Niduenes A-F(1-6),six novel sesterterpenoids with unprecedented 5/5/5/5/6 pentacyclic ring skeleton were isolated from endophytic fungus Aspergillus nidulans.Compounds 1 and 2 represent the first examples of aromatic ...Niduenes A-F(1-6),six novel sesterterpenoids with unprecedented 5/5/5/5/6 pentacyclic ring skeleton were isolated from endophytic fungus Aspergillus nidulans.Compounds 1 and 2 represent the first examples of aromatic pentacyclic sesterterpenoids.Their structures and configurations were elucidated by spectroscopic data and single-crystal X-ray diffraction analyses.Compound 4 demonstrated potent resensitization of SW620/AD300 cells to paclitaxel(PTX).Rhodamine 123 accumulation assay and docking analysis further support that 4 inhibitory the efflux function of P-glycoprotein(P-gp).展开更多
Three novel sesterterpenoids glasesterterpenoids A-C(1-3),featuring an unprecedented 7-cyclohexyldecahydronaphthalene carbon skeleton,were isolated from the root of Lindera glauca(L.glauca).Their structures were eluci...Three novel sesterterpenoids glasesterterpenoids A-C(1-3),featuring an unprecedented 7-cyclohexyldecahydronaphthalene carbon skeleton,were isolated from the root of Lindera glauca(L.glauca).Their structures were elucidated by quantum chemical calculations and spectroscopic methods.The biogenetic pathway for 1-3 is proposed.In the bioassay,glasesterterpenoid C exhibited DNA topoisomerase 1(Top1)inhibitory activity compared with the positive control,camptothecin.These findings represent the first examples of sesterterpenoids with a 7-cyclohexyldecahydronaphthalene carbon skeleton from the root of L.glauca.展开更多
Bipolarpenoids A–J(1–10),ten undescribed ophiobolin-derived sesterterpenoids,were identified from the fungus Bipolaris oryzae.Their structures were elucidated by high resolution electrospray ionization mass spectrom...Bipolarpenoids A–J(1–10),ten undescribed ophiobolin-derived sesterterpenoids,were identified from the fungus Bipolaris oryzae.Their structures were elucidated by high resolution electrospray ionization mass spectrometry(HRESIMS),spectroscopic analyses,quantum chemical ^(13)C nuclear magnetic resonance(NMR),electronic circular dichroism(ECD)calculations,and single-crystal X-ray diffraction analyses.Notably,compounds 1 and 2 were uniquely characterized by a multicyclic caged pentacyclo[8.4.0.0^(1,5).0^(4,9).0^(7,11)]tetradecane-bridged system;compounds 4–6 featured unprecedented5/8/5/6 and 5/8/5/5 fused cores,respectively;compound 7 represented the first example of 3,4-secoophiobolin-alkaloid hybrid with a modified 5/6/8/5/5 fused carbon skeleton.Compound 9 showed potential anti-inflammatory effect in RAW264.7 macrophages and ulcerative colitis mice.展开更多
Psoriasis is a common immune-mediated skin disorder manifesting in abnormal skin plaques,and remains a challenge in its management.Blocking the release or inflammatory effects of two proinflammatory molecules of the S...Psoriasis is a common immune-mediated skin disorder manifesting in abnormal skin plaques,and remains a challenge in its management.Blocking the release or inflammatory effects of two proinflammatory molecules of the S100-alarmin family,S100A8 and S100A9,in keratinocytes is a promising strategy for future therapeutic approaches.Undulanoids A−D(1−4),four novel sesterterpenoids possessing a highly congested pentacyclic 6/5/5/6/5 ring system with eight stereogenic centers,including three all-carbon quaternary centers,two quaternary carbon centers at the bridgehead,and a 1,4,11-trimethyltricyclo[5.3.1.04,11]undecane fragment,were isolated from Aspergillus undulatus.Their structures were elucidated by spectroscopic data and single-crystal X-ray diffraction.Strikingly,undulanoid B(2),the most promising lead compound,inhibits the expression of genes related to tumor necrosis factor and interleukin-17 signaling pathways.Furthermore,reverse target prediction,cellular thermal shift assay,and dynamic simulation indicated that compound 2 could target with the expression of S100A9 and keratinocyte proliferation.As the pioneering S100A8/A9 complex and inhibit its secretion.Moreover,compound 2 showed a potent therapeutic effect on the psoriasiform skin lesions induced by imiquimod in mice by inhibiting the expression of S100A9 and keratinocyte proliferation.As the pioneering examples of natural products demonstrate inhibitory action against S100A8/A9 complex,this discovery provides a series of compelling lead compounds with novel molecular scaffold for treating psoriasis.展开更多
