Aspergillus, P.Micheli, 1729

Zhao, Wen-Yu, Yi, Jing, Chang, Yi-Bo, Sun, Cheng-Peng & Ma, Xiao-Chi, 2022, Recent studies on terpenoids in Aspergillus fungi: Chemical diversity, biosynthesis, and bioactivity, Phytochemistry (113011) 193, pp. 1-25 : 2-21

2. Terpenoid metabolites in the fungi Aspergillus

2.1. Monoterpenoids

Monoterpenoids are rarely isolated from the genus Aspergillus . Only two monoterpenoids were obtained from the marine-derived fungus A. versicolor SD- 330 in the last ten years, and identified as pestalotiolactones C (1) and D (2, Fig. 1 ) through HRMS, NMR, and ECD spectra, as well as X-ray diffraction. They showed antimicrobial activities against Aeromonas hydrophilia , Edwardsiella tarda , and Vibrio anguillarum ( Li et al., 2019b) .

2.2. Sesquiterpenoids

Sesquiterpenoids represent a large structural group of metabolites of Aspergillus . The sesquiterpenoids in Aspergillus usually exist as oxygenated derivatives, such as alcohols, ketones, and lactones. A total of 107 sesquiterpenoids have been reported in the genus Aspergillus in the last decade, including drimane-, bisabolane-, cadinane-, humulane-, protoilludane-, and other types.

2.2.1. Drimane-type sesquiterpenoids

The skeleton of drimane-type sesquiterpenoids is a bicyclic sesquiterpenoid, and the C-6, C-11, C-12, and C-13 positions of the skeleton are often oxidized. A new lactone ring between C-11 and C-12 can be observed in some cases, while the C-6 and C-13 positions often have substituents. In the last decade, 28 drimane-type sesquiterpenoids (3–30, Fig. 2 ) were isolated from the genus Aspergillus , including A. ustus , A. insuetus , A. versicolor , A. ochraceus Jcma 1F17, A. oryzae QXPC-4, A. flavus GZWMJZ-288, and A. flocculosus .

Zhou and coworkers collected A. ustus in Guangxi Province, China, and investigated its specialised metabolites, resulting in the identification of five drimanes O -methylalbrassitriol (3), 9 α -hydroxyl-9-formyl- 5 α -drim-7-en-6-one (4), drim-8-en-6 β,7 α,11-triol (5), 6-strobilactone-B ester of (E, E)-6-carbonyl-7-hydroxy-2,4-octadienoic acid (6), and (2 E,4 E,6 E)-6-(1-carboxyocta-2,4,6-triene)-11,12-epoxy-9-hydroxy-11- methoxy-drim-7-ene (7) (Zhou et al., 2011a). (E)-6-(4 ′ -hydroxy-2 ′ -butenoyl)-strobilactone A (8), as a bicyclic sesquiterpene, was purified from the marine-derived fungus A. insuetus and showed a cytotoxic effect against molt-4 cell lines ( Cohen et al., 2011). Compound 9 was isolated from A. sp. YLF-14 and named as 5 β, 8a β -dimethyl-3,4,4a β,5,6,7,8,8a-octahydronaphthalene-1,2,5 α -trimethano (9) ( Luo et al., 2011).

A. versicolor is a fungus isolated from Codium fragile collected in Dalian, China ( Liu et al., 2012), and the investigation on specialised metabolites of A. versicolor yielded albican-11,14-diol (10). A pair of stereoisomers, (E, E)-6,7-epoxy-2,4-octadienoic acids (11 and 12) were obtained from A. ustus ( Liu et al., 2013) . It is speculated that the difference in their structure lies in the configuration of the epoxy moieties, which requires further determination of their absolute configurations. The investigation of specialised metabolites of A. sp. IBSF002-96 and A. ochraceus Jcma 1F17 affordedSF002–96–1 (13), 6 β,9 α -dihydroxy-14- p -nitrobenzoylcinnamolide (14), (5 R,5a S,9a S)-9b-hydroxy-6,6, 9a-trimethyl-1-oxo-1,3,5,5a,6,7,8,9,9a,9-bdecahydronaphtho(1,2-c) furan-5-yl hexanoate (15), (5 R,5a S,9 R,9a R,9b R)-9,9b-dihydroxy-6,6, 9a-trimethyl-1-oxo-1,3,5,5a,6,7,8,9,9a,9b-decahydronaphtho(1,2-c) furan-5-yl hexanoate (16), and (1 R,5 R,5a S,9 R,9a R,9b R)-1,9,9b-trihydroxy-6,6,9a-trimethyl-1,3,5,5a,6,7,8,9,9a,9b-decahydronaphtho(1, 2-c)furan-5-yl hexanoate (17) in 2013–2014 ( Fang et al., 2014; Felix et al., 2013, 2014). Moreover, insulicolides B (25) and C (26), 14- O -acetylinsulicolide A (27), and 12-hydroxy-8-ene-3-oxodrimenol (28) were isolated from A. ochraceus Jcma 1F17 and A. flavus GZWMJZ- 288 in 2018 ( Tan et al., 2018; Xu et al., 2018), respectively. Compound 26 displayed antiproliferative activities against ACHN, OS-RC-2, and 786-O cells ( Tan et al., 2018). Among them, compounds 14 and 25–27 were sesquiterpenoids with a nitrobenzoyl moiety, which is rare in natural products ( Fang et al., 2014).

A. oryzae QXPC-4 was isolated from Coccinella septempunctata collected from Fang Mountain in the suburbs of Nanjing, China, and Ren et al. investigated its fermentation medium to afford seven drimane-type sesquiterpenoid astellolides C–I (18–24) ( Ren et al., 2015). In addition, Yurchenko et al. collected A. flocculosus , and investigated its culture medium, leading to the isolation and identification of 6 β,9 α,14-trihydroxycinnamolide (29) and 6 β,7 β,14-trihydroxyconfertifolin (30) ( Yurchenko et al., 2019).

2.2.2. Bisabolane-type sesquiterpenoids

Bisabolenes are believed to be produced from farnesyl pyrophosphate (FPP) and are present in specialised metabolites of several fungi, such as Fusarium verticillioides , Synechococcus sp. PCC 7002, and A. sydowii ( Davies et al., 2014; Dickschat et al., 2011; Hu et al., 2020).

The fermentation of Aspergillus fungi was investigated to identify 52 bisabliane-type sesquiterpenoids (31–82) from 2010 to 2020 ( Fig. 3 ). Three rare phenolic bisabolane dimers, disydonols A-C (31–33), were isolated from A. sp. obtained from Xestospongia testudinaria , along with four bisabolane-type sesquiterpenoids with a 1,4-disubstituted benzene ring, aspergiterpenoid A (34), ()-sydonol (35), and ()-sydonic acid (36), ()-5-(hydroxymethyl)-2-(2 ′,6 ′,6 ′ -trimethyltetrahydro-2 H -pyran- 2-yl)phenol (37) ( Li et al., 2012; Sun et al., 2012b). Chung et al. isolated A. sydowii from marine sediment ( Taiwan, China), and investigated specialised metabolites from its culture broth to afford a library of sydonol derivatives, including (7 S)-(+)-7- O -methylsydonol (38), (7 S, 11 S)-(+)-12-hydroxysydonic acid (39), and 7-deoxy-7,14-didehydrosydonol (40) ( Chung et al., 2013).

