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Drimane-type sesquiterpenoids from fungi

  • Corresponding author: Liao-Bin Dong, China Pharmaceutical University, Nanjing 211198, China. E-mail: ldong@cpu.edu.cn
  • Available Date: 11-Mar.-2022
  • Sesquiterpenoids are comprised of three C5 units and derived from farnesyl diphosphate. In these C15 family of terpenoids, the drimane-type sesquiterpenoids are unique as their chemical structure of decahydronaphthalene along with the methyl group decorations resemble the A/B rings of labdane derived diterpenoids and the eastern part of many meroterpenoids. In the past few decades, due to this chemical structural feature as well as their diverse and significant bioactivities, great efforts have been made to perform chemical and biological research on this family of natural products, leading to the characterization of a large of new compounds and a few biosynthetic pathways. In this review, to highlight their diverse chemical structures, biological activities, and biosynthetic pathways, we collected 164 new drimane-type sesquiterpenes from fungi between January 2004 and October 2021 and classified them into three major subfamilies.
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Drimane-type sesquiterpenoids from fungi

    Corresponding author: Liao-Bin Dong, China Pharmaceutical University, Nanjing 211198, China. E-mail: ldong@cpu.edu.cn
  • 1. State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu, China
  • 2. The Public Laboratory Platform, China Pharmaceutical University, Nanjing 211198, Jiangsu, China

Abstract: Sesquiterpenoids are comprised of three C5 units and derived from farnesyl diphosphate. In these C15 family of terpenoids, the drimane-type sesquiterpenoids are unique as their chemical structure of decahydronaphthalene along with the methyl group decorations resemble the A/B rings of labdane derived diterpenoids and the eastern part of many meroterpenoids. In the past few decades, due to this chemical structural feature as well as their diverse and significant bioactivities, great efforts have been made to perform chemical and biological research on this family of natural products, leading to the characterization of a large of new compounds and a few biosynthetic pathways. In this review, to highlight their diverse chemical structures, biological activities, and biosynthetic pathways, we collected 164 new drimane-type sesquiterpenes from fungi between January 2004 and October 2021 and classified them into three major subfamilies.

    • Terpenoids, as the largest and most structurally diverse family of natural products with over 80,000 known members, are found in all system of life, mainly from terrestrial and marine plant, fungi, and liverworts, as well as a relatively minor fraction from prokaryotes (http://dnp.chemnetbase.com)[1]. Terpenoids are all derived from the same basic C5 units – isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), and are classified based on carbon members with monoterpenoids (C10), sesquiterpenoids (C15), diterpenoids (C20), sesterterpenoids (C25), triterpenoids (C30), etc.[2]. Sesquiterpenoids are normally biosynthesized sequentially by sesquiterpene synthases that catalyze the cyclization of linear precursor, farnesyl diphosphate (FPP), forming the carbon skeleton, and sesquiterpene oxidases that are able to tailor the carbon skeletons to produce a myriad of biologically active components with complex chemical structures. Various cyclization reactions take place from the cationic intermediates to yield a wide range of structures, such as sibirene, γ-humulene, β-bisabolene, and drimane carbon skeletons, etc.[3].

      Drimane-type sesquiterpenoids are a large group of natural products that contain over 350 members with diverse oxidation patterns in a common structural scaffold and possess significant pharmaceutical functions[4]. The first drimane-type sesquiterpenoid, (-)-drimenol (Figure 1), was isolated and characterized from the bark of Drimys Winteri Forst (common name Canelo) in 1959[5], since then the majority of researches into drimane-type sesquiterpenoids have been focusing on their isolation, total synthesis, bioactivities, and biosynthesis. During the past two decades, some excellent reviews have summarized the distribution, biological activities, and organic synthesis efforts of this intriguing type of drimane-type sesquiterpenoids from the liverworts, ferns, and higher plants, etc.[4,6,7], however, no review focusing on this type of sesquiterpenoids from fungi has been published. Given that a large quantity of drimane-type sesquiterpenoids were reported from fungi after the last review published at 2004, and many of them exhibited significant bioactivities, herein, we collected the chemical structures, biological activities, as well as biosynthetic pathways towards them from fungi between January 2004 and October 2021. In total, 164 diverse drimane-type sesquiterpenoids are described.

      Figure 1.  Drimane carbocyclic core (left, i) and chemical structure of (-)-drimenol (right).

    Structures, classifications and bioactivities
    • Classic drimane is characterized by the carbocyclic skeleton i (Figure 1) that is comprised of a trans-decahydronaphthalene and decorated with five methyl groups at C-4, C-8, C-9, and C-10, as well as a double bond between C-7 and C-8. In this group, C-11 and C-12 are frequently oxidated to link diverse substitutes or substructures. In total, 74 drimane-type sesquiterpenoids can be grouped into this classic drimane type (Figures 2 and 3).

