenolic bisabolane-type sesquiterpenoids, (7S,11S)-(+)-11-hydroxyl-sydonol (14) and (7S,11S)-(+)-11-hydroxyl aspergiterpenoid A (15), were isolated from a cultivation extract of Aspergillus sp. CM 112 which was isolated from the stems of Cephalotaxus mannii Hook. f. collected in Xishuangbanna, Yunnan, China.²⁷

Figure 2

Chemical structures of bisabolane-type sesquiterpenes 5-23.

In addition, Trichoderma species have been an important of bisabolane sesquiterpenoid-producing fungi. Bisabolan-1,10,11-triol (16) was isolated from a culture of the endophytic fungus Trichoderma asperellum cf44-2, which was obtained from the inner tissue of the marine brown alga Sargassum sp. from the Zhoushan Islands.²⁸ An examination of the endophytic fungus T. asperellum A-YMD-9-2, which was obtained from the marine red alga Gracilaria verrucosa, led to the isolation of 7 chromanoid norbisabolane derivatives, trichobisabolins I-L (17-20) and trichaspsides C-E (21-23).²⁹

Among these sesquiterpenoids, there were 14 cyclonerane-type sesquiterpenoids (Figure 3). All of them were isolated from Trichoderma species. 9-Cycloneren-3,7,11-triol (24), 11-cycloneren-3,7,10-triol (25), and 7,10-epoxycycloneran-3,11,12-triol (26) were isolated and identified from T. asperellum cf44-2, an endophytic fungus of the marine brown alga Sargassum sp. (Sargassaceae).³⁰ Four cyclonerane sesquiterpenes, 11-methoxy-9-cycloneren-3,7-diol (27), 10-cycloneren-3,5,7-triol (28), methyl 3,7-dihydroxy-15-cycloneranate (29), and 8-acoren-3,11-diol (30), were isolated from a culture of Trichoderma harzianum X-5, an endophytic fungus which was obtained from the marine brown alga Laminaria japonica.³¹ 3,7,11-Trihydroxycycloneran-10-one (31), cycloneran-3,7,10,11-tetraol (32), cycloneran-3,7,11-triol (33), 11,12,15-trinorcycloneran-3,7,10-triol (34), 7,10S-epoxycycloneran-3,15-diol (35), 7,10R-epoxycycloneran-3,15-diol (36), and (10Z)-15-acetoxy-10-cycloneren-3,7-diol (37) were isolated from a culture of T. asperellum A-YMD-9-2, an endophytic fungus obtained from the marine red alga G. verrucosa.³²

Figure 3

Chemical structures of cyclonerane-type sesquiterpenoids 24-37.

Cadinane-type sesquiterpenoids have been isolated from several Trichoderma and Aspergillus species (Figure 4). They show a broad spectrum of antibacterial activity and latent hepatic protection effects. Trichocadinins B-G (38-43), 6 cadinane-type sesquiterpene derivatives with C-14 carboxyl functionality, were isolated from a culture extract of Trichoderma virens QA-8, an endophytic fungus which was separated from the fresh inner tissue of the medicinal plant Artemisia argyi.³³ Compounds 38 to 40 showed activity against a broad spectrum of bacteria, while compound 43 had activity against aquatic pathogens Edwardsiella tarda and Vibrio anguillarum with MIC ( Minimum Inhibitory Concentration) values of 1 and 2 µg/mL, respectively.³³ Eight cadinane-sesquiterpenes 44 to 51 were isolated from the endophytic fungus A. flavus, which was isolated from the toxic medicinal plant Tylophora ovata.³⁴ Compounds 48 to 51 exhibited latent hepatic protection effects at 10 µM.³⁴ 4-Cadinen-11,12-diol (52) and 4-cadinen-11,13-diol (53) were isolated from a culture of T. asperellum A-YMD-9-2, an endophytic fungal strain which was obtained from the marine red alga G. verrucosa.³⁵ Structures 44, 48, and 49 were derived from cadinane precursors by cleavage of certain C-C bonds. According to Liu et al,^³⁴ they also belonged to cadinane-type sesquiterpenoids despite without a distinct cadinane framework.