Sydonic acid derivatives were also purified from the culture medium of A. versicolor 125a, A. sp. xy02, A. versicolor , A. sydowii SCSIO 41301, A. flavus QQSG-3, A. sydowii J05B–7F-4, A. sp. SCSIO06786, and A. austroafricanus , and defined as ()-(R)-cyclo-hydroxysydonic acid (41), ()-(7 S,8 R)-8-hydroxysydonic acid (42), ()-(7 R,10 S)-10- hydroxysydonic acid (43), ()-(7 R,10 R)-iso-10-hydroxysydonic acid (44), ()-12-acetoxy-1-deoxysydonic acid (45), ()-12-acetoxysydonic acid (46), ()-12-hydroxysydonic acid (47), ()-(R)-11-dehydrosydonic acid (48), (7 R,10 S)-7,10- epoxysydonic acid (49), (7 S,10 S)-7,10-epoxysydonic acid (50), (7 R,11 S)-7,12-epoxysydonic acid (51), (7 S,11 S)- 7,12-epoxysydonic acid (52), 7-deoxy-7,14-didehydro-12-hydroxysydonic acid (53), (Z)-7-deoxy-7,8-didehydro-12-hydroxysydonic acid (54), (E)-7-deoxy-7,8-didehydro-12-hydroxysydonic acid (55), (7 S,11 R)-12-hydroxy-sydowic acid (56), (7 R,8 R)-8-hydroxysydowic acid (57), (7 S,10 S)-10-hydroxy-sydowic acid (58), (7 R,8 R)-1,8-epoxy- 11-hydroxy-sydonic acid (59), (7 S,11 R)-12-acetoxy-sydowic acid (60), 7-deoxy-7,14-didehydro-12-acetoxy-sydonic acid (61), (E)-7-deoxy-7,8- didehydro-12-acetoxy-sydonic acid (62), 7-deoxy-7,14-didehydro-11- hydroxysydonic acid (63), (7 R)-11-hydroxy-sydonic acid methyl ester (64), (+)-austrosene (65), β -D -glucopyranosyl aspergillusene A (70), phenolic bisabolene sesquiterpenoids (72–74), aspergillusene D (77), ent -aspergoterpenin C (78), 7- O -methylhydroxysydonic acid (79), 7 ′ - oxygenated sydowic acid (80), ()-austrosene (81), and 3-hydroxy-4-(5- hydroxy-5-methyl-1-methylenehexyyl)-benzoic acid (82), based on their detailed spectral analyses ( Ebrahim et al., 2017; Elsbaey et al., 2019b; Li et al., 2015, 2019b; Liu et al., 2017a, 2019a; Pang et al., 2020; Wang et al., 2018; Wu et al., 2018b).

In addition, seven bisabolane-type sesquiterpenoids were isolated from A. fumigatus , A. flavus QQSG-3, and A. sp. ( Chen et al., 2018; Liu et al., 2016c; Wang et al., 2015a; Wu et al., 2018b), namely E -β -trans -5, 8,11-trihydroxybergamot-9-ene (66), β -trans -2b,5,15-trihydroxybergamot-10-ene (67), asperchondols A (68) and B (69), bisabolane sesquiterpenoid 71, and fumagillenes A (75) and B (76).

2.2.3. Cadinane-type sesquiterpenoids

In the last decade, only nine cadinane-type sesquiterpenoids were discovered from A. clavatus and A. flavus ( Liu et al., 2019c; Wang et al., 2016b), and identified as aspergillusone D (83) and aspergilloids A-H (84–91, Fig. 4 ). Among them, compound 84 is a rare dimeric cadinene linked by an ester bond, and cadinane 85 features an unusual three-ring system. Biological studies have suggested that they possess cytotoxic activities against MCF-7 and A549 cells as well as hepatoprotective activities ( Liu et al., 2019c; Wang et al., 2016b).

2.2.4. Humulane-type sesquiterpenoids

The skeleton of humulene sesquiterpenoids was also believed to originate from FPP in the enzymatic cyclization reaction. Wang and coworks obtained an Antarctic fungus A. ochraceopetaliformis SCSIO 05702, and further investigated its culture medium fermentation, leading to the isolation of nine humulanes, ochracenes A-I (92–100, Fig. 5 ) ( Wang et al., 2017a). Among them, compounds 93 and 94 were rare 8,9- seco -humulanes, which were first discovered in nature. In the biogenesis pathway of 92–100, two steps of cyclization of FPP can produce the bicyclohumulane skeleton, which can be converted to key intermediate I by methyl migration. A series of subsequent oxidation, ring-opening, or oxidative decarboxylation reactions eventually produces compounds 92–100 ( Fig. 5 ). Meanwhile, compounds 93 (IC 50 = 14.6 μM) and 94 (IC 50 = 18.3 μM) displayed inhibitory activities against NO production ( Wang et al., 2017a).

2.2.5. Protoilludane-type sesquiterpenoids

A. sp. SCS-KFD66 is an endophyte of Sanguinolaria chinensis collected from Haikou Bay, China ( Qiu et al., 2018). Three protoilludane-type sesquiterpenoids with antioxidant activities, asperpenes A-C (101–103), were discovered from culture medium fermentation, and their structures are shown in Fig. 6.

2.2.6. Other sesquiterpenoids

In addition to the above-mentioned sesquiterpenoids, seven analogues (104–110, Fig. 7 ) were isolated from Aspergillus fungi in the last ten years, including asperaculanes A (104) and B (105) from A. aculeatus ATCC 16872 ( Gao et al., 2014), aspergiketone (106) from A. fumigatus ( Liu et al., 2016b) , 4 α,8 α -dihydroxyeudesman-11-en-1-one (107) from A. flavus YPGA 10 ( Liu et al., 2019c), linear sesquiterpenoids aspterrics A (108) and B (109) from A. terreus YPGA 10 ( Li et al., 2019d), and a tricyclic one asperpene D (110) from A. sp. SCS-KFD66 ( Yang et al., 2003).

2.3. Diterpenoids

Diterpenoids originate from geranylgeranyl pyrophosphate (GGPP) and demonstrate a variety of bioactivities, such as antitumour, and antimalarial effects, and some of them originate from plants that have been used in the clinic, such as andrographolide and taxol ( Liu et al., 2019b).

To date, 56 diterpenoids have been isolated from Aspergillus fungi in the last decade. According to their structural characteristics, they were classified as labdane-, isopimaric-, cleistanthane-, and indole-type diterpenoids.