      Figure 2.  Chemical structures of classic drimanes 1–63.

      Phellinuins F (1) and G (2), possessing two additional hydroxyl groups attached at C-3 and C-12 comparing with the chemical structure of drimenol, were isolated from the cultures of mushroom Phellinus tuberculosus, a higher fungus belongs to the genus of Phellinus[8]. Another five new drimane-type sesquiterpenoids, phellinuins A–E (37), with additional oxidized C-13 methyl groups were reported from the same species[8]. 11-Hydroxyacetoxydrim-7-en-3β-ol (8) and 12-hydroxy-3-oxodrimenol (9), two classic drimane-type sesquiterpenoids with a rare α-hydroxyl ester and a C-3 ketone group, respectively, were discovered from the wood-decaying fungus Phellinidium sulphurascen[9]. Both compounds (8 and 9) were screened againt five human cancer cell lines but with no cytotoxic activities detected. A new drimane-type sesquiterpenoid, 3-keto-drimenol (10), was isolated from the cultures of basidiomycete Clitocybe conglobate and showed inhibitory activities against two isozymes of 11β-hydroxysteroid dehydrogenases (11β-HSD1 and 11β-HSD2), which are able to catalyze the interconversion of active cortisol and inactive cortisone[18]. Sulphureuines B, C, and G (1113), which have a modified C-7 and C-8 double bond (saturated or hydroxylation), along with sulphureuine H (14) were discovered from the edible mushroom Laetiporus sulphureus[10]. Among them, sulphureuine B (11) was able to induce U-87MG cell apoptosis through endoplasmic reticulum stress, mitochondrial, and death receptor mediated pathways[10,11]. Pestalotiophol A (15) was obtained from an endophytic fungus Pestalotiopsis adusta, and its absolute configuration was determined by comparing the calculated and experimental ECD curves of its fully benzoylated derivative[12]. Ustusols A–C (1618) were identified from the marine-derived fungus Aspergillus ustus 094102, of which 16 showed significant antifungal activities against a panel of plant pathogenic fungi including Thielaviopsis paradoxa, Pestalotia calabae, and Gloeosporium musarum with MICs values of 1.6, 1.6 and 3.1 μM, respectively[13-15]. Chemical investigations of the fungus Aspergillus ustus isolated from the marine sponge Suberites domuncula led to the isolation of 3β,9α,11-trihydroxy-6-oxodrim-7-ene (with the same chemical structure of ustusol A, 16), 2α,9α,11-trihydroxy-6-oxodrim-7-ene (19) and 2α,11-dihydroxy-6-oxodrim-7-ene (20)[16]. Two 9α-hydroxyl drimane-type sesquiterpenoids, 9α-hydroxyl-9-formyl-5α-drim-7-en-6-one (21) and O-methylalbrassitriol (22), were isolated from the cultures of a mangrove-derived fungus A. ustus[17]. Deoxyuvidin B (23) was obtained from A. ustus TK-5, an endophytic fungus isolated from the fresh tissues of Pyura momus in the Turkish sea[14]. 12-Hydroxyalbrassitriol (24), drim-8(12)-en-6β,7α,9α,11-tetraol (26), and drim-68(12)-dien-9α,11-diol (27) were isolated from the cultures of the tin mine tailings-associated fungus Penicillium sp.[19]. Chemical investigations of Paecilomyces sp. TE-540 resulted in the isolation and identification of ustusols D (28) and E (25), of which 28 possesses two double bonds at Δ6 and Δ8[20]. Likewise, chemical investigation of A. ustus led to the discovery of ustusal A (29)[21]. Two new drimane sesquiterpenoids, 11,12-dihydroxy-15-drimeneoic acid (30) and 3α,11,15-trihydroxydrimene (31), were isolated from the cultures of basidiomycete Agaricus arvensis[22]. Drim-8-en-6β,7β,11-triol (32), which was reported from both the mangrove-derived fungi A. ustus and Pleosporales sp. CF09-1[15], represents the first case of drimane-type natural product having a double bond between C-8 and C-9. Repeated chemical studies on the mangrove-derived endophytic fungus Diaporthe sp. resulted in the isolation and identification of a series of new drimane-type compounds, including diaporols B–I (3340), Q (41), and R (42)[23,24]. Comparison with the usual drimane-type sesquiterpenoid, compound 33 possesses a special oxygenated C-5 position, and its absolute configuration was elucidated by X-ray diffraction analysis. Notably, this C-5 hydroxyl group was rarely found in this family. All compounds were tested for their cytotoxicity against four cell lines, HCT116 (human colon cancer), MDA-MB-231 (human breast cancer), SMMC-7721 (human hepatic carcinoma), HepG2 (human hepatic carcinoma), SW480 (human colon adenocarcinoma cell line), however, only 42 exhibited moderate cytotoxicity against SW480 cell line with IC50 value of 8.7±1.3 µΜ[23,24].