This review covers the isolation,structural determination,plausible biosynthetic pathways,and biological activities of 166 natural terpenoids including 57 sesquiterpenoids,65 diterpenoids,15 sesterterpenoids,and 29 tr...This review covers the isolation,structural determination,plausible biosynthetic pathways,and biological activities of 166 natural terpenoids including 57 sesquiterpenoids,65 diterpenoids,15 sesterterpenoids,and 29 triterpenoids from January 2017 to December2022.展开更多
Two chimeric sesterterpene synthases(Aa TPS1 and Aa TPS2)were functionally characterized from Alternaria alternata MB-30 isolated from the leaves of a sesterterpenoid-producing Lamiaceae plant Leucosceptrum canum.Aa T...Two chimeric sesterterpene synthases(Aa TPS1 and Aa TPS2)were functionally characterized from Alternaria alternata MB-30 isolated from the leaves of a sesterterpenoid-producing Lamiaceae plant Leucosceptrum canum.Aa TPS1 generated a 5/8/6/5 tetracyclic sesteraltererol(1)and its absolute stereochemistry was determined by X-ray crystallographic analysis of its derivative 10,11-epoxysesteraltererol(2),which enabled revision of the absolute configuration of C7 of sesterfisherol produced by Nf SS and PTTS014 characterized previously and its derivative 10,11-epoxysesterfisherol.Aa TPS2 produced a 5/15 bicyclic preterpestacin I(3).Site-directed mutagenesis suggested that F192 in Aa TPS1 was likely involved in controlling of the hydroxylation of C12,and eight amino acids were important for the enzyme activity of Aa TPS1 and Aa TPS2.The engineered Escherichia coli and Saccharomyces cerevisiae strains were constructed for the productions of compounds 1 and 3,and the highest titer of compound 1 reached 62.3 mg/L in shake-flask culture.Both compounds 1 and 2 showed anti-adipogenic activity.展开更多
Obesity that is highly associated with numerous metabolic diseases has become a global health issue nowdays.Plant sesterterpenoids are an important group of natural products with great potential;thus,their bioactiviti...Obesity that is highly associated with numerous metabolic diseases has become a global health issue nowdays.Plant sesterterpenoids are an important group of natural products with great potential;thus,their bioactivities deserve extensive exploration.RNA-seq analysis indicated that leucosceptroid B,a sesterterpenoid previously discovered from the glandular trichomes of Leucosceptrum canum,significantly regulated the expression of 10 genes involved in lipid metabolism in Caenorhabditis elegans.Furthermore,leucosceptroid B was found to reduce fat storage,and downregulate the expression of two stearoyl-CoA desaturase(SCD)genes fat-6 and fat-7,and a fatty acid elongase gene elo-2 in wild-type C.elegans.In addition,leucosceptroid B significantly decreased fat accumulation in both fat-6 and fat-7 mutant worms but did not affect the fat storage of fat-6;fat-7 double mutant.These findings indicated that leucosceptroid B reduced fat storage depending on the downregulated expression of fat-6,fat-7 and elo-2 and thereby inhibiting the biosynthesis of the corresponding unsaturated fatty acid.These findings provide new insights into the development and utilization of plant sesterterpenoids as potential antilipemic agents.展开更多
Mangicol-type sesterterpenoids possess potent anti-inflammatory activity,characterized by a 5-5-6-5tetracyclic carbon skeleton formed by mangicdiene synthase Fg MS.Two proposed mechanisms for mangicdiene formation inv...Mangicol-type sesterterpenoids possess potent anti-inflammatory activity,characterized by a 5-5-6-5tetracyclic carbon skeleton formed by mangicdiene synthase Fg MS.Two proposed mechanisms for mangicdiene formation involve either C6-C10 cyclization(path a) or C2-C10 cyclization(path b) after the C10carbocation formation,but neither has been experimentally validated.Here,we have identified a second mangicdiene synthase Man D,which is derived from Fusarium sp.JNU-XJ070152-01 and shares high amino acid sequence identity with Fg MS.Through heterologous expression of man D in Aspergillus oryzae NSAR1,we observed production not only of mangicdiene(1) and variecoltetraene(2),previously identified by expression of Fg MS in Escherichia coli,but also two novel sesterterpene skeletons fusadiene(3)and fusatriene(4).The identification of fusadiene and fusatriene supports the occurrence of two key carbocation intermediates in path b,thus experimentally confirming that mangicdiene is built via path b for the first time,consistent with previous density functional theory(DFT) calculation results.展开更多