2.3.1. Labdane-type diterpenoids

During the last decade, eight labdanes (111–118, Fig. 8 ) were discovered from A. wentii EN-48, A. terreus GX 7–3B, A. duricaulis KACC 41137, and A. wentii SD-310 ( Deng et al., 2013; Kwon et al., 2015; Liu et al., 2016a; Sun et al., 2012a), namely asperolides A-C (111–113), botryosphaerin F (114), asperolides D (115) and E (116), and breviones L (117) and M (118). It should be noted that since compounds 111–116 possessed a tetranorlabdane skeleton, some scholars believe that these compounds are derived from the addition reaction of sesquiterpenes rather than the degradation of diterpenoids ( Deng et al., 2013). More evidence is needed to support the origin of 111–116. Breviones L (117) and M (118) have a pentacyclic carbon framework consisting of a seco -diterpenoid and a polyketide moiety, and possess neuroprotective activities ( Kwon et al., 2015).

2.3.2. Isopimaric-type diterpenoids

The study on specialised metabolites of Aspergillus fungi led to the discovery of twenty-six isopimaric-type diterpenoids (119–144, Fig. 9 ) in the last decade. Aspergiloid I (121) is a new class of nor -diterpenoids with a 6/5/6 tricyclic ring carbon skeleton and an α, β -unsaturated spirolactone moiety that was isolated from the culture broth of A. sp. YXf3, together with two analogues, aspergiloids D (119) and E (120) ( Guo et al., 2014; Yan et al., 2013; Zhi et al., 2011). Its biosynthetic route was speculated to start from classical diterpene I, which would form the intermediate II by decarboxylation ( Fig. 10 ). Further Baeyer–Villiger oxidation yielded the 7-membered lactone III. Finally, 121 can be produced by hydrolysis, decarboxylation, and lactonization reactions ( Guo et al., 2014).

Miao and colleagues obtained thirteen nor -isopimaranes, aspewentins A-M (122–134), from A. wentii SD-310 collected from a leaf of Ginkgo biloba , and found that they possessed antibacterial activities towards Cartonella marine, Heterosigma akashiwo , Artemia salina , Alexandrium sp. , and Escherichia coli ( Li et al., 2016, 2018; Miao et al., 2014). Additionally, isopimaric-type diterpene derivatives were reported in A. wentii SD-310, namely wentinoids A-F (135–140) ( Kato et al., 2019; Wang et al., 2017b). Taichunins A-D (141–144) were purified from A. taichungensis IBT 19404, among them, compounds 141–143 have a 6/5/6 tricyclic ring carbon skeleton similar to that of 121.

2.3.3. Cleistanthane-type diterpenoids

Cleistanthanes belong to the family of tricyclic diterpenoids with an aromatic C-ring, and are often oxidized at C-1, C-6, and C-7 to form hydroxy and carbonyl groups. The investigation of A. sp. YXf3 and A. candidus resulted in the isolation of seven cleistanthane-type diterpenoids from 2010 to 2020. They were identified as aspergiloids A-C (145–147) and F–H (148–150) and 6-deoxyaspergiloid C (151) in Fig. 11 ( Han et al., 2020; Yan et al., 2013; Zhi et al., 2011). Among them, compounds 145, 146, and 148–150 are cleistanthanes with a fourth ring formed between C-7 and C-16.

2.3.4. Indole-type diterpenoids

Indole-type diterpenoids are a common class of alkaloids derived from farnesyl geranylgeranyl diphosphate and indole-3-glycerol phosphate, and this type of compound also features a complex structure formed via oxidation, prenylation, hydroxylation, and cyclization. Filamentous fungi, especially Aspergillus and Penicillium , produce this type of specialised metabolites [3,4]. Recently, fifteen indole diterpenoids (152–166, Fig. 12 ) were discovered from Aspergillus fungi.

The fermentation of A. oryzae , a fungus isolated from Heterosiphonia japonica , was investigated to obtain indole diterpenoids asporyzins A-C (152–154) ( Qiao et al., 2010). Sun and coworkers collected A. flavus OUCMDZ-2205 from Penaeus vannamei and isolated its fermentation broth to afford two isopentenylated indole diterpenoids (2 R,4b R,6a S, 12b S,12c S,14a S)-4b-deoxy- β -aflatrem (155) and (2 R,4b S,6a S,12b S, 12c R)-9-isopentenylpaxilline (156). They all displayed antiproliferative activities towards A549 cells by inducing cell cycle arrest ( Sun et al., 2014). Emindole SC (157) was isolated from A. sclerotiicarbonarius with an antiinsectan activity ( Petersen et al., 2015).

In nature, natural products with chlorine atoms are rare, while it is worth noting that three chlorinated indole-diterpenoids 19-hydroxypenitrem A (158), and asperindoles A (160) and C (162), as well as their analogues 19-hydroxypenitrem E (159) and asperindoles B (161) and D (163), were isolated from marine-derived A. nidulans EN-330 and A. sp. KMM 4676 ( Elena et al., 2018; Zhang et al., 2015). Furthermore, they displayed remarkable antimicrobial and antiproliferative effects. In addition, unusual 2,3- seco -indole diterpenoids anthcolorins G1 (164) and H2 (165) and 2-carbonyl-3-hydroxylemeniveol (166) were discovered from the fermentation of A. versicolor ( Elsbaey et al., 2019b; Zhang et al., 2021).

2.4. Sesterterpenoids

Sesterterpenoids are a relatively rare branch of the terpenoid family and widely exist in plants, microorganisms, marine organisms, and some insects, especially sponges ( Qiu et al., 2018). To date, forty-seven sesterterpenoids have been reported from Aspergillus fungi in the recent decade, including thirty-five ophiobolins (167–201, Fig. 13 ), six asperanes (202–207, Fig. 14 ), and six other-type sesterterpenoids (208–213, Fig. 15 ).

2.4.1. Ophiobolin-type sesterterpenoids

Ophiobolins are a class of sesterterpenoids with a 5/8/5 tricyclic system and are commonly found in the genus Aspergillus . Recently, Liu and coworkers obtained A. ustus , and investigated its fermentation broth to afford five ophiobolin-type sesterterpenoids (5 α,6 α)-ophiobolin H (161), (5 α,6 α)-5- O -methylophiobolin H (162), 5- O -methylophiobolin H (163), (6 α)-21,21- O -dihydroophiobolin G (164) and (6 α)-18,19,21,21- O -tetrahydro-18,19-dihydroxyophiobolin G (165) ( Liu et al., 2011). In 2013, they found five sesterterpenoids (6 α)-21-deoxyophiobolin G (174), (6 α)-16,17-dihydro-21-deoxyophiobolin G (175), and ophiobolins U–W (176–178), derived from this fungus as well ( Liu et al., 2013). Subsequent investigation of the fungi Aspergillus resulted in the isolation of nine ophiobolins, including ophiobolin O (172) and 6- epi -ophiobolin O (173) from A. sp. ( Zhang et al., 2012), and ophiobolins X-Z (179, 180, and 182), 21-dehydroophiobolins U (181) and K (185), and 21- epi --ophiobolins Z (183) and O (184) from A. ustus 094,102 (Zhu et al., 2018).