      Nebularic acids A (43) and B (44) were isolated from the cultures of Lepista nebularis by bioassay-guided chromatography, of which 43 exhibited moderate activity against Bacillus subtilis ATCC 6633, and 44 exhibited significant antifungal activities against Penicillium avellaneum UC 4376, Fusarium culmorum JP15, and Kluyveromyces maxianus, as well as weak antibacterial activities against Staphylococcus aureus SG511 at 50 µg mL–1[25]. Isodrimenediol 2-acetate (45) and isodrimenediol diacetate (46) were reported from Trametes sp. G048 in 2012[26]. Five new compounds, funatrols A–D (4750) and isodrimenediol (51), were discovered from the fungus Funalia trogii. The double bond between C-8 and C-12 of 47 and 48 was rarely epoxidated among this family natural products. Compounds 47–51 were tested for their cytotoxicity against five human cancer cell lines, however, none of them were active[27]. Xylariaine A (52) was discovered from the fungus Xylaria polymorpha and exhibited weak anti-acetylcholinesterase activities at a concentration of 50 μg/mL with an inhibition ratio of 12.4%[28]. Cryptoporol A (53) and drimane-3,8,11,12-tetraol (54) were identified from the fruiting bodies of Cryptoporus volvatus and the extract of Marasmius cladophyllus F070624009, respectively[29,30]. Agriminia pilosa has been used in traditional Chinese medicine to treat taeniasis. Chemical studies on its endophytic fungus Fusarium sp. resulted in the isolation and characterization two new sesquiterpenoids, agripilols A (55) and B (56)[31]. Methoxylaricinolic acid (57) was discovered from the fruiting bodies of Stereum ostrea and exhibited marginal inhibitory activity with an IC50 of 50 μg/mL against lipid peroxidation in rat liver microsomes evaluated through the thiobarbituric acid method[32]. Chemical investigations into the fungus of Fomes officinalis led to the isolation of fomeffic acid (58) which showed weak cytotoxicity against HL-60 and Bel-7402 cancer cell lines with IC50 values of 51.2 and 88.7 μM, respectively[33]. Sulphureuine D (59), with a rearranged drimane sesquiterpenoid skeleton, was isolated from the cultures of fungus Laetiporus sulphureus[10]. It was evaluated for the cytotoxicities against five cancer cell lines in HL-60, SMMC-7721, A-549, MCF-7, and SW-480, however, noncytotoxic to all cell lines (IC50 > 40 μM).

      In this classic drimane-type sesquiterpenoids, the C-6 position is commonly hydroxylated and linked with a polyketide chain, fatty acid or cinnamic acid by an ester bond. In 2019, xylodonin C (60) was reported from the basidiomycete Xylodon flaviporus, the C-6 hydroxyl group of which was esterified with a cinnamic acid[34]. Xylodonin C (60) exhibited weak inhibitory effects against receptor activator of nuclear factor-kappa-B (NF-κB) ligand-induced osteoclastogenesis in mouse bone marrow macrophages[34]. Ustusoic acids A (61) and B (62), along with ustusolate A (63), all possessing a polyketide chain present at C-6 position, were identified from A. ustus and Aspergillus ustus 094102, respectively[13]. Among them, compound 63 showed weak cytotoxicity against HL-60 and A549 cells with IC50 values of 20.6 and 30.0 µM, respectively[13].

      The C-11 of this classic drimane type is another position that is frequently found linking with isocitric acids or phthalimidine derivatives via an ether bond. Three drimane-type sesquiterpene ethers, cryptoporic acids J, K, and N (6466), were isolated from the fruiting bodies of Cryptoporus sinensis. Structurally, all of them possess a common drimane framework and an additional isocitric acid chain which is linked by an ether bond at C-11. Cryptoporic acids J (64) and K (65) were evaluated for their inhibitory activities of NO production from macrophage RAW 264.7. As a result, none of them showed activities. Moreover, cryptoporic acid N (66) was evaluated for its cytotoxic activity against four cell lines (A549, MCF-7, PC-3, and PANC-1), and it exhibited very weak cytotoxicity to all cell lines with an IC50 larger than 100μM[35,36]. Six novel drimane-type congeners, fendlerinines A–F (6772), which had different phthalimidine derived structures attached at C-11 via an ether bond, were isolated from the fungus Hypoxylon fendleri BCC32408. These compounds were evaluated their antibacterial activities but with no activities[37]. Cryptoporic acids R (73) and S (74) were isolated from the fruiting bodies of Cryptoporus volvatus[38,39]. Cryptoporic acid R (73) was evaluated the antiviral effects against PRSSV but exhibited very weak activity with the PRRSV inhibition ratios < 5.0% at 50 μg/mL[38]. Cryptoporic acid S (74) was evaluated for antioxidant activity using the methods of DPPH-RSA and FRAP assay, and it only exhibited moderate antioxidant activity with EC50 values of DPPH radical scavenging of 48.9 μg/mL and FRAP result of 0.76 mmol/g[39].