A biosynthetic gene cluster for the bioactive fungal sesterterpenoids variecolin(1)and variecolactone(2)was identified in Aspergillus aculeatus ATCC 16872.Heterologous production of 1 and 2 was achieved in Aspergillus...A biosynthetic gene cluster for the bioactive fungal sesterterpenoids variecolin(1)and variecolactone(2)was identified in Aspergillus aculeatus ATCC 16872.Heterologous production of 1 and 2 was achieved in Aspergillus oryzae by expressing the sesterterpene synthase VrcA and the cytochrome P450 VrcB.Intriguingly,the replacement of VrcB with homologous P450s from other fungal terpenoid pathways yielded three new variecolin analogues(5-7).Analysis of the compounds’anticancer activity in vitro and in vivo revealed that although 5 and 1 had comparable activities,5 was associated with significantly reduced toxic side effects in cancer-bearing mice,indicating its potentially broader therapeutic window.Our study describes the first tests of variecolin and its analogues in animals and demonstrates the utility of synthetic biology for creating molecules with improved biological activities.展开更多
基金financially supported by the National Key Research and Development Program of China(No.2021YFA0910500)the National Natural Science Foundation of China(Nos.U22A20380,82104028,82173706 and 82373755)+2 种基金Innovative Research Groups of the National Natural Science Foundation of China(No.81721005)the Science and Technology Major Project of Hubei Province(No.2021ACA012)the Fundamental Research Funds for the Central Universities,HUST(No.2021JYCXJJ058)。
文摘Niduenes A-F(1-6),six novel sesterterpenoids with unprecedented 5/5/5/5/6 pentacyclic ring skeleton were isolated from endophytic fungus Aspergillus nidulans.Compounds 1 and 2 represent the first examples of aromatic pentacyclic sesterterpenoids.Their structures and configurations were elucidated by spectroscopic data and single-crystal X-ray diffraction analyses.Compound 4 demonstrated potent resensitization of SW620/AD300 cells to paclitaxel(PTX).Rhodamine 123 accumulation assay and docking analysis further support that 4 inhibitory the efflux function of P-glycoprotein(P-gp).
基金supported by the National Natural Science Foundation of China(No.82104524)the Basic and Applied Research Program of Guangzhou City(No.2024A04J9954)。
文摘Three novel sesterterpenoids glasesterterpenoids A-C(1-3),featuring an unprecedented 7-cyclohexyldecahydronaphthalene carbon skeleton,were isolated from the root of Lindera glauca(L.glauca).Their structures were elucidated by quantum chemical calculations and spectroscopic methods.The biogenetic pathway for 1-3 is proposed.In the bioassay,glasesterterpenoid C exhibited DNA topoisomerase 1(Top1)inhibitory activity compared with the positive control,camptothecin.These findings represent the first examples of sesterterpenoids with a 7-cyclohexyldecahydronaphthalene carbon skeleton from the root of L.glauca.
基金financially supported by the National Key Research and Development Program of China(No.2021YFA0910500)the National Natural Science Foundation of China(Nos.U22A20380,82173706,and 82104028)+1 种基金the Fundamental Research Funds for the Central Universities(No.2024BRA018)the Science and Technology Major Project of Hubei Province(No.2021ACA012)。
文摘Bipolarpenoids A–J(1–10),ten undescribed ophiobolin-derived sesterterpenoids,were identified from the fungus Bipolaris oryzae.Their structures were elucidated by high resolution electrospray ionization mass spectrometry(HRESIMS),spectroscopic analyses,quantum chemical ^(13)C nuclear magnetic resonance(NMR),electronic circular dichroism(ECD)calculations,and single-crystal X-ray diffraction analyses.Notably,compounds 1 and 2 were uniquely characterized by a multicyclic caged pentacyclo[8.4.0.0^(1,5).0^(4,9).0^(7,11)]tetradecane-bridged system;compounds 4–6 featured unprecedented5/8/5/6 and 5/8/5/5 fused cores,respectively;compound 7 represented the first example of 3,4-secoophiobolin-alkaloid hybrid with a modified 5/6/8/5/5 fused carbon skeleton.Compound 9 showed potential anti-inflammatory effect in RAW264.7 macrophages and ulcerative colitis mice.