Nitride ophiobolins have also been reported in the last decade, such as asperophiobolins A-K (186–196) from A. sp. ZJ-68 ( Cai et al., 2019). According to their structural characteristics, these compounds feature an additional five-membered lactam ring between C-5 and C-21, and 191 with 192 and 193 are stereoisomers at C-6 and C-18. In addition, Choi and coworkers found that the fermentation of A. flocculosus , displayed significant cytotoxicity, and investigated its specialised metabolites to afford five ophiobolin derivatives with an unsaturated side chain, namely 14,15-dehydro-6- epi -ophiobolin K (197), 14,15-dehydroophiobolin K (198), 14,15-dehydro-6- epi -ophiobolin G (199), 14, 15-dehydro-ophiobolin G (200), and 14,15-dehydro-(Z)-14-ophiobolin G (201) ( Choi et al., 2019).

2.4.2. Asperane-type sesterterpenoids

The asperanes belong to the group of 7/6/6/5 tetracyclic sesterterpenoids with a hydroxylated skeleton discovered from Aspergillus fungi. In 2002, the first asperane-type sesterterpenoid was discovered from the genus Aspergillus ( Cueto et al., 2002) . To date, only one study including six asperane-type sesterterpenoids were isolated from Aspergillus fungi in the last decade, namely asperunguisins A-F (202–207, Fig. 14 ), and they were all produced from the endolichenic fungus A. unguis . Among them, compound 202 showed cytotoxicity against

A549 cells ( Li et al., 2019c).

2.4.3. Other sesterterpenoids

In addition to the above-mentioned sesterterpenoids, six others (208–213, Fig. 15 ) were reported in Aspergillus fungi. Asperterpenoid A (208), isolated from A. sp. 16–5c, features a 5/7/3/6/5 pentacyclic carbon skeleton and possesses inhibitory activity against tyrosine phosphatase B ( Huang et al., 2013). Compound 208 originated from GFPP, which would undergo the first step of cyclization to generate 11/5 fused ring system I, followed by migration of a σ bond to generate 11/6 fused intermediate II. The second cyclization reaction produced 11/6/5 fused tricyclic intermediate III, and further cyclization formed intermediate IV with five rare fused rings. Finally, intermediate V was oxidized to generate compound 208 ( Fig. 16 ) ( Huang et al., 2013).

unusual 5/8/6/6 tetracyclic carbon skeleton with inhibitory activities against acetylcholinesterase, asperterpenols A (209) and B (210), from A. sp. 085,242 ( Xiao et al., 2013). In addition, aspergstressin (211), a hybrid polyketide sesterterpenoid, was discovered from A. sp. WU 243 stimulated by cobalt salt, in which the fungus Xenograpsus testudinatus was isolated ( Ding et al., 2016).

Two sesterterpenoids, aspterpenacids A (212) and B (213), feature a 5/3/7/6/5 fused ring system identified by Liu et al. (2016). The unusual 5/6/7/3/5 carbon skeleton was started from GFPP by head-to-tail connection and cyclization ( Fig. 17 ). The following steps included hydrogen migration, carbon cyclization, oxidation, reduction, and acetylation ( Liu et al., 2016d).

2.5. Triterpenoids

Based on the structural characteristics of triterpenoids, they are usually divided into two types: tetracyclic triterpenoids (neoalsamitin A, toosendanin, masticadienonic acid, etc.) and pentacyclic triterpenoids (saikogenin E, sanguisorbin B, pulsatiloside A 3, etc.). Recently, eight tetracyclic triterpenoids (214–221, Fig. 18 ) were reported in Aspergillus fungi together with a pentacyclic triterpene (222) isolated from A. amstelodami ( Elsbaey et al., 2019a) , and they were identified as 6 β, 16 β -diacetoxy-25-hydroxy-3,7-dioxo-29-nordammara-1,17 (20)-dien-21,24-lactone (214) from A. fumigatus KMM 4631 ( Afiyatullov et al., 2012), 16- O -deacetylhelvolic acid 21,16-lactone (215), 6- O -propionyl-6,16- O -dideacetylhelvolic acid 21,16-lactone (216), 1,2-dihydro-6,16- O- dideacetylhelvolic acid 21,16-lactone (217), 1,2-dihydro-6, 16- O- dideacetylhelvolic acid 21,16-lactone (218), 16- O -propionyl-16- O -deacetylhelvolic acid (219), and 6- O -propionyl-6- O -deacetylhelvolic acid (220) from A. fumigatus HNMF 0047 ( Kong et al., 2018), and 3,7-diketo-cephalosporin P1 (221) from A. fumigatus SCSIO 41012 ( Limbadri et al., 2018), respectively. Among them, compounds 219 and 220 showed potent antibacterial activities against Streptococcus agalactiae and Staphylococcus aureus ( Kong et al., 2018) .

Xiao and coworkers obtained two sesterterpenoids sharing an

2.6. Meroterpenoids

Meroterpenoids represent natural products partially biosynthesized from terpenoids, including two major classes, polyketide–terpenoids and non-polyketide–terpenoids, based on their biosynthetic origins. These natural products are most often isolated from fungi and marine organisms, including the genus Aspergillus . During the last decade, sixtysix meroterpenoids (223–288) mostly belonging to the polyketide–terpenoids have been reported in the genus Aspergillus , and their structures are shown in Figs. 19 , 23 and 25 . Meroterpenoids are known for their diversity in structure, and the compounds here are classified by the number of acyl units that have contributed to the polyketide moiety.

2.6.1. Meroterpenoids containing triketide–terpenoid moieties

Asperdemin (223) was isolated from A. versicolor and its structure was meroterpene with an α, β -unsaturated ester group. It showed weak cytostatic and membranolytic activity. Furthermore, compound 223 can induce hemolysis of human erythrocytes ( Yurchenko et al., 2010). A. similanensis KUFA 0013 isolated from Rhabdermia sp. afforded a chevalone derivative, chevalone E (224) ( Prompanya et al., 2014). Three territrem derivatives, territrems D (225) and E (226) and 11 α -dehydroxyisoterreulactone A (227), were isolated from the rice fermentation solid-state culture medium of A. terreus SCSGAF 0162. Among them, compound 227 showed antiviral activity against HSV-1, and compounds 225 and 226 showed inhibitory activities against acetylcholinesterase ( Nong et al., 2014).

Two meroterpenoids with a 1,4-disubstituted phenolic moiety and an

α -pyrone moiety, namely yaminterritrems A (228) and B (229), were isolated from A. terreus ( Liaw et al., 2015) . As shown in Fig. 20 , compound 229 may be derived from the phenyl- α -pyrone moiety of sesquiterpenes. Compound 228 may have the same precursor as compound 229. The precursor formed via an unusual cycloheptane moiety formed compound A, then intermediate B was yielded by oxidation. Subsequently, 228 can be produced from intermediate B via the cleavage of the C4–C5 bond in the ring A of the terpenoid unit and a retro-aldol reaction ( Liaw et al., 2015).

Four highly oxygenated putative rearranged triketide-sesquiterpenoid meroterpenoids, named aspertetranones A-D (230–233), were obtained from A. sp. ZL0–1b14. Aspertetranones A-D (230–233) possess the skeleton of rearranged triketide-sesquiterpenoid hybrid. The precursor drimane-type merosesquiterpene can be produced by cyclization of farnesylated pyrone, subsequently, the terpenoid part of 230–233 can yiled via oxidation and retro-aldol/aldol rearrangement. Further nucleophilic attack and dehydration afforded final products 230–233 ( Fig. 21 ) ( Wang et al., 2015b).