Figure 4

Chemical structures of cadinane-type sesquiterpenoids 38-53.

Oxytropiols A-J (54-63), 10 guaiane-type sesquiterpenoids (Figure 5), were isolated from the locoweed endophytic fungus Alternaria oxytropis from the desert plant Oxytropis glabra in Inner Mongolia, China.^³⁶ Compound 54 displayed biological effects on the root growth of Arabidopsis thaliana.³⁶

Figure 5

Chemical structures of guaiane-type sesquiterpenoids 54-63.

Ten hirsutane-type sesquiterpenoids were isolated from Chondrostereum and Cerrena sp. (Figure 6), including chondroterpenes A-H (64-71) and cerrenins B and C (72-73). Chondroterpenes A-H (64-71), 5,5,5-tricyclic hirsutane-type sesquiterpenes, were isolated from Chondrostereum sp. NTOU4196, a fungal strain which was isolated from the marine red alga Pterocladiella capillacea in Taiwan.³⁷ Chondroterpene A (64) exhibited significant NO production inhibitory activity in murine BV-2 microglial cells.³⁷ Cerrenins B and C (72-73), 2 isohirsutane sesquiterpenoids, were isolated from a broth extract of Cerrena sp. A593 from the plant Pogostemon cablin, which was collected from Yangchun city in the Guangdong Province.³⁸

Figure 6

Chemical structures of hirsutane-type sesquiterpenoids 64-73 and tremulane-type sesquiterpenoids 74-82.

An investigation of the metabolites from different cocultures of Nigrospora oryzae and Irpex lacteus from seeds of Dendrobium officinale (collected from Wenshan City in the Yunnan Province, China) in solid medium revealed 2 tremulane sesquiterpenes, 5-demethyl conocenol C and nigrosirpexin A (74-75).³⁹ Compound 75 showed antifungal activities against Colletotrichum gloeosporioides and Didymella glomerata, with MICs of 8 and 1 µg/mL, respectively.³⁹ Six 5,6-seco-tremulane sesquiterpenoids (76-81) were isolated from a culture broth from the fresh fruiting bodies of the medicinal fungus I. lacteus HFG1102.⁴⁰ One tremulane sesquiterpenoid, leptosphins B (82), was isolated from solid fermentation cultures of an endophytic fungus Leptosphaeria sp. XL026, which was isolated from the leaves of Panax notoginseng.⁴¹ The structures of these tremulane-type sesquiterpenoids 74 to 82 are displayed in Figure 6.

Three sesquiterpenoids with an eremophilane skeleton have also been identified from plant endophytic fungi (Figure 7). The eremophilane sesquiterpenoid leptosphins A (83) was isolated from solid fermentation cultures of the endophytic fungus Leptosphaeria sp. XL026 from the leaves of P. notoginseng.⁴¹ Microsphaeropsisins B and C (84-85) were isolated from the cocultivation of the mangrove endophytic fungus Trichoderma sp. 307 and the aquatic pathogenic bacterium Acinetobacter johnsonii B2.⁴²

Figure 7

Chemical structures of sesquiterpenoids 83-102.

Many different types of sesquiterpenoids have been identified in the same fungi. For instance, one 2,3-seco-protoilludane-type sesquiterpenoid (86), 8 protoilludane-type sesquiterpenoids (87-94), 4 illudalane-type sesquiterpenoids (95-98), and 1 botryane-type sesquiterpenoid (99) were identified from a liquid culture of the endophytic fungus Phomopsis sp. TJ507A which was isolated from the medicinal plant Phyllanthus glaucus.⁴³ Two seco-sativene sesquiterpenoids, bipolenins D and E (100-101), and 1 seco-longifolene sesquiterpenoid, bipolenin F (102), were obtained from cultures of the endophytic fungus Bipolaris eleusines.⁴⁴ The structures of these sesquiterpenoids (86-102) are shown in Figure 7.