      Figure 3.  Chemical structures of classic drimanes 64–74.

    • This class of drimane-type sesquiterpenoids possesses a typical lactone ring that is formed by three different dehydration reactions: (i) between 11-OH and 12-COOH (i.e. 11,12-lactone drimanes); (ii) between 12-OH and 11-COOH (i.e. 12,11-lactone drimanes); (iii) between 11-OH and 15-COOH (i.e. 11,15-lactone drimanes). In total, 80 drimane-type sesquiterpenoids can be grouped into this class.

    • In this section, thirty-nine 11,12-lactone drimanes were collected (Figure 4). Nebularilactones A (75) and B (76), possessing lactone rings formed by dehydration of 11-OH and 12-COOH groups and additional hydroxyl groups with different configurations at C-1, were isolated from a culture of L. nebularis by bioassay-guided chromatography[25]. Chaetothyrins A–C (77, 86, 95) with different oxidation states were obtained from an endolichenic fungus Chaetothyriales sp. (4341B). The absolute configuration of 77 was determined by X-ray diffraction analysis[40]. 3α,6β,-Dihydroxycinnamolide (79) was isolated from the fruiting bodies of fungus Inonotus rickii and showed moderate inhibitory activity against a human colon cancer cell line SW480 with IC50 of 20.4 μM[41]. 3β,6β-Dihydroxycinnamolide (80) was discovered in Fomitiporia punicata[42]. 3β,6α-Dihydroxycinnamolide (81) and 2-keto-3β,6β-dihydroxycinnamolide (83) were isolated from the cultures of basidiomycete Cyathus africanus. Both compounds (81 and 83) could enhance nerve growth factor (NGF)-mediated neurite outgrowth using rat pheochromocytoma (PC12) cells at a concentration of 10 µM[43]. Inotolactones E–H (78, 84, 82, and 96) were identified from Inonotus obliquus, of which 78 exhibited moderate neuroprotective activity against H2O2-induced injury in SH-SY5Y cells at 25 μM[44]. Chemical re-investigation into the fungus of Diaporthe sp. which was isolated from the leaves of Rhizophora stylosa led to the isolation of diaporol S (85), the relative configuration of which was confirmed by X-ray diffraction analysis[24]. Two similar drimane-type lactones, talaminoid C (87) and 1α,7α-dihydroxyconfertifolin (88) were discovered from the solid culture broths of fungus Talaromyces minioluteum[45] and endophytic fungus of Dracaena cambodiana[46], respectively. In 2015, three new 11,12-lactone drimanes, astellolides C–E (8991), were isolated from the liquid cultures of Aspergillus oryzae (No. QXPC-4)[47]. The relative configuration of 90 was elucidated by X-ray diffraction analysis. All compounds were tested for their cytotoxicities against human hepatoma, colon, women carcinoma, etc., however, none of them showed activity. Agripilolactone (92) was isolated from Fusarium sp., an endophytic fungus in A. pilosa[48]. Chemical investigations of fungus X. polymorpha resulted in the isolation and identification of xylariaines B (93) and C (94). Compound 93 showed weak anti-acetylcholinesterase activities at a concentration of 50 μg/mL with inhibition ratios of 18.0%[28]. Inotolactone C (97) was isolated from mushroom I. obliquus and its structure was elucidated by spectroscopic methods[49].

      Figure 4.  Chemical structures of 11,12-lactone drimanes 75–97.