Six meroterpenoids, ochraceopones A-E (234–238) and isoasteltoxin (241), were isolated from A. ochraceopetaliformis SCSIO 05702. The structures of 234–237 feature an α -pyrone metrosesquiterpenoid and a linear tetracyclic carbon skeleton. This type of compound was first reported in nature. The same α -pyrone moiety also existed in the structure of 238. Compounds 234–238 were derived from the polyketide and mevalonate hybrid biogenetic pathways ( Fig. 22 ). The mixed biosynthesis of polyketide and mevalonate yields intermediate i, followed by epoxidation, polyene cyclization, and retro-aldol/aldol rearrangement to afford compound 238 and intermediate iv. Further oxidation of intermediate iv resulted in the production of compounds 235 and 236, and O -methylation and dehydration of compound 235 generated compounds 234 and 237 ( Wang et al., 2016a).

Two compounds, subglutinols C (242) and D (243) were isolated from the liquid culture medium of the entomopathogenic filamentous fungus Metarhizium robertsii ARSEF 23 ( Tsunematsu et al., 2016). An α -pyrone merosesquiterpenoid with an angular tetracyclic carbon skeleton, ochraceopone F (239), was isolated from A. flocculosus 01NT.1.1.5 ( Shin et al., 2018). A meroterpenoid 12- epi -aspertetranone D (240) with a linear tetracyclic backbone was isolated from the fermentation culture medium of A. flocculosus (Xu et al., 2018) .

2.6.2. Meroterpenoids containing tetraketide–terpenoid moieties

Austalide R (244) was isolated from A. sp., and showed a broad spectrum of antibacterial activity (Zhou et al., 2014). Terretonins H (245) and I (246) were obtained from the specialised metabolites of A. ustus KMM 4664 ( Oleinikova et al., 2016). A highly oxygenated tetracyclic meroterpenoid, namely terretonin M (247), was isolated from A. terreus TM 8 ( Shaaban et al., 2018).

To date, the terretonin derivatives have mainly been reported in the genus Aspergillus ( Guo et al., 2012) . A terretonin derivative with anti-inflammatory activity, namely terretonin D1 (248), was isolated from A. terreus ML-44 ( Wu et al., 2018a). Spiroterreusnoids A–F (249–254) obtained from A. terreus were six spiro -dioxolane-containing adducts bearing 2,3-butanediol moieties and 3,5-dimethylorsellinic acid based on meroterpenoids ( Qi et al., 2019).

A. terreus EN-539 was collected in Qingdao, China, and the investigation of its specialised metabolites afforded two meroterpenoids aperterpenes O (255) and N (256) ( Li et al., 2019a). Asperaustins A-C (257, 267, and 268) were isolated from A. sp. ZYH026 collected from the South China Sea. Among them, 257 features an unusual spiro (4.5) deca-3,6-dien-2-one moiety and a unique 5/6/6/6/5 pentacyclic skeleton ( Wen et al., 2019).

The study of A. sp. 085241B resulted in the isolation of two meroterpenoids, acetoxydehydroaustin B (258) and 1,2-dihydro-acetoxydehydroaustin B (259) ( Song et al., 2011). Insuetolides A-C (260–262) were isolated from A. insuetus . Their structures were identified as meroterpenoids with a new carbon skeleton derived from the cyclization of farnesyl and 3,5-dimethylorsellinic acid ( Cohen et al., 2011). In the biosynthetic route of compounds 260–262 ( Fig. 24 ), the terminal double bond of the sesquiterpene unit oxidizes to an epoxide, followed by reaction with an orsellinic acid unit to form the basic skeleton. Further multiple oxidation reactions produced 260–262 ( Cohen et al., 2011).

Compound 263 was obtained from A. sp. 16–5c, and named 2-hydroacetoxydehydroaustin ( Long et al., 2017). An unusual austinoid 1, 2-dehydro-terredehydroaustin (264) was isolated from A. terreus H010. It showed anti-inflammatory activity against the production of NO ( Liu et al., 2018). The investigation of liquid culture medium of A. sp. TJ23 led to the isolation of aspermerodione (265) and andiconin C (266). Analysis of their structures revealed that compound 265 was a novel terpene-polyketide hybrid meroterpenoid with an unusual 2, 6-dioxabicyclo[2.2.1]heptane core skeleton, and 266 was a heptacyclic analogue of 265 ( Qiao et al., 2018).

In addition, the investigation of Aspergillus fungi resulted in the isolation of twenty-two meroterpenoids, namely austalides M-Q (269–273) from A. sp. (Zhou et al., 2011b), 1,2-dihydroterretonin F (274) from A. ustus ( Liu et al., 2013) , austalides S–U (275–277) from A. aureolatus HDN 14-107( Peng et al., 2016), austalides V (278) and W (279) from A. ustus VKM F-4692 ( Harmer et al., 2017), guignardones J-M (280–283) from A. flavipes AIL 8 ( Bai et al., 2015), yanuthones K-M (284–286) and yanuthone X2 (287) from A. niger ATCC1015 -derived KB100116 and its yanAΔ strain (6-MSA PKS deleted) ( Petersen et al., 2014), and asperpene E (288) from A. sp. SCS-KFD66( An et al., 2020) Among them, austalides V (278) and W (279) both possess a 5/6/6/6/6/5/5 heptacyclic ring system, whereas asperpene E (288) was the first example of a natural product bearing a 2-substituted-8-oxo-7--phenyl-7,9-dihydrofuran-10-carboxylic acid skeleton.

3. Biosynthesis of terpenoids in genus Aspergillus

The terpenoids originate from isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) as building bricks via the condensation reaction. Both higher plants and fungi use IPP and DMAPP to synthesize terpenoids via the mevalonate (MVA) pathway ( Liaw et al., 2015; Zhang et al., 2021b). Compared with plants, fungi are easier to cultivate and reproduce. They have more plasticity in genetic manipulation, which provides favorable conditions for the biosynthesis of terpenoids of fungal origin ( Sanchez et al., 2012).

3.1. Biosynthesis of diterpenoids

Prenylated indole alkaloids such as indole diterpenoids frequently occur in filamentous fungi, especially Penicillium and Aspergillus species ( Matsuda and Abe, 2016). The biosynthesis of typical indole-type diterpenoids, such as paxilline and shearinine originally obtained from the genus Penicillium , has been well discussed in recent years ( Liu et al., 2016a). The biosynthesis of indole-type diterpenoids in Aspergillus has been proven to have similar to that of Penicillium ( He et al., 2018) .