Two drimane-type sesquiterpenoids have been isolated from Phoma and Trichoderma species (Figure 8). One rare 14-nordrimane-type sesquiterpenoid, named phomanolide (103), was obtained from a culture broth of the endophytic fungus Phoma sp. which was isolated from the roots of Aconitum vilmorinianum.⁴⁵ Compound 103 showed antiviral activities against influenza A virus (A/Puerto Rico/8/34, H1N1) with an IC₅₀ value of 2.96 ± 0.64 µg/mL.⁴⁵ One sesquiterpenoid, 11-hydroxy-15-drimeneoic acid (104), was isolated from the endophytic fungus Trichoderma koningiopsis A729 derived from Morinda officinalis.⁴⁶

Figure 8

Chemical structures of sesquiterpenoids 103-117.

Eudesmane and bergamotane sesquiterpenoids have been identified from Penicillium sp. and are displayed in Figure 8. Penicieudesmols A-D (105-108), eudesmane-type sesquiterpenoids, were isolated from a fermentation broth of the endophytic fungus Penicillium sp. J-54 which was isolated from the healthy leaves of Ceriops tagal collected in Dong Zhai Gang Mangrove Reserve in Hainan, China.⁴⁷ Purpurolide A (109), an unprecedented sesquiterpene lactone with a rarely encountered 5/5/5 spirocyclic skeleton, was isolated from cultures of the endophytic fungus Penicillium purpurogenum IMM003 from a leaf tissue of the medicinal plant Edgeworthia chrysantha.⁴⁸ Compound 109 displayed potent pancreatic lipase inhibition in the assay with IC₅₀ values of 2.83 ± 0.52 µM, compared to the standard kaempferol (1.50 ± 0.21 µM).⁴⁸

Some sesquiterpenoids exhibited potent antibacterial and antipathogenic effects. Two trichothecene sesquiterpenoids, trichothecrotocins A and B (110-111), and a merosesquiterpenoid racemate, (+)-trichothecrotocin C (112), were obtained from the potato endophytic fungus Trichothecium crotocinigenum by bioguided isolation.⁴⁹ Compounds 110 to 112 all showed potent inhibitory activities toward Alternaria solani and Fusarium oxysporum.⁴⁹ A pair of enantiomeric norsesquiterpenoids, (+)- and (−)-preuisolactone A (113-114), featuring a tricyclo[4.4.0^1,6.0^2,8]decane carbon scaffold were isolated from Preussia isomera XL-1326, an endophytic fungi from the stems of P. notoginseng.⁵⁰ Additionally, compounds 113 and 114 exhibited remarkable antibacterial activity against Micrococcus luteus with an MIC value of 10.2 µM.⁵⁰ The structures of these sesquiterpenoids 110 to 114 are shown in Figure 8. Other types of sesquiterpenoids that have been isolated from plant endophytic fungi are shown in Figure 8. For instance, emericellins A (115) and B (116) represent a skeleton of a sesquiterpenoid with a tricyclo[4,4,2,1]hendecane scaffold which were isolated from liquid cultures of the endophytic fungus Emericella sp. XL 029 associated with the leaves of P. notoginseng.⁵¹ A biscyclic sesquiterpene, seiricardine D (117), was isolated from a fermentation broth of Cytospora sp. which was derived from the hypocotyls of the Chinese mangrove C. tagal.⁵²

Diterpenoids

Diterpenoids are a group of natural products that contain 20 atoms of carbon derived from the condensation of 4 isoprenyl units. Diterpenoids have attracted increasing attention from chemists because of their diversified structures and potent biological activities. A total of 14 diterpenoids isolated from plant endophytic fungi between 2017 and 2019 were collected in this paper, including isopimarane, abietane, harziane, and cyclopiane types. They exhibited antibacterial, cytotoxic, and quinone reductase-inducing activities. Furthermore, Trichoderma species were the most important diterpenoid-producing endophytic fungi.

