Bistachybotrysins D and E (1 and 2), one stereoisomeric pair of phenylspirodrimane dimers, were isolated from Stachybotrys chartarum CGMCC 3.5365. They represent novel phenylspirodrimane dimers with a central [6,5,6]-...Bistachybotrysins D and E (1 and 2), one stereoisomeric pair of phenylspirodrimane dimers, were isolated from Stachybotrys chartarum CGMCC 3.5365. They represent novel phenylspirodrimane dimers with a central [6,5,6]-tricyclic carbon scaffold containing a cyclopentanone core. The structures of 1 and 2 were elucidated through extensive spectroscopic data analysis, and their absolute configurations were characterized by calculated electronic circular dichroism (ECD). Compounds 1 and 2 displayed potent cytotoxic activity against the four human tumor cell lines HCT116, BGC823, Daoy and HepG2 with IC_ (50)values ranging from 6.7 μmol/L to 11.6 μmol/L. Furthermore, a plausible biogenetic pathway for 1 and 2 is proposed.展开更多
By integrating one strain-many compounds(OSMAC)and LC-MS-based molecular networking strategies,distachydrimanes A-F(1-6),six novel phenylspirodrimane dimers and hybrids representing two types of unprecedented terpenoi...By integrating one strain-many compounds(OSMAC)and LC-MS-based molecular networking strategies,distachydrimanes A-F(1-6),six novel phenylspirodrimane dimers and hybrids representing two types of unprecedented terpenoid-polyketide hybrid skeletons,were isolated from the modified fermented rice substrate of a coral-derived fungus Stachybotrys chartarum.All the structures incorporating their absolute configurations were elucidated based on comprehensive spectroscopic analyses,mainly including HRESIMS and NMR data,single-crystal X-ray diffraction(Cu Kα),and comparison of the experimental electronic circular dichroism(ECD)data.Architecturally,compounds 1-6 represent an unprecedented class of dimeric phenylspirodrimanes with an unexpected C-18-C-23′linkage,of which compounds 1-3 also feature an unexpected 5-methyl-1,3-benzenediol moiety via a carbon-carbon linkage.The bioactivity assay demonstrated that compounds 1,5 and 6 induced cell proliferation inhibition,G0/G1 cell cycle arrest,senescence and mitochondrial-mediated apoptosis in L1210 cells,highlighting their potentials as a new category of anticancer agents.展开更多
Phenylspirodrimanes are a class of structurally diverse meroterpenoids,including the bioactive dimer stachybocin A(1)and the high-reactivity monomer stachybotrydial(2),which are isolated from the genus Stachybotrys.Wh...Phenylspirodrimanes are a class of structurally diverse meroterpenoids,including the bioactive dimer stachybocin A(1)and the high-reactivity monomer stachybotrydial(2),which are isolated from the genus Stachybotrys.Whereas the biosynthetic pathway of these phenylspirodrimane meroterpenoids has remained elusive.Herein,we deciphered the complete biosynthetic pathway of 2 with unprecedented two gene clusters and five discrete genes by genome mining,gene inactivation,heterologous expression,biochemical experiments,and especially combining with transcriptome-based hierarchical clustering and expression correlation analyses.Totally,11 genes for the phenylspirodrimane core skeleton formation,8′-methyl oxidation,and 3-OH epimerization were efficiently discovered and functionally characterized.Notably,these biosynthetic genes are distributed across seven distinct regions,with a rare combination of multiple gene clusters and genes outside the clusters.Bioactivity assays revealed that four intermediates 6−8,and 9a exhibited significant inhibitory effect on the inactivated state hNaV1.2 channels with IC50 values of 0.15,0.04,0.28,and 1.91μmol/L,respectively.These findings expand our understanding of phenylspirodrimane-type meroterpenoid biosynthesis and underscore the utility of transcriptome-based hierarchical clustering and expression correlation analyses for identifying unclustered biosynthetic genes in fungi.展开更多