Aflatrem is a potent tremorgenic toxin belonging to the family indole-type diterpenoid isolated from A. flavus . Ogata and coworkers have revealed that this type of compound is derived from indole, farnesyl diphosphate (FPP), and IPP ( Fig. 26 ) ( Ogata et al., 2007). The condensation of FPP and IPP by the GGPP synthase encoded gene paxG (in Penicillium species) or AtmG (in Aspergillus species) led to the production of GGPP, followed by catalysis in the presence of the prenyltransferase encoded gene PaxC (AtmC), to afford 3-geranylgeranyl indole ( Tagami et al., 2013). The epoxidation and cyclization of 3-geranylgeranyl indole catalyzed by the flavin-dependent monooxygenase PaxM (AtmM) and the integral membrane protein encoded gene paxB (AtmB) yielded paspaline ( Tagami et al., 2013). Paspaline is the common indole-terpenoid found in both Penicillium and Aspergillus species, and plays an intermediate role in the biosynthesis of indole-diterpenoids. The atmP/Q and prenyltransferase genes encoded atmD in the A. oryzae transformant produced paspaline to obtain aflatrem and its analogues β -aflatrem, as well as paspalinine ( Tagami et al., 2014).

3.2. Biosynthesis of sesterterpenoids

The biosynthesis of ophiobolins with tricyclic 5/8/5 rings involved multiple gene clusters ( Chai et al., 2016). The first sesterterpene synthase, AcOS, was identified from A. clavatus NRRL 1 by a genome mining approach with the A. oryzae NSAR 1 expression system in 2013. Heterologous expression of the AcOS encoded gene led to the production of the major sesterterpenoid ophiobolin F and three minor products, including two ophiobolanes and clavaphyllene ( Fig. 27 ) ( Chiba et al., 2013).

3.3. Biosynthesis of triterpenoids

Helvolic acid is a nortriterpenoid representing a class of fungiderived triterpenoids isolated from A. fumigatus HNMF 0047 with antibiotic activity against Staphylococcus aureus ( Kong et al., 2018) . As shown in Fig. 28 , Yao and coworkers performed a stepwise introduction of nine genes into A. oryzae NSAR 1, which resulted in the isolation of helvolic acid and its 21 derivatives. In this biosynthetic pathway, (3 S)-2, 3-oxidosqualene was cyclized by oxidosqualene cyclase HelA to yield protosta-17(20) Z,24-dien-3 β -ol. The subsequent oxidation and acetylation finally yield helvolic acid ( Romsdahl and Wang, 2019).

3.4. Biosynthesis of meroterpenoids

Pyripyropene A isolated from A. fumigatus Af 293 belongs to the meroterpenoid containing a triketide–terpenoid moiety and fussed with a pyridine ring derived from nicotinic acid ( Itoh et al., 2010) ( Fig. 29 ). Its biosynthesis depended on a gene cluster with 9 genes, and then this gene cluster was heterologous expressed in A. oryzae M–2–3. Fed with a precursor, nicotinic acid, the results obtained indicated the generation of 4-hydroxy-6-(3-pyridinyl)-2 H -pyran-2-one (HPPO) under the co-expression of the CoA ligase and polyketide synthases genes (Pyr1 and Pyr2). After adding Pyr6 and Pyr5, an epoxyfarnesyl-HPPO was afforded, which suggested that Pyr6 and Pyr5 encoded a prenyltransferase and FAD-dependent monooxygenase, respectively. Subsequently, Pyr4 catalyzed the cyclization of the resulting epoxide to give deacetyl-pyripyropene E, which could ultimately lead to pyripyropene A ( Itoh et al., 2010).

3,5-Dimethylorsellinic acid (DMOA) is an aromatic polyketide widely produced by fungi, especially in the genus Aspergillus . DMOA plays as a basic block in the biosynthesis of a class of intriguing meroterpenoids containing tetraketide–terpenoid moieties, such as austinol from A. nidulans , terretonin from A. terreus and andilesins A-C from A. variecolor ( Kishi et al., 2014) .

Austinol is a fungal meroterpenoid derived from DMOA and has a unique chemical structure with a remarkable spiro-lactone ring system. As shown in Fig. 30 , PrhL or AusA acted as a polyketide synthase to synthesize DMOA in the biosynthetic pathway of austinol, followed by farnesylation by PrhE or AusN, methylesterification by PrhM or AusD, epoxidation of the prenyl chain by PrhF or AusM, and cyclization of the farnesyl moiety by PrhH or AusL to yield the key intermediate protoaustinoid A. The hydroxylation of protoaustinoid A by AusB produced berkeleyone A. In the presence of AusE, berkeleyone A was converted into preaustinoid A, together with AusC, and preaustinoid A was converted into preaustinoid A3 with a spiro-lactone ring system. Austinol was derived from preaustinoid A3. It should be noted that AusE is a multifunctional dioxygenase that catalyzes multistep oxidation reactions, while AusC can catalyze Baeyer-Villiger oxidation ( Matsuda et al., 2013, 2016).

4. Biological activities of the terpenoids from genus Aspergillus

Fungal origin terpenoids seem to occupy a broader chemical space than those from plants. In addition, fungal-derived terpenoids also show a diversity of biological activities that are not inferior to their plant-derived analogues and have unique advantages in terms of their antibacterial and anticancer activities ( Fig. 31 ).

4.1. Anti-inflammatory activity

Inflammation, as an innate immune response, plays a role in the protection of the host from invading pathogens and irritants, while persistent inflammation results in a series of inflammatory-related diseases ( Zhang et al., 2021a). Therefore, many isolated natural products have been investigated for their anti-inflammatory effects. In 2014, Felix and colleagues evaluated the promoter activity of sesquiterpenoids 15–17 on IFN-γ inducible protein 10 (CXCL10), a small chemotactic cytokine that is responsible for the recruitment of T-helper-1 (Th1) natural killer (NK) cells and macrophage. As a result, 15 and 16 dose-dependently inhibited IFN-γ/TNF-α/IL-1β induced CXCL10 promoter activity, reduced CXCL10 mRNA levels and suppressed CXCL10 synthesis ( Felix et al., 2014). Humulane-type sesquiterpenoids 93 and 94 displayed inhibitory effects on NO production, and their IC 50 values were defined as 14.6 and 18.3 μM, respectively ( Wang et al., 2017a). Cyclooxygenase-2 (COX-2) is an inducible isozyme that overexpresses inflammation and tumors. It can accelerate cellular proliferation, inflammation, angiogenesis, and cancer invasiveness. Liaw and coworkers found that compound 229 could dose-dependently suppress COX-2 mRNA and expression levels in LPS-induced RAW264.7 macrophages, and its EC 50 value was 18.3 μM. This suggests that compound 229 could have anti-inflammatory activity ( Liaw et al., 2015).

Meroterpenoids 230–233 were evaluated for their anti-inflammatory activities, and compounds 230 and 233 showed weak activities since they inhibited 42% and 47% IL-6 production at a concentration of 40 μM, respectively ( Wang et al., 2015b). In addition, compounds 248 and 264 displayed a certain inhibitory effect on NO production ( Liu et al., 2018; Wu et al., 2018a).