      In this class, a relatively small amount of sesquiterpenoids could be found attaching primary metabolism subunit at C-1, C-6 or C-7 positions (Figure 5). Compounds 98105 belong to the 11,12-lactone drimanes but each conjugated with an additional N-acetyl-L-valine at C-1 position. Berkedrimane B (98) was a new drimane sesquiterpenoid connected with an N-acetyl-L-valine at C-1 from Talaromyces purpureogenus[53]. (1R, 5R, 9S, 10S, 2'S)-Berkedrimanes A (99) and B (100) were isolated from the Berkeley Pit extremophilic fungus Penicillium solitum by bioassay-guided methods. Both Compounds were able to moderately inhibit two signal transduction enzymes, caspase-3 and caspase-1, whose overexpression has been correlated with Alzheimer’s disease and other diseases, and decrease the interleukin 1-β production in the induced THP-1 (pro-monocytic leukemia cell line) assay[50,51]. Purpurides B (101) and C (102) were isolated from the aciduric fungus Penicillium purpurogenum JS03-21 and showed moderate antibacterial activity against E. aerogenes and P. aeruginosa with MIC values of 1.2-2.6 μM[52]. Minioluteumides A–D (103106) were discovered from the marine fungus Talaromyces minioluteus (also named Penicillium minioluteum)[54]. Notably, minioluteumide A was decorated by a chlorine atom which was extremely rare in drimane-type sesquiterpenoids. Talaminoid B (107), the only drimane-type sesquiterpenoid containing both the amino acid residue and butanediol group, was isolated from T. minioluteus (P. minioluteum)[45].

      Figure 5.  Chemical structures of 11,12-lactone drimanes 98–109.

      SF002-96-1 (108) was isolated from an Aspergillus species of IBWF002-96. Compound 108 could dose dependently inhibit the promoter activity of survivin in transfected Colo 320 cells with IC50 value of 3.42 μM. The authors further confirmed that the inhibitory mechanism was the binding of STAT3 and NF-κB (two critical transcription factors) to the promoter of the survivin gene being blocked, and thus triggered apoptosis in Colo 320 cells[55]. O-Methyl-12-oxoxylodonin B (109), possesses a drimane lactone skeletal with a cinnamic acid at C-6 by an ester bond, was isolated from Xylodon flaviporus[34]. It was tested for its inhibitory activities against RANKL-stimulated osteoclastogenesis in mouse BMMs and showed relatively weak activities with IC50 value of 10.1 μM. Four p-hydroxybenzoate derivatives, astellolides F–I (110113) were isolated from the liquid cultures of Aspergillus oryzae (No. QXPC-4) and were evaluated for their cytotoxic activities but none of them showed any bioacitivities[47].

    • In this section, thirty-five 12,11-lactone drimane sesquiterpenoids were introduced (Figure 6). 9α-Hydroxy-5α-drim-7-ene-6-one-11,12-olide (114), a drimane-type sesquiterpenoid containing a 12,11-lactone ring and an enone group, was isolated from fungus Aspergillus carneus Blochwitz[56]. Strobilactones A (115) and B (116) were identified from the edible mushroom Strobilurus ohshimae, and both compounds exhibited weak cell growth inhibitory activities against cultured COLO 201 cells. Additionally, compound 116 showed moderate antibacterial activities against Staphylococcus aureus and Pseudomonas aeruginosa[57]. Sulphureuines E (117) and F (118) were obtained from L. sulphureus, and were evaluated for their cytotoxicities against five cancer cell lines of HL-60, SMMC-7721, A-549, MCF-7, and SW-480, however, no activities were detected[10]. Pestalotiophol B (120) was identified in P. adusta, an endophytic fungus of Sinopodophyllum hexandrum[12]. In 2017, two new drimane-type sesquiterpenoids named polymorphines A (119) and B (143) were isolated from the EtOAc extract of fermentation broths of fungus Xylaria polymorpha (Pers.: Fr.) Grer, of which 143 contained a benzoic acid substitute at C-1 via an ester bond and exhibited anti-acetylcholinesterase and α-glucosidase inhibitory activities[58]. Two new drimane sesquiterpenoids, 11,12-epoxy-3α,6β,9α,11α-tetrahydroxydrimene (121) and 11,12-epoxy-3α,9α,11α-trihydroxydrimene (122), were isolated from Trichaptum biforme, and the drimane lactone functional group in both compounds was reduced to a hemiacetal group[59].

      Figure 6.  Chemical structures of 12,11-lactone drimane.