Phenylspirodrimanes are a kind of meroterpenoids with structural diversity and complexity,exhibiting a wide of biological properties,especially for the lactam derivatives consisting a y-lactam moiety and N-linked side...Phenylspirodrimanes are a kind of meroterpenoids with structural diversity and complexity,exhibiting a wide of biological properties,especially for the lactam derivatives consisting a y-lactam moiety and N-linked side chains.These compounds were derived from multi-step combination of enzymatic and non-enzymatic conversions of intermediates in their biosynthetic pathways.Stachbotrydial(2)with an o-phthalaldehyde unit was supposed as the high-reactivity intermediate of phenylspirodrimane lactams via nonenzymatic reaction with amines.In the present work,an effective and non-enzymatic diversification strategy was developed for the structural diversification of phenylspirodrimane lactams including monomers and dimers from 2 by feeding structurally various mono-and diamines in the fungus Stachybotrys chartarum cultures.In total,24 phenylspirodrimane lactams(1,3-25)including 18 new compounds were synthesized.Among them,stachybocin A(1),a bioactive phenylspirodrimane lactam dimer,was produced with the yield of 18.7 mg/g of cell dry weight.The structures of these compounds were elucidated by extensive spectroscopic data,single-crystal X-ray diffraction(Cu Kα),and calculated electronic circular dichroism(ECD)analyses.Bioassay revealed that compounds 1,17,and 24 displayed significant inhibitory effect on the inactivated state of hNav 1.2 channels with IC_(50) values of 0.22,2.08,and 0.53μmol/L,respectively.In addition,1 showed potent protein tyrosine phosphatase 1B(PTP1B)inhibitory N-methyl-b-aspartate(NMDA)receptor antagonistic,and anti-inflammatory activities.展开更多
基金financially supported by CAMS Innovation Fund for Medical Sciences (Nos. CIFMS-2016-I2M-3-012 and CAMS-I2M2-002)
文摘Bistachybotrysins D and E (1 and 2), one stereoisomeric pair of phenylspirodrimane dimers, were isolated from Stachybotrys chartarum CGMCC 3.5365. They represent novel phenylspirodrimane dimers with a central [6,5,6]-tricyclic carbon scaffold containing a cyclopentanone core. The structures of 1 and 2 were elucidated through extensive spectroscopic data analysis, and their absolute configurations were characterized by calculated electronic circular dichroism (ECD). Compounds 1 and 2 displayed potent cytotoxic activity against the four human tumor cell lines HCT116, BGC823, Daoy and HepG2 with IC_ (50)values ranging from 6.7 μmol/L to 11.6 μmol/L. Furthermore, a plausible biogenetic pathway for 1 and 2 is proposed.
基金financially supported by the National Natural Science Foundation for Distinguished Young Scholars(No.81725021)the Innovative Research Groups of the National Natural Science Foundation of China(No.81721005)+4 种基金the National Natural Science Foundation of China(No.81573316)the Fundamental Research Funds for the Central Universities(Nos.2020kfyXJJS083,2021yjsCXCY094 and 2172019kfyXJJS166)the Tongji-Rongcheng Center for Biomedicine,Huazhong University of Science and Technology(No.0231514141)the Research and Development Program of Hubei Province(No.2020BCA058)the Hubei Provincial Natural Science Foundation of China(No.2019CFB646)。
文摘By integrating one strain-many compounds(OSMAC)and LC-MS-based molecular networking strategies,distachydrimanes A-F(1-6),six novel phenylspirodrimane dimers and hybrids representing two types of unprecedented terpenoid-polyketide hybrid skeletons,were isolated from the modified fermented rice substrate of a coral-derived fungus Stachybotrys chartarum.All the structures incorporating their absolute configurations were elucidated based on comprehensive spectroscopic analyses,mainly including HRESIMS and NMR data,single-crystal X-ray diffraction(Cu Kα),and comparison of the experimental electronic circular dichroism(ECD)data.Architecturally,compounds 1-6 represent an unprecedented class of dimeric phenylspirodrimanes with an unexpected C-18-C-23′linkage,of which compounds 1-3 also feature an unexpected 5-methyl-1,3-benzenediol moiety via a carbon-carbon linkage.The bioactivity assay demonstrated that compounds 1,5 and 6 induced cell proliferation inhibition,G0/G1 cell cycle arrest,senescence and mitochondrial-mediated apoptosis in L1210 cells,highlighting their potentials as a new category of anticancer agents.