A number of diterpenoids showed outstanding biological activities. Koninginols A-C (118-120) were isolated from the endophytic fungus T. koningiopsis A729, which was derived from M. officinalis.⁴⁶ Compounds 118 and 119 exhibited significant antibacterial activity against Bacillus subtilis with MIC values of 10 and 2 µg/mL, respectively.⁴⁶ Six isopimarane-type diterpenoids, botrysphins A-F (121-126), were obtained from the endophytic fungus Botrysphaeria laricina from the healthy tissues of Rhodobryum umgiganteum in Lijiang, Yunnan Province, China.⁵³ Compound 124 showed significant quinone reductase-inducing activity in Hepa 1c1c7 cells.⁵³ The structures of these active diterpenoids are shown in Figure 9.

Figure 9

Chemical structures of diterpenoids 118-131.

Several different types of diterpenoids, including abietane, harziane, proharziane, and cyclopiane, were separated from plant endophytic fungi (Figure 9). One abietane-type diterpenoid, hydroxyldecandrin G (127), was isolated from the endophytic fungus Xylaria sp. XC-16 residing in the deciduous tree Toona sinensis.⁵⁴ One Harziane diterpene, 3R-hydroxy-9R,10R-dihydroharzianone (128), and 1 proharziane diterpene, 11R-methoxy-5,9,13-proharzitrien-3-ol (129), were isolated from T. harzianum X-5, an endophytic fungus which was obtained from the marine brown alga L. japonica.³¹ A cyclopiane diterpene, leptosphin C (130), was isolated from solid fermentation cultures of the endophytic fungus Leptosphaeria sp. XL026 from the leaves of P. notoginseng.⁴¹ One diterpenoid, 3S-hydroxyharzianone (131), was isolated from a culture of T. asperellum A-YMD-9-2, an endophytic fungal strain from the marine red alga G. verrucosa.³⁵ Compound 131 may be an intermediate in the biosynthesis of harziandione from harzianone.³⁵

Sesterterpenoids

Almost all sesterterpenoids isolated from plant endophytic fungi evaluated in this paper were ophiobolin-type derivatives (Figure 10). A total of 28 sesterterpenoids were obtained from Aspergillus and Bipolaris species. Ophiobolin-type derivatives are a group of structurally irregular and tricarbocyclic natural products belonging to the sesterterpenoid family whose structures contain a tricyclic 5-8-5 carbotricyclic skeleton derived from the condensation of 5 isoprenyl units. These ophiobolin-type sesterterpenoids showed diverse biological activities.

Figure 10

Chemical structures of ophiobolin-type sesterterpenoids 132-159.

Eleven ophiobolin-type sesterterpenoids, asperophiobolins A-K (132-142), were isolated from cultures of the endophytic fungus Aspergillus sp. ZJ-68 from fresh leaves of the mangrove plant Kandelia candel, which was collected from the Zhanjiang Mangrove Nature Reserve in the Guangdong Province, China.⁵⁵ Compounds 139 to 141 exhibited inhibitory effects on lipopolysaccharide-induced nitric oxide production in RAW 264.7 macrophage cells with IC₅₀ values ranging from 9.6 to 25 µM, and compound 139 showed comparable inhibition of Mycobacterium tuberculosis protein tyrosine phosphatase B with an IC₅₀ value of 19 µM.⁵⁵ Bipolarins A-H (143-150), 8 tetracyclic ophiobolin-type sesterterpenes featuring a rare oxaspiro[4.4]nonane moiety, were isolated from cultures of the fungus Bipolaris sp. TJ403-B1 from the leaves of wheat, which was collected from Wuhan City in the Hubei Province, China.⁵⁶ Additionally, compound 147 exhibited significant selective antimicrobial activity against Enterococcus faecalis with an MIC value 8 µg/mL.⁵⁶ Phytochemical investigation of EtOAc extracts of the endophytic fungus Bipolaris sp. TJ403-B1 from the leaves of wheat led to the isolation and characterization of 9 ophiobolin-type sesterterpenes, bipolaricins A-I (151-159).⁵⁷