      In this class, a large part of compounds could be found linking a chain substituent or phenylpropanoid congeners at C-6 via an ester bond. (E)-6-(4′-Hydroxy-2′-butenoyl)-strobilactone A (130) was identified from fungus Aspergillus insuetus and exhibited mild cytotoxicity towards MOLT-4 human leukemia cells[60]. Ustusolates B–E (127, 131133) were isolated from a marine-derived fungus A. ustus 094102. Among them, compounds 127 and 133 exhibited moderate cytotoxicity against A549 and HL-60 cells with IC50 values of 10.5 and 9.0 µM, respectively[13]. (2′E,4′E)-5′-Carboxypenta-2′,4′-dienoyl (134) was obtained from the fungus A. ustus and showed cytotoxic activity against a panel of tumor cell lines including L5178Y, HeLa, and PC12 cells[16]. (6-Strobilactone-B) ester of (E,E)-6,7-dihydroxy-2,4-octadienoic acid (128) was isolated from the fungus Aspergillus ustus isolated from the marine sponge S. domuncula[16]. Two new 12,11-lactone drimanes, 135 and 136, which were discovered in an Aspergillus species, were named as (5R,5aS,9aS)-9b-hydroxy-6,6,9a-trimethyl-1-oxo-1,3,5,5a,6,7,8,9,9a,9b-decahydro-naphtho[1,2-c]furan-5-ylhexanoate and (5R,5aS,9R,9aR,9bR)-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-ylhexanoate, respectively. Both compounds dose-dependently inhibited the IFN-c/TNF-a/IL-1b induced CXCL10 promoter activity in transiently transfected human DLD-1 colon carcinoma cells with IC50 values of 12.4 μM and 55.0 μM, respectively[61]. Ustusolate G (137) and (E,E)-6,7-epoxy-2,4-octadienoic acid (140) were isolated from A. ustus[21,62].

      Aspergillus flavus is notorious for its mutagenic mycotoxins production, however, some components with potential biological activities were reported from this fungus. For instance, asperienes A–D (123126) exhibited anti-tumor activities. Notably, compound 123 showed strong activity to MCF-7 cells with the IC50 value of 1.4 μM[63]. Chemical investigations of mangrove-derived fungus A. ustus led to the isolation of (6-strobilactone-B) ester of (E,E)-6-carbonyl-7-hydroxy-2,4-octadienoic acid (129) and (2'E,4'E,6'E)-6-(1'-carboxyocta-2',4',6'-triene)-11,12-epoxy-9-hydroxy-11-methoxy-drim-7-ene (141).

      Compound 129 exhibited moderate cytotoxicity against the P388 cell line with IC50 value of 8.7 μM[17]. 11-Hydroustusolate E (138), 6',11-hydroustusolate E (139), and (2'E,4'E,6'E)-6-(1'-carboxyocta-2',4',6'-triene)-11,12-epoxy-9,11-dihydroxydrim-7-ene (142) were discovered from A. ustus TK-5[14]. Compounds 139 and 142 showed moderate inhibitory activity on neuraminidase. Five new drimane-type sesquiterpenoids, 11-xylodonins A (144) and B (147), 1-hydroxyxylodonin A (145), 22-hydroxyxylodonins A (146) and B (148), were isolated from the basidiomycete X. flaviporus. All of these compounds were evaluated for their inhibitory effects against receptor activator of nuclear factor-kappa-B ligand-induced osteoclastogenesis in mouse bone marrow macrophages. As a result, compounds 144, 146, and 148 showed significant activities with IC50 values of 1.6, 0.9, and 2.1 μM, respectively[34].

    • In this section, seven 11,15-lactone drimane sesquiterpenoids were described (Figure 7). Fudecadiones A (152) and B (149) were obtained from the soil fungus Penicillium sp. BCC 17468, of which 152 exhibited moderate anticancer activity against MCF-7, KB, and NCI-H187 cell lines[64]. Marasmals B (150) and C (151) were isolated from Marasmius sp. and showed conidial germination inhibition in Magnaporthe oryzae, Phytophthora infestans, and Fusarium graminearum[65]. Three tetracyclic compounds, marasmene B (153), nigrofomins A (154) and B (155), possess a rare dioxabicyclooctane moiety, were isolated from Marasmius sp. IBWF 96046 and fruiting bodies of Nigrofomes melanoporus, respectively. Compound 153 was able to completely inhibited the spores germination of Magnaporthe oryzae at a concentration of 100 μg/mL[65], while compounds 154 and 155 showed weak cytotoxicity against acute T-cell leukemia (Jurkat), human nasopharyngeal carcinoma (NPC-TW01), and lung cancer (NCI-H661) cells with IC50 values in the range of 99.4 to 246.3 µM[66].

      Figure 7.  Chemical structures of 11,15-lactone drimanes.