基金financially supported by the National Key Research and Development Program of China(2021YFA0910500)the National Natural Science Foundation of China(U22A20380,82373755,82173706,82404468)+2 种基金the Fundamental Research Funds for the Central Universities(2024BRA018,China)the Science and Technology Major Project of Hubei Province(2021ACA012,China)Hubei Provincial Natural Science Foundation of China(2025AFB227).
文摘Psoriasis is a common immune-mediated skin disorder manifesting in abnormal skin plaques,and remains a challenge in its management.Blocking the release or inflammatory effects of two proinflammatory molecules of the S100-alarmin family,S100A8 and S100A9,in keratinocytes is a promising strategy for future therapeutic approaches.Undulanoids A−D(1−4),four novel sesterterpenoids possessing a highly congested pentacyclic 6/5/5/6/5 ring system with eight stereogenic centers,including three all-carbon quaternary centers,two quaternary carbon centers at the bridgehead,and a 1,4,11-trimethyltricyclo[5.3.1.04,11]undecane fragment,were isolated from Aspergillus undulatus.Their structures were elucidated by spectroscopic data and single-crystal X-ray diffraction.Strikingly,undulanoid B(2),the most promising lead compound,inhibits the expression of genes related to tumor necrosis factor and interleukin-17 signaling pathways.Furthermore,reverse target prediction,cellular thermal shift assay,and dynamic simulation indicated that compound 2 could target with the expression of S100A9 and keratinocyte proliferation.As the pioneering S100A8/A9 complex and inhibit its secretion.Moreover,compound 2 showed a potent therapeutic effect on the psoriasiform skin lesions induced by imiquimod in mice by inhibiting the expression of S100A9 and keratinocyte proliferation.As the pioneering examples of natural products demonstrate inhibitory action against S100A8/A9 complex,this discovery provides a series of compelling lead compounds with novel molecular scaffold for treating psoriasis.
文摘This review covers the isolation,structural determination,plausible biosynthetic pathways,and biological activities of 166 natural terpenoids including 57 sesquiterpenoids,65 diterpenoids,15 sesterterpenoids,and 29 triterpenoids from January 2017 to December2022.
基金supported financially by the National Natural Science Foundation of China(Nos.21937006 and 22107103)the Yunnan Key Research and Development Program(No.2019ZF011–2)the“Western Light”Program of the CAS(to Y.Liu)。
文摘Two chimeric sesterterpene synthases(Aa TPS1 and Aa TPS2)were functionally characterized from Alternaria alternata MB-30 isolated from the leaves of a sesterterpenoid-producing Lamiaceae plant Leucosceptrum canum.Aa TPS1 generated a 5/8/6/5 tetracyclic sesteraltererol(1)and its absolute stereochemistry was determined by X-ray crystallographic analysis of its derivative 10,11-epoxysesteraltererol(2),which enabled revision of the absolute configuration of C7 of sesterfisherol produced by Nf SS and PTTS014 characterized previously and its derivative 10,11-epoxysesterfisherol.Aa TPS2 produced a 5/15 bicyclic preterpestacin I(3).Site-directed mutagenesis suggested that F192 in Aa TPS1 was likely involved in controlling of the hydroxylation of C12,and eight amino acids were important for the enzyme activity of Aa TPS1 and Aa TPS2.The engineered Escherichia coli and Saccharomyces cerevisiae strains were constructed for the productions of compounds 1 and 3,and the highest titer of compound 1 reached 62.3 mg/L in shake-flask culture.Both compounds 1 and 2 showed anti-adipogenic activity.