Triterpenoids

Triterpenoids are common terpenoids with a 30-carbon skeleton based on 6 isoprene units. Triterpenes have attracted attention for development as pharmaceuticals.

In this paper, we summarized 11 triterpenoids isolated from endophytic fungi (Figure 11). Nine triterpenoids, kadhenrischinins A-H (160-167) and 7β-schinalactone C (168), were isolated from the endophytic fungus Penicillium sp. SWUKD4.1850 from Kadsura angustifolia.⁵⁸ One pentanortriterpenoid, 23,24,25,26,27-pentanorlanost-7,9(11)-dien-3β,22-diol (169), and 1 triterpenoid, lanost-8-en-3β,22S,23S-triol (170), were obtained from a culture of the fungus Diplodia cupressi associated with the moss Polytrichum commune.⁵⁹

Figure 11

Chemical structures of triterpenoids 160-170.

Meroterpenoids

Meroterpenoids have received much attention from chemists for their remarkable structural diversity and widespread biological activities. Meroterpenoids are hybrid terpenoids derived from a mixed-biosynthetic pathway, which is composed of the terpenoid pathway and nonterpenoid pathway. Based on their different biosynthetic origins, meroterpenoids can be grouped into 2 major classes: polyketide-terpenoids and nonpolyketide-terpenoids. The main species of meroterpenoid-producing endophytic fungi were Talaromyces, Aspergillus, Bipolaris, and Penicillium.

Six meroterpenoids (171-176) (Figure 12) belonging to 3,5-dimethylorsellinic acid-derived polyketide-terpenoids have been isolated from Alaromyces and Aspergillus species. Amestolkolides A-D (171-174), 4 meroterpenoids, were isolated from the mangrove endophytic fungus Talaromyces amestolkiae YX1 cultured on a wheat solid-substrate medium and amestolkolides A and B (171-172) exhibited anti-inflammatory activity in vitro by inhibiting nitric oxide (NO) production in lipopolysaccharide activated in RAW264.7 cells with IC₅₀ values of 30 ± 1.2 and 1.6 ± 0.1 mM, respectively.⁶⁰ The fungus T. amestolkiae YX1 was isolated from healthy leaves of the marine mangrove Kandelia obovata, which were collected in April 2012 from Zhanjiang Mangrove Nature Reserve in the Guangdong Province, China.⁶⁰ One meroterpenoid, named 2-hydroacetoxydehydroaustin (175), was isolated from the endophytic fungus Aspergillus sp. 16-5c from mangrove leaves of Sonneratia apetala, which were collected at Hainan Island, China.⁶¹ An unusual austinoid meroterpenoid, 1,2-dehydro-terredehydroaustin (176), was isolated from the mangrove endophytic fungus Aspergillus terreus.⁶²

Figure 12

Chemical structures of terpene-polyketide hybrid meroterpenoids 171-192.

Cochlioquinones are 6/6/6/6-tetracyclic meroterpenoids that consist of a sesquiterpenoid and a polyketide. The endophytic fungus Bipolaris sp. L1-2 from Lycium barbarum afforded 11 cochlioquinone derivatives (177-187), including bipolahydroquinones A-C (177-179), cochlioquinones I-N (180-185), and isocochlioquinones F-G (186-187).⁶³ Compounds 179, 180, and 182 to 184 showed cytotoxicity against NCI-H226 and/or MDA-MB-231 with IC₅₀ values ranging from 5.5 to 9.5 µM.⁶³