4.2. Antiproliferative activity

Cancer is the most common type of malignant tumor originating from epithelial tissue, and has become a leading cause of death worldwide. The cancer risk rapidly increases as populations grow, age, and adopt lifestyle behaviour, therefore, research and development of anti-tumor drugs are urgent. Natural products are an important resource for anti-tumor agents, and many isolated specialised metabolites from the genus Aspergillus were assayed for their antiproliferative activities against cancer cells. Sun and coworkers found that phenolic bisabolane dimers 31 and 33 possessed antiproliferative activities against HepG2 and Caski human tumor cell lines with IC 50 values from 5.99 μM to 25.51 μM ( Sun et al., 2012b).

Wang et al. investigated the chemical constituents and anti-tumor effects of the fermentation of A. clavatus , and revealed that aspergillusone D (83) could inhibit the growth of MCF-7 and A549 cells, and their IC 50 values were assigned as 5.9 and 0.2 μM, respectively ( Wang et al., 2016b). Aspergiketone (106), isolated from A. fumigatus by Liu et al. (2016), possessed antiproliferative activities against HL-60 and A549 cells (IC 50, 12.4 and 22.1 μM) ( Liu et al., 2016b). Meng et al. identified a sesquiterpene from A. terreus , namely botryosphaerin F (114), and reported its inhibitory activities against MCF-7 and HL-60 cells, and their IC 50 values were 4.49 and 3.43 μM, respectively ( Deng et al., 2013). Ophiobolin-type sesterterpenoids 172, 173, and 197–201 were also assayed for their cytotoxicities against tumor cell lines, including P388, HCT-15, NUGC-3, NCI–H23, ACHN, PC-3, and MDA-MB-231 ( Choi et al., 2019; Zhang et al., 2012), which demonstrated that compound 197 exhibited the strongest cytotoxicity against HCT-15 (IC 50 = 0.21 μM), NUGC-3 (IC 50 = 0.19 μM), and MDA-MB-231 (IC 50 = 0.14 μM) cells ( Choi et al., 2019).

Drimane-type sesquiterpenoid SF002–96–1 (13) dose-dependently inhibited survivin promoter activity with an IC 50 value of 3.42 μM. Its underlying mechanism involved suppressing survivin mRNA levels and survivin synthesis, resulting in the apoptosis of Colo 320 cells ( Felix et al., 2013). Insulicolides B (25) and C (26) and 14- O -acetylinsulicolide A (27) were isolated from A. ochraceus Jcma 1F17 by Tan et al. (2018). Among them, insulicolide C (26) displayed potent antiproliferative activities against ACHN, OS-RC-2, and 786-O cells, and its IC 50 values ranged from 0.89 μM to 8.2 μM. Further research revealed that 26 could induce late apoptosis in 786-O cells ( Tan et al., 2018). 22Rv1 cells are human prostate adenocarcinoma cells, and Elena et al. found that indole-diterpenoid 160 could concentration-dependently inhibit the growth of 22Rv1 cells (IC 50 = 4.86 μM) by inducing apoptosis ( Elena et al., 2018). Compound 204 is an asperane-type sesterterpenoid with cytotoxicity against A549 cells (IC 50 = 6.2 μM). Subsequent research suggested that compound 204 could promote apoptosis by inducing G 0 /G 1 cell cycle arrest ( Li et al., 2019c).

4.3. Antibacterial and antifungal activity

Small molecules produced by fungal metabolism are one of the most important sources of antibacterial drugs, while penicillin, streptomycin, and vancomycin are prominent among them ( Saleem et al., 2010). To date, there are still many bacterial infections causing diseases that are not well treated, especially when drug resistance has become a global health problem. A growing body of studies has indicated that Escherichia coli , Salmonella enterica , and Salmonella typhi cause bacterial enteritis, and Candida albicans is able to enhance the severity of dextran sulfate solution (DSS)-induced colitis ( Panpetch et al., 2020). In addition, bacterial infection is related to glomerulonephritis and neurodegenerative diseases ( Nasr et al., 2013; Patrick et al., 2019). Terpenoids of Aspergillus origin have shown certain potential in antibacterial activity.

The antibacterial activity of sesquiterpene 10 against E. coli and Staphyloccocus aureus was measured by a disk diffusion assay at a concentration of 30 μg/disk and their inhibitory diameters were 7 and 10.3 mm, respectively ( Liu et al., 2012, 2013). In 2012, Li and colleagues evaluated the antibacterial activity of bisabolane-type sesquiterpenoids 34–37 against eight bacterial strains ( S. albus , Bacillus subtilis , B. cereus , Sarcina lutea , E. coli , Micrococcus tetragenus , Vibrio Parahaemolyticus , and V. anguillarum ). The results showed that 36 exhibited a broad spectrum of antibacterial activity against all test strains, while 35 and 37 had selective activity against S. albus , B. subtilis , and M. tetragenus with MIC (minimum inhibitory concentration) values ranging from 1.35 μM to 5.00 μM ( Li et al., 2012). Bisabolane analogues 50, 51, 53, and 55 also exhibited inhibitory activities against S. aureus ATCC 25923 with IC 50 values ranging from 31.5 μM to 41.9 μM ( Miao et al., 2014; Wang et al., 2018). In a similar study, 68 and 69 showed weak inhibitory activity against S. aureus ATCC 25923 with MIC values of 50 and 25 μM, respectively ( Liu et al., 2016c). Compounds 78 and 79 were obtained from the deep-sea sediment-derived fungus A.versicolor SD-330, and both compounds 78 and 79 have selective inhibitory activity against E. coli QDIO-1, E. tarda QDIO-4, V. harveyi QDIO-9, and V. parahaemolyticus QDIO-10 with MIC values less than or equal to 27.03 μM ( Li et al., 2019b).

In a study evaluating inhibitory activity towards nine human and aquatic pathogenic bacteria, as well as four plant pathogenic fungi, diterpenoids 125–129 displayed certain activity against the aquatic pathogens Edwardsiella tarda , Micrococcus luteus , Pseudomonas aeruginosa , Vibrio harveyi , and V. parahemolyticus , each with MIC values of 13.24 μM. In addition, 125 and 129 showed inhibitory activity against the plant pathogen Fusarium graminearum with MIC values of 6.62 and 13.24 μM, respectively. It appears that compound 125 has better activity against bacteria and fungi than 126 and 127, suggesting that isopimarane diterpenoids with hydroxy substitution at C-9 are more active than those with hydroxy substitution at C-1 or C-3 ( Li et al., 2016). Structurally similar compounds 130–134 showed similar activity against E. coli , E. tarda , V. harveyi , V. parahaemolyticus , and F. graminearum ( Li et al., 2018) . Compound 135 exhibited inhibitory activity against Phytophthora parasitica , F. oxysporum , F. graminearum , and Botryosphaeria dothidea with MIC values of 25.32, 12.66, 3.16, and 12.66 mM, respectively ( Wang et al., 2017b). Both 19-hydroxypenitrem A (158) and its dechlorinated derivative 19-hydroxypenitrem E (159) were obtained from A. nidulans EN-330, while 158 showed antimicrobial activity against four human and aquatic pathogens against S. aureus with an MIC value of 20.5 μM, which suggested that the Cl-substitution at C- 6 in the skeleton of indole-diterpenoid enhanced the antimicrobial activity ( Zhang et al., 2015). Another indole-diterpenoid 166 showed antimicrobial activities against E. coli and Candida albicans with MIC values of 20.6 and 22.8 μM, respectively ( Zhang et al., 2021).