基金supported by National Key R&D Program of China(2024YFA0919900)National Natural Science Foundation of China(No.81803403)CAMS Innovation Fund for Medical Sciences(CIFMS,No.2021-I2M-1-029,China).
文摘Phenylspirodrimanes are a class of structurally diverse meroterpenoids,including the bioactive dimer stachybocin A(1)and the high-reactivity monomer stachybotrydial(2),which are isolated from the genus Stachybotrys.Whereas the biosynthetic pathway of these phenylspirodrimane meroterpenoids has remained elusive.Herein,we deciphered the complete biosynthetic pathway of 2 with unprecedented two gene clusters and five discrete genes by genome mining,gene inactivation,heterologous expression,biochemical experiments,and especially combining with transcriptome-based hierarchical clustering and expression correlation analyses.Totally,11 genes for the phenylspirodrimane core skeleton formation,8′-methyl oxidation,and 3-OH epimerization were efficiently discovered and functionally characterized.Notably,these biosynthetic genes are distributed across seven distinct regions,with a rare combination of multiple gene clusters and genes outside the clusters.Bioactivity assays revealed that four intermediates 6−8,and 9a exhibited significant inhibitory effect on the inactivated state hNaV1.2 channels with IC50 values of 0.15,0.04,0.28,and 1.91μmol/L,respectively.These findings expand our understanding of phenylspirodrimane-type meroterpenoid biosynthesis and underscore the utility of transcriptome-based hierarchical clustering and expression correlation analyses for identifying unclustered biosynthetic genes in fungi.
基金financially supported by National Natural Science Foundation of China(No.81803403)CAMS Innovation Fund for Medical Sciences(Nos.CIFMS-2022-I2M-JB-011 and CIFMS-2021-12M-1-029).
文摘Phenylspirodrimanes are a kind of meroterpenoids with structural diversity and complexity,exhibiting a wide of biological properties,especially for the lactam derivatives consisting a y-lactam moiety and N-linked side chains.These compounds were derived from multi-step combination of enzymatic and non-enzymatic conversions of intermediates in their biosynthetic pathways.Stachbotrydial(2)with an o-phthalaldehyde unit was supposed as the high-reactivity intermediate of phenylspirodrimane lactams via nonenzymatic reaction with amines.In the present work,an effective and non-enzymatic diversification strategy was developed for the structural diversification of phenylspirodrimane lactams including monomers and dimers from 2 by feeding structurally various mono-and diamines in the fungus Stachybotrys chartarum cultures.In total,24 phenylspirodrimane lactams(1,3-25)including 18 new compounds were synthesized.Among them,stachybocin A(1),a bioactive phenylspirodrimane lactam dimer,was produced with the yield of 18.7 mg/g of cell dry weight.The structures of these compounds were elucidated by extensive spectroscopic data,single-crystal X-ray diffraction(Cu Kα),and calculated electronic circular dichroism(ECD)analyses.Bioassay revealed that compounds 1,17,and 24 displayed significant inhibitory effect on the inactivated state of hNav 1.2 channels with IC_(50) values of 0.22,2.08,and 0.53μmol/L,respectively.In addition,1 showed potent protein tyrosine phosphatase 1B(PTP1B)inhibitory N-methyl-b-aspartate(NMDA)receptor antagonistic,and anti-inflammatory activities.