Two terpene-polyketide hybrid terpenoids (188-189) (in Figure 12) were separated from the endophytic fungus Aspergillus sp. TJ23. Bioassay-guided isolation of cultures of the fungus Aspergillus sp. TJ23 from the leaves of the Hypericum perforatum plant yielded a terpene-polyketide hybrid spiromeroterpenoid, spiroaspertrione A (188), bearing a unique spiro[bicyclo[3.2.2]nonane-2,1′-cyclohexane]carbocyclic skeleton.⁶⁴ A terpene-polyketide hybrid meroterpenoid, aspermerodione (189), characterized by an unusual 2,6-dioxabicyclo[2.2.1]heptane core skeleton was isolated and identified from liquid cultures of the endophytic fungus Aspergillus sp. TJ23.⁶⁵ Aspemerodione (189) was found to be a potential inhibitor of PBP2a and worked synergistically with the β-lactam antibiotics oxacillin and piperacillin against MRSA (Methicillin-resisitant Staphylococcus Aureus).⁶⁵

Polyketide-terpenoids have also been identified in Penicillium (Figure 12). Isopenicins A-C (190-192), 3 meroterpenoids possessing 2 types of terpenoid-polyketide hybrid skeletons, were isolated from cultures of the Penicillium sp. sh18 from the stems of Isodon eriocalyx var. laxiflora.⁶⁶

Additionally, 8 guignardone-type nonpolyketide-terpenoids have been obtained from plant endophytic fungi (Figure 13). Chemical investigation of a TCM (Traditional Chinese Medicine) endophytic fungal strain of Phyllosticta sp. J13-2-12Y from the leaves of Acorus tatarinowii resulted in the isolation of 3 unusual meroterpenoids, phyllomeroterpenoids A-C (193-195).⁶⁷ Five meroterpenoids, phyllostictones A-E (196-200), were isolated from Phyllosticta capitalensis, an endophytic fungus from Cephalotaxus fortunei Hook.⁶⁸

Figure 13

Chemical structures of guignardone-type nonpolyketide-terpenoids 193-200.

Conclusion

This paper summarizes the chemical structure types and related biological activities of terpenoids isolated from plant endophytic fungi in China between 2017 and 2019 by reviewing research progress in the relevant literature (Table 1). This paper exhibited 200 terpenoids, mainly from the plant endophytic fungi species Trichoderma, Aspergillus, Bipolaris, Penicillium, Phomopsis, and Alternaria, including monoterpenoids 1 to 4, sesquiterpenoids 5 to 117, diterpenoids 118 to 131, sesterterpenoids 132 to 159, triterpenoids 160 to 170, and meroterpenoids 171 to 200. These terpenoids showed diverse biological activities such as antibacterial, antifungal, antipathogenic, antitumor, anti-inflammatory, and hyperglycemic activities, as well as enzyme inhibition, cytotoxicity, latent hepatic protection, promotion of root growth, and other activities.

Table 1

Summary of Terpenoids 1-200 Isolated From Endophytic Fungi in This Review.