基金supported by the National Science Fund for Distinguished Young Scholars(No.31525005)National Natural Science Foundation of China(Nos.21937006,31770390 and 31800298)+3 种基金Yunnan Key Research and Development Program(No.2019ZF011-2)Yunnan Innovative Research Team for Discovery and Biosynthesis of Bioactive Natural Products(No.2018HC012)Science Foundation of Yunnan(No.2018FA017)Youth Innovation Promotion Association and “Western Light” Program of CAS(awarded to LIU Yan)
文摘Obesity that is highly associated with numerous metabolic diseases has become a global health issue nowdays.Plant sesterterpenoids are an important group of natural products with great potential;thus,their bioactivities deserve extensive exploration.RNA-seq analysis indicated that leucosceptroid B,a sesterterpenoid previously discovered from the glandular trichomes of Leucosceptrum canum,significantly regulated the expression of 10 genes involved in lipid metabolism in Caenorhabditis elegans.Furthermore,leucosceptroid B was found to reduce fat storage,and downregulate the expression of two stearoyl-CoA desaturase(SCD)genes fat-6 and fat-7,and a fatty acid elongase gene elo-2 in wild-type C.elegans.In addition,leucosceptroid B significantly decreased fat accumulation in both fat-6 and fat-7 mutant worms but did not affect the fat storage of fat-6;fat-7 double mutant.These findings indicated that leucosceptroid B reduced fat storage depending on the downregulated expression of fat-6,fat-7 and elo-2 and thereby inhibiting the biosynthesis of the corresponding unsaturated fatty acid.These findings provide new insights into the development and utilization of plant sesterterpenoids as potential antilipemic agents.
基金financially supported by grants from the National Key Research and Development Program of China (No.2024YFE0102000)the National Natural Science Foundation of China (Nos.81925037,82321004,U22A20371,U24A20782,32170060,22177037,22207039,22307045)+6 种基金the Guangdong Major Project of Basic and Applied Basic Research (No.2023B0303000026)the Guangdong Natural Science Funds for Distinguished Young Scholars (No.2022B1515020028,China)the Guangdong International Science and Technology Cooperation Base (No.2021A0505020015,China)the Guangdong Basic and Applied Basic Research Foundation (Nos.2023B1515040016,2023A1515110388)the Innovative and Research Teams Project of Guangdong Higher Education Institution (No.2021KCXTD001,China)the Guangzhou Science and Technology Project (Nos.202206010020,2024A04J6241,2023A04J0080,China)the Fundamental Research Funds for the Central Universities (Nos.21623105,21624210)。
文摘Mangicol-type sesterterpenoids possess potent anti-inflammatory activity,characterized by a 5-5-6-5tetracyclic carbon skeleton formed by mangicdiene synthase Fg MS.Two proposed mechanisms for mangicdiene formation involve either C6-C10 cyclization(path a) or C2-C10 cyclization(path b) after the C10carbocation formation,but neither has been experimentally validated.Here,we have identified a second mangicdiene synthase Man D,which is derived from Fusarium sp.JNU-XJ070152-01 and shares high amino acid sequence identity with Fg MS.Through heterologous expression of man D in Aspergillus oryzae NSAR1,we observed production not only of mangicdiene(1) and variecoltetraene(2),previously identified by expression of Fg MS in Escherichia coli,but also two novel sesterterpene skeletons fusadiene(3)and fusatriene(4).The identification of fusadiene and fusatriene supports the occurrence of two key carbocation intermediates in path b,thus experimentally confirming that mangicdiene is built via path b for the first time,consistent with previous density functional theory(DFT) calculation results.
基金This work was performed for the iGEM 2021 Competition,and the financial support received from the Department of Chemistry,City University of Hong Kong,is greatly appreciated.We also thank Prof.Katsuya Gomi(Tohoku University)and Profs.Katsuhiko Kitamoto and Jun-ichi Maruyama(The University of Tokyo)for providing the expression vectors and the fungal strain.We are grateful to Dr.Man-Kit Tse(City University of Hong Kong)and Dr.Shek-Man Yiu(City University of Hong Kong)for their assistance with NMR spectra acquisition and X-ray diffraction data collection and analysis,respectively.This work was supported in part by an Early Career Scheme grant from the Research Grants Council(RGC)of Hong Kong(Project No.21300219(Y.M))M.V.B acknowledges support from the City University of Hong Kong(Project No.9610518).
文摘A biosynthetic gene cluster for the bioactive fungal sesterterpenoids variecolin(1)and variecolactone(2)was identified in Aspergillus aculeatus ATCC 16872.Heterologous production of 1 and 2 was achieved in Aspergillus oryzae by expressing the sesterterpene synthase VrcA and the cytochrome P450 VrcB.Intriguingly,the replacement of VrcB with homologous P450s from other fungal terpenoid pathways yielded three new variecolin analogues(5-7).Analysis of the compounds’anticancer activity in vitro and in vivo revealed that although 5 and 1 had comparable activities,5 was associated with significantly reduced toxic side effects in cancer-bearing mice,indicating its potentially broader therapeutic window.Our study describes the first tests of variecolin and its analogues in animals and demonstrates the utility of synthetic biology for creating molecules with improved biological activities.