    • In this section, nine drimane-type sesquiterpenoid dimers and a trimer were described (Figure 8). Structurally, all compounds are comprised of two or three drimane monomers as well as citric/isocitric acid moieties. Since the first drimane-type sesquiterpenoid containing this isocitric acid moiety was named cryptoporic acid A[67], these dimers and trimers are also categorized into the subfamily of cryptoporic acid natural products (CAs). Before 2004, CAs were isolated mainly from the basidiomycete Roseoformes subflexibilis[68] and Haploporus odorus[69], and fungus Cryptoporous volvatu[67]. In 2011, two new dimeric drimane sesquiterpenes, cryptoporic acids J (156) and K (157), were isolated from a fermentation extract of M. cladophyllus F070624009, of which 156 had an inhibitory zone ca. 8 mm against Bacillus subtilis[29]. Later, a similar dimeric drimane-type sesquiterpenoid, porialbocin A (158), along with several known drimane dimers were isolated and characterized from the basidiomycete Poria albocincta BCC 26244[70]. Porialbocin A (158) showed a relatively broad biological activities including antiplasmodial, antimycobacterial, and cytotoxic activities[70]. Cryptoporic acids L (159), M (160)[33] and O (163)[36] were isolated from C. sinensis, while 5‴, 6‴-cryptoporic acid G dimethyl ester (161) and 5″-cryptoporic acid E isopropyl ester (162) were isolated from C. volvatus. Very recently, Kyo et al. reported an untargeted metabolomics-based prioritization workflow that relies on MS/MS molecular networking to estimate scaffold-level distribution, thus prioritizing fungus species for natural product discovery. Targeted isolation of the fruiting body of Cryptoporus volvatus yielded the only trimeric CAs during this period, cryptoporic acid T (164), which was comprised of three cryptoporic acid subunits. Compound 164 was evaluated for its cytotoxicity against the human colon cancer cell line, HCT-116, however, it showed no activities[71].

      Figure 8.  Chemical structures of drimane dimers and trimer.

    Biosynthesis
    • Drimane-type natural products are a group of very distinctive sesquiterpenoids that are found in terrestrial plants, endophytic fungi, and sponges. They are originated from the line precursor of all sesquiterpenoids, farnesyl diphosphate (FPP), which is then catalyzed by drimenol synthase to produce dazzling related-natural products. Two well-known biosynthetic pathways towards the five carbon precursors (IPP and DMAPP) are involved in all terpenoid biosynthesis. One is mevalonic acid (MVA) pathway that majorly found in fungi and higher plants, and the other is 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway that majorly found in bacteria[72]. Of course, drimane-type sesquiterpenoids have no exception[73]. So far, more than 350 drimane-type sesquiterpenoids have been reported,[4] however, only three biosynthetic pathways towards these natural products were demonstrated[76,78,81].

      As early as in 1985, Pickett proposed a biosynthetic pathway for the biosynthesis of the best known drimane dialdehyde polygodial, which was isolated from the crop plants and shown as an antifeedant for a number of herbivorous insects, speculating the sesquiterpene alcohol drimenol might be a direct precursor[74]. However, after around 30 years, in 2014, Ro et al. genetically disclosed the first drimenol synthase cDNA (VoTPS3) from the valerian plant (Valeriana officinalis), and confirmed that VoTPS3 synthesized (-)-drimenol by in vitro biochemical characterization and feeding experiments[75]. In this report, a mechanistic consideration of (-)-drimenol synthesis suggested that drimenol synthase might use a protonation-initiated cyclization mechanism that was atypical in sesquiterpene synthases. Later, Henquet et al. identified another drimenol synthase (PhDS) and a cytochrome P450 drimenol oxidase (PhDOX1) from plant Persicaria hydropiper (also named water-pepper)[76]. Through co-expression both genes, PhDS and PhDOX1, in yeast and the in vitro biochemical experiments of PhDOX1, the authors revealed that the PhDOX1 could hydroxylate C-12 methyl group to form drimendiol, a likely precursor of polygodial and cinnamolide. Notably, the drimenol synthase PhDS only exhibited 30% sequence with that of VoTPS3 and rarely had two DDxxD motifs, implying different cyclization mechanisms of both terpene synthases. The enzymes for further drimendiol oxidations towards polygodial remained to be disclosed. Apart from the above two partial elucidations of the biosynthetic pathways of drimane-type sesquiterpenoids, another two related studies were performed by fungi derived drimane-type sesquiterpenoids that will be detailly interpreted below.