Types	Compounds	Endophytic fungi species	Production location within the plant	Plant species	Production location	Reference
Monoterpenoids	1-4	Periconia sp.	Leaves	Aquilaria agallocha	Sanya, Hainan	²¹
Sesquiterpenoids	5-6	Aspergillus fumigatus	Roots	Ligusticum wallichii	Dujiangyan, Sichuan	²⁴
	7-10	Aspergillus flavus	Branches	Kandelia obovata	Huizhou, Guangdong	²⁵
	11-13	Aspergillus versicolor	Leaves	Elaeocarpus decipiens Hemsl.	Cuiping Hill, Hubei	²⁶
	14-15	Aspergillus sp.	Stems	Cephalotaxus mannii Hook. f.	Xishuangbanna, Yunnan	²⁷
	16	Trichoderma asperellum	Inner tissues	Sargassum sp.	Zhoushan Islands, Zhejiang	²⁸
	17-23	Trichoderma asperellum	Inner tissues	Gracilaria verrucosa	Yangma Island, Shandong	²⁹
	24-26	Trichoderma asperellum	Tissues	Sargassum sp.	Zhoushan Islands, Zhejiang	³⁰
	27-30	Trichoderma harzianum	Inner tissues	Laminaria japonica	Chang Islands, Shandong	³¹
	31-37	Trichoderma asperellum	Inner tissues	Gracilaria verrucosa	Yangma Island, Shandong	³²
	38-43	Trichoderma virens	Root tissues	Artemisia argyi	Qichun, Hubei	³³
	44-51	Aspergillus flavus	Leaves	Tylophora ovata	Guangxi	³⁴
	52-53	Trichoderma asperellum	Inner tissues	Gracilaria verrucosa	Yangma Island, Shandong	³⁵
	54-63	Alternaria oxytropis	-	Oxytropis glabra	Inner Mongolia	³⁶
	64-71	Chondrostereum sp.	Thallus	Pterocladiella capillacea	Keelung, Taiwan	³⁷
	72-73	Cerrena sp.	-	Pogostemon cablin	Yangchun, Guangdong	³⁸
	74-75	Irpex lacteus (coculture with Nigrospora oryzae)	Seeds	Dendrobium officinale	Wenshan, Yunnan	³⁹
	76-81	Irpex lacteus	Fruiting bodies	-	Changbai Mountain, Jilin	⁴⁰
	82-83	Leptosphaeria sp.	Leaves	Panax notoginseng	Shijiazhuang, Hebei	⁴¹
	84-85	Trichoderma sp.	Stems bark	Clerodendrum inerme	Zhanjiang, Guangdong	⁴²
	86-99	Phomopsis sp.	Leaves	Phyllanthus glaucus	Lushan Mountain, Jiangxi	⁴³
	100-102	Bipolaris eleusines	Tissues	Potato	Kunming, Yunnan	⁴⁴
	103	Phoma sp.	Roots	Aconitum vilmorinianum	Kunming, Yunnan	⁴⁵
	104	Trichoderma koningiopsis	Branches	Morinda officinalis	Gunagdong	⁴⁶
	105-108	Penicillium sp.	Leaves	Ceriops tagal	Dong Zhai Gang, Hainan	⁴⁷
	109	Penicillium purpurogenum	Leaves	Edgeworthia chrysantha	Hangzhou, Zhejiang	⁴⁸
	110-112	Trichothecium crotocinigenum	Tissues	Potato	Lincang, Yunnan	⁴⁹
	113-114	Preussia isomera	Stems	Panax notoginseng	Wenshan, Yunnan	⁵⁰
	115-116	Emericella sp.	Leaves	Panax notoginseng	Shijiazhuang, Hebei	⁵¹
	117	Cytospora sp.	Leaves	Ceriops tagal	Dong Zhai Gang, Hainan	⁵²
Diterpenoids	118-120	Trichoderma koningiopsis	Branches	Morinda officinalis	Gunagdong	⁴⁶
	121-126	Botrysphaeria laricina	Tissues	Rhodobryum umgiganteum	Lijiang, Yunnan	⁵³
	127	Xylaria sp.	-	Toona sinensis	Yangling, Shaanxi	⁵⁴
	128-129	Trichoderma harzianum	Inner tissues	Laminaria japonica	Chang Islands, Shandong	³¹
	130	Leptosphaeria sp.	Leaves	Panax notoginseng	Shijiazhuang, Hebei	⁴¹
	131	Trichoderma asperellum	Inner tissues	Gracilaria verrucosa	Yangma Island, Shandong	³⁵
Sesterterpenoids	132-142	Aspergillus sp.	Leaves	Kandelia candel	Zhanjiang, Guangdong	⁵⁵
	143-150	Bipolaris sp.	Leaves	Wheat	Wuhan, Hubei	⁵⁶
	151-159	Bipolaris sp.	Leaves	Wheat	Wuhan, Hubei	⁵⁷
Triterpenoids	160-168	Penicillium sp.	Branches	Kadsura angustifolia	Xichou, Yunnan	⁵⁸
Triterpenoids	169-170	Diplodia cupressi	Tissues	Polytrichum commune	Lijiang, Yunnan	⁵⁹
Meroterpenoids	171-174	Talaromyces amestolkiae	Leaves	Kandelia obovata	Zhanjiang, Guangdong	⁶⁰
	175	Aspergillus sp.	Leaves	Sonneratia apetala	Hainan	⁶¹
	176	Aspergillus terreus	Leaf	Kandelia obovata	Zhanjiang, Guangdong	⁶²
	177-187	Bipolaris sp.	Leaves	Lycium barbarum	Ningxia	⁶³
	188	Aspergillus sp.	Leaves	Hypericum perforatum	Dragon Rack, Hubei	⁶⁴
	189	Aspergillus sp.	Leaves	Hypericum perforatum	Shennongjia, Hubei	⁶⁵
	190-192	Penicillium sp.	Stems	Isodon eriocalyx var. laxiflora	Kunming, Yunnan	⁶⁶
	193-195	Phyllosticta sp.	Leaves	Acorus tatarinowii	Nanning, Guangxi	⁶⁷
	196-200	Phyllosticta capitalensi	Leaves	Cephalotaxus fortunei Hook.	Feng County, Shaanxi	⁶⁸