Meroterpenoids 219 and 220, with MIC values of 26.85 and 3.52 μM have better activities than the positive control tobramycin, with an MIC value of 68.52 μM, against S. agalactiae ( Kong et al., 2018) . Another meroterpenoid 260 exhibited antifungal activity against Neurospora crassa with MIC values of 140 μМ, while it did not affect the proliferation of molt-4 cells at 113 mM ( Cohen et al., 2011). The inhibition of penicillin-binding protein 2a (PBP2a) was considered a solution for overcoming the resistance of MRSA. Aspemerodione (265) was found to be a potent inhibitor of PBP2a, and worked synergistically with the β- lactam antibiotics oxacillin and piperacillin against MRSA. Chevalone E (224) was also found to show synergism with oxacillin against MRSA ( Prompanya et al., 2014; Qiao et al., 2018). It was previously reported that yanuthones have antifungal activity towards C. albicans , with yanuthone D being the most active with an IC 50 value of 3.3 μM ( Petersen et al., 2015). In 2014, yanuthones K and L (284 and 285) showed strong activities against C. albicans with IC 50 values that were 5-fold higher than that of yanuthone D, while Yanuthone X 2 (287) showd 15-fold higher IC 50 values than yanuthone D in the same test ( Petersen et al., 2014).

4.4. Antiviral activity

Viral infectious diseases have always been a serious threat to human life and health. Some existing viral diseases, such as HIV/AIDS, hepatitis B, and influenza, have not been completely eradicated and cause millions of deaths each year. Viruses are masters of molecular regulation, and can overturn host defence systems to maintain survival, replication, and proliferation ( Marc, 2017). Viruses evolve to thrive and survive in all species. From 1981 to 2019, 185 kinds of antiviral drugs were approved for application in the clinic worldwide, and 19.45% of the approved antiviral drugs are directly or indirectly derived from natural products, such as grazoprevir, elbasvir, baloxavir, and tecovirimat ( Newman and Cragg, 2020). Meanwhile, an increasing number of scientists have discovered that specialised metabolites from Aspergillus species possess antiviral activities. In 2014, Fang et al., isolated and identified a drimane-type sesquiterpenoid 14, and found that it displayed antiviral effects against influenza virus H3N2 and enterovirus EV71 with IC 50 values of 17.0 and 9.4 μM, respectively ( Fang et al., 2014). In the same year, Nong and colleagues discovered the inhibition of 11 α -dehydroxyisoterreulactone A (227) against HSV-1 with an IC 50 value of 35.04 μM ( Nong et al., 2014). Subsequently, Wang et al. assayed the antiviral activities of merosesquiterpenoids against influenza viruses H1N1, H3N2, and H3N3, and demonstrated that 234 had potent antiviral activity against H3N3 (IC 50 = 0.23 ± 0.05 μM), while its analogue 260 showed inhibitory activities against both H1N1 and H3N2 with IC 50 values of 12.2 ± 4.10 and 0.66 ± 0.09 μM, respectively ( Wang et al., 2016a). In addition, a research group from China reported that meroterpenoid 255 displayed moderate inhibitory activity against influenza neuraminidase (IC 50 = 18.0 μM), suggesting that the compound has the potential to stop the replication and spread of the virus ( Li et al., 2019a).

4.5. Other activity

Additionally, the isolated specialised metabolites from the fungus Aspergillus displayed antioxidation and hepatoprotective effects as well as the inhibition of acetylcholinesterase (AChE). Qiu and coworkers reported that protoilludane-type sesquiterpenoids 101 and 103 displayed weak DPPH radical scavenging activities in 2018 ( Qiu et al., 2018). Liu et al. constructed a model of liver injury through acetaminophen (APAP)-induced damage of HepG2 cells, and revealed that sesquiterpenoids 87–91 could improve the survival rates of HepG2 cells after administration of APAP ( Liu et al., 2019c). AChE is a serine hydrolase that can hydrolyze the neurotransmitter acetylcholine ( Thapa et al., 2017), and is related to central nervous system diseases, such as Alzheimer’ s and Parkinson’ s diseases ( Lane et al., 2004; Nicolatalesa, 2001). Xiao et al., reported that sesterterpenoids 209 and 210 and meroterpenoids 249–254 showed inhibitory activities against AChE with IC 50 values from 2.3 μM to 32.51 μM ( Qi et al., 2019; Xiao et al., 2013). In subsequent research, territrems D (225) and E (226) had potent inhibitory activities against AChE, as reported by Qi and coworkers, and their IC 50 values were 4.2 ± 0.6 and 4.5 ± 0.6 nM, respectively ( Nong et al., 2014).

Figures

Fig. 1. Structures of monoterpenoids 1 and 2.

Fig. 2. Structures of drimane-type sesquiterpenoids 3–30.

Fig. 3. Structures of bisabliane-type sesquiterpenoids 31–82.

Fig. 4. Structures of cadinane-type sesquiterpenoids (83–91).

Fig. 5. Structures and postulated biogenetic pathway for ochracenes A I (92–100).

Fig. 6. Structures of protoilludane-type sesquiterpenoids 101–103.

Fig. 7. Structures of other-type sesquiterpenoids 104–110.

Fig. 8. Structures of labdane-type diterpenoids 111–118.

Fig. 9. Structures of isopimaric-type diterpenoids 119–144.

Fig. 10. Postulated biogenetic pathway for aspergiloid I (121).

Fig. 11. Structures of cleistanthane-type diterpenoids 145–151.

Fig. 12. Structure of indole-type diterpenoids 152–166.

Fig. 13. Structures of ophiobolin-type sesterterpenoids 167–201.

Fig. 14. Structures of asperane-type sesterterpenoids 202–207.

Fig. 15. Structures of other sesterterpenoids 208–213.

Fig. 16. Postulated biogenetic pathway for asperterpenoid A (208).

Fig. 17. Postulated biogenetic pathway for aspterpenacids A (212) and B (213).

Fig. 18. Structures of triterpenoids 214–222.

Fig. 19. Structures of meroterpenoids 223–243.

Fig. 23. Structures of meroterpenoids 244–268.

Fig. 25. Structures of meroterpenoids 269–288.

Fig. 20. Postulated biogenetic pathway for yaminterritrems A (228) and B (229).

Fig. 21. Postulated biogenetic pathway for aspertetranones A-D (230–233).

Fig. 22. Postulated biogenetic pathway for ochraceopones A-E (234–238).

Fig. 24. Postulated biogenetic pathway for insuetolides A–C (260–262).

Fig. 26. Biosynthesis of aflatrem and β-aflatrem in A. oryzae.

Fig. 27. Biosynthesis of ophiobolin F catalyzed by AcOS.

Fig. 28. Biogenetic pathway for helvolic acid.

Fig. 29. Biosynthesis of pyripyropene A.

Fig. 30. Biogenetic pathway for austinol.

Fig. 31. Biological activities of the terpenoids from the genus Aspergillus.