    • Astellolides, a group of drimane-type sesquiterpene esters, are widely distributed in filamentous fungi, and some of them exhibit diverse biological activities such as antimicrobial, anti-inflammatory, and anti-tumor activities[47,77,78]. Astellolide was produced by a filamentous fungus A. oryzae which has been developed as a powerful workhorse for heterologous production of biosynthetic gene clusters (BGCs) of fungal origin[79,80]. The biosynthetic pathway toward astellolide has been unveiled by Koyama et al. through a combination of gene disruption and biochemical experiments. The astellolide BGC, ranging from astA to astK, was identified and confirmed by gene disruption in the cclA disruption strain. In vitro enzyme characterization demonstrated that AstC as a class II terpenoid cyclase with a DxDTT motif (a variation of conserved DxDD motif) was responsible for the cyclization of farnesyl pyrophosphate (FPP) to produce the drimane skeleton. AstI and AstK, belonging to the haloacid dehalogenase (HAD)-like superfamily, were speculated to perform successive depyrophosphorylation reactions of drimanyl pyrophosphate leading to drim-8-ene-11-ol. A P450 AstD and a predicted short-chain dehydrogenase AstE were speculated that they might be involved in the lactone formation. Subsequently, three P450s, AstB, AstF, and AstJ, were proposed to be responsible for following multiple hydroxylations of astellolide that were supported by gene knockout experiments. Biochemical experiments suggested that the linkage between terpenoid skeleton and the phenyl moiety was carried out by a multi-module non-ribosomal peptide synthetase (NRPS) enzyme AstA. Finally, AstG was responsible for transferring the acetyl group to C-15 to produce astellolide A (Scheme 1).

      Figure 1.  A biosynthetic pathway toward astellolide proposed by Koyama et al.

    • Most fungi-derived drimane-type sesquiterpenoids possess a common γ-butyrolactone ring and are frequently esterified at C-6 position. Very recently, Huang et al. elucidated the biosynthetic pathway of this type of esters isolated from the fungus Aspergillus calidoustus. In combination of bioinformatics analysis and a gene disruption campaign, the authors identified a BGC containing six genes that might be related to drimane sesquiterpene esters biosynthesis[81]. The FPP was initially identified and catalyzed to form the drimenol by a terpene cyclase, DrtB, which had the same activity observed in plant-derived drimenol cyclases. A cytochrome P450, DrtD, was able to catalyze multiple hydroxylations of C-6, C-9 and C-12, and perform further oxidation of hydroxy groups at C-6 and C-11 to ketone and aldehyde, respectively. Subsequently, an FAD-binding oxidoreductase DrtC oxidized C-11 or C-12 to obtain a carboxylic acid which was then condensed with the γ-OH to form the γ-butyrolactone ring. The polyketide synthase DrtA could synthesize different lengths (C6 and C8) of PKS chains, which were then dehydrated to varying degrees by the short-chain dehydrogenase DrtF. At last, PKS chains were transferred into drimane skeleton by the acyltransferase DrtE to form the diverse sesquiterpene esters. The oxidases mediating the C-2 and C-3 hydroxylations, however, were not found in this BGC and suggested functioned by unknown endogenous enzymes outside the BGC in A. calidoustus (Scheme 2).

      Figure 2.  Summary of the biosynthetic pathways towards drimane sesquiterpene esters proposed by Huang et al.

      Although the above two biosynthetic pathways merely focused on the drimane lactone type of sesquiterpenoids, these results should help us to speculate the possible biosynthetic pathways towards the other two types of drimane-type sesquiterpenoids. For the classic drimanes, the core carbon skeleton might be constructed by a drimenol synthase to form the key precursor drimenol, which might then undergo multiple post-modifications by different enzymes including cytochrome P450s, acyltransferase, fatty acid synthetase, etc. to produce a large number of polyoxidized drimane natural products. For the drimane dimer and trimer which consists of two or three monomers via ether and ester bonds, the ligase, dehydratase, transferase, etc., might play key roles for the formation of these ether and ester linkages.

    Conclusions
    • The drimane-type sesquiterpenoids belong to a unique sesquiterpenoid family as its chemical structure maps the A/B rings of labdane derived diterpenoids as well as the eastern part of many meroterpenoids[82]. Due to their intriguing structural features and diverse biological activities, the efforts to discover new drimane-type sesquiterpenoids, especially in fungi, with effective biological activities as well as in-depth explore the hidden enzymatic mechanism had long been a hot topic in terpenoids chemistry. In this review, we summarized 164 drimane-type sesquiterpenoids that were reported between January 2004 and October 2021. The topics include the isolation, classification, bioactivities, and biosynthesis. Although the biosynthetic pathway of drimane-type sesquiterpenoids derived from plants and fungi have been largely disclosed, the detailed biochemical mechanism how to produce drimane skeleton by the drimenol synthases, along with discovery of more decorated oxygenase still require further studies. Furthermore, given that no drimane-type sesquiterpenoids has been reported from bacteria so far, whether it exists in bacteria (a much more readily genetically manipulated and tractable workhorse) or the related biosynthetic logic of this type of intriguing natural products in bacteria is identical with that in plants or fungi are still waiting to be answered. This review not only provides a chemical structure toolbox, but also lays the foundation for exploring the functions of biology and chemistry in drimane-type sesquiterpenoids.

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