A total of 200 terpenoids were isolated from plant endophytic fungi in China between 2017 and 2019. Among these 200 compounds, 113 and 30 natural products from plant endophytic fungi were sesquiterpenoids and meroterpenoids, respectively (Figure 14(A)). According to the above analysis, we concluded that sesquiterpenoids were the most important kind of terpenoids and meroterpenoids were the second most important ones. After analyzing 113 characteristic sesquiterpenoids isolated from plant endophytic fungi, we found that sesquiterpenoids consisted of different types (such as bisabolane, cadinane, cyclonerane, guaiane, hirsutane, tremulane, protoilludane, edudesmane, illudalane, and eremophilane) and the bisabolane-type was the main class of sesquiterpenoids (Figure 14(B)). Meanwhile, Trichoderma and Aspergillus species were the main terpenoid-producing plant endophytic fungi (Figure 14(C); Table 1). The data in Table 1 reveal that endophytic fungi producing terpenoids were mainly isolated from the leaves and tissues of plants, which were widely distributed in southern China.

Figure 14

(A) The number of terpenoids reviewed in this paper (including monoterpenoids, sesquiterpenoids, diterpenoids, sesterterpenoids, triterpenoids, and meroterpenoids); (B) the number of different sesquiterpenoid types isolated from plant endophytic fungi; and (C) the number of terpenoids produced from different endophytic fungi.

It is interesting that some terpenoids play an important biological role on the development of their plant host. For example, trichothecrotocins A and B (110-111), and (+)-trichothecrotocin C (112), indicated an unknown relationship of host-endophytic fungus-toxin-phytopathogen which would make them candidates of antiphytopathogenic agents, with a prospect of application as fungicides in agriculture.

In conclusion, this paper provides a research foundation for excavating the diverse structure and activity of terpenoids from plant endophytic fungi. The data analysis indicated that plant endophytic fungi are a momentous source of novel and active terpenoids. This paper proposed the future development direction of research on endophytic fungi and active substances and provided references for future research. It has been recognized that the abundant plant endophytic fungi resources have great ecological significance and economic value for the development and utilization of their active substances.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported in part by Shandong Administration of Traditional Chinese Medicine (2019-0989) and the National Natural Science Foundation of China Youth Project (81903479).

ORCID iD

Mengyujie Liu

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