Aspergillus P.Micheli 1729

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 J05 B –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 A 549 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 7–3 B, 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 A 549 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 A 549 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 shari