This study identified six novel azaphilones,isochromophilones G-L(1-6),and three novel biosynthetically related congeners(7-9)from Diaporthe sp.SCSIO 41011.The structures and absolute configurations were elucidated th...This study identified six novel azaphilones,isochromophilones G-L(1-6),and three novel biosynthetically related congeners(7-9)from Diaporthe sp.SCSIO 41011.The structures and absolute configurations were elucidated through comprehensive spectroscopic analyses combined with experimental and calculated electronic circular dichroism(ECD)spectra.Significantly,three highly oxygenated azaphilones contain an acetyl group at the terminal chain(4)or linear conjugated polyenoid moieties(5 and 6),which occur infrequently in the azaphilone family.Additionally,several compounds demonstrated inhibition of lipopolysaccharide(LPS)-induced nuclear factor kappa-B(NF-κB)activation in RAW 264.7 macrophages at 20μmol·L^(-1).The novel compound(1)effectively inhibited receptor activator of NF-κB ligand(RANKL)-induced osteoclast differentiation without exhibiting cytotoxicity in bone marrow and RAW264.7 macrophages,indicating its potential as a promising lead compound for osteolytic disease treatment.This research presents the first documented evidence of azaphilone derivatives as inhibitors of RANKL-induced osteoclastogenesis.展开更多
Co-culturing the mangrove endophytic fungus Penicillium sclerotiorum THSH-4 with Penicillium sclerotiorum ZJHJJ-18 in PDB medium resulted in the production of nine new azaphilones derivatives,peniazaphilones A—I(1-9)...Co-culturing the mangrove endophytic fungus Penicillium sclerotiorum THSH-4 with Penicillium sclerotiorum ZJHJJ-18 in PDB medium resulted in the production of nine new azaphilones derivatives,peniazaphilones A—I(1-9),and six known azaphilones derivatives(10-15).Their structures were elucidated by analysis of detailed spectroscopic data,single-crystal X-ray diffraction,ECD spectra,^(13)C NMR calculation and DP4+analysis.It is noteworthy that compound 1 with an isoquinoline quinone moiety,was isolated from natural source for the first time.Besides,compound 2 is the third reported phenylhydrazone derivative from fungi.In the bioactivity assays,compounds 1,12,14 and 15(IC_(50)=4.71-17.64μmol/L)exhibited potent inhibition of LPS-induced NO release from RAW264.7 without obvious cytotoxicity within 50μmol/L compared to the positive control indomethacin(IC_(50)=35.27μmol/L).Moreover,compounds 1 and 13 displayed moderate to strong cytotoxicity to A549 and MDA-MB-435,with IC_(50) values in the range of 6.84-14.63μmol/L.Together compound 1 showed moderate broad-spectrum antibacterial activity.展开更多
Monascus azaphilone pigments(MonAzPs)are beneficial secondary metabolites secreted by Monascus spp.,which have great potentials to be used in industrial fields besides food industry.But there is very little knowledge ...Monascus azaphilone pigments(MonAzPs)are beneficial secondary metabolites secreted by Monascus spp.,which have great potentials to be used in industrial fields besides food industry.But there is very little knowledge about their regulatory mechanism,which limits the large-scale production and utilization of MonAzPs.In this study,we firstly studied the effect on MonAzPs production by inhibiting and enhancing histone deacetylase gene hos2(Mrhos2)expression in Monascus ruber.UPLC detection revealed that inactivation of Mrhos2 dramatically decreased MonAzPs production,while overexpression of Mrhos2 significantly increased MonAzPs production.Transcriptional level analysis shows Mrhos2 regulates expression of MonAzPs biosynthesis genes.Immunoaffinity enrichment assisted mass spectrometry assay reveals deletion of Mrhos2 perturbs lysine acetylation of enzymes in the metabolic pathway of acetyl-CoA and malonyl-CoA.Collectively,transcription activation and protein acetylation modification mediated by MrHos2 are involved in regulating the MonAzPs production,and MrHos2 can be used as a target to increase MonAzPs production.展开更多
Three new azaphilone compounds,isochromophilones X-XII(1-3),together with two known ones sclerotioramine(4)and isochromophilone VI(5)were isolated from the cultures of an endophytic fungus Diaporthe sp.The structures ...Three new azaphilone compounds,isochromophilones X-XII(1-3),together with two known ones sclerotioramine(4)and isochromophilone VI(5)were isolated from the cultures of an endophytic fungus Diaporthe sp.The structures were elucidated by extensive HRESIMS and NMR spectroscopic analyses.All compounds were tested for their cytotoxicities against five human cancer cell lines by MTT method,among which compound 1 showed moderate inhibitory effects on these cell lines.This was the first report of azaphilones isolated from Diaporthe sp.展开更多
Endophytic fungi are promising producers of bioactive small molecules.Bioinformatic analysis of the genome of an endophytic fungus Penicillium dangeardii revealed 43 biosynthetic gene clusters,exhibited its strong abi...Endophytic fungi are promising producers of bioactive small molecules.Bioinformatic analysis of the genome of an endophytic fungus Penicillium dangeardii revealed 43 biosynthetic gene clusters,exhibited its strong ability to produce numbers of secondary metabolites.However,this strain mainly produce rubratoxins alone with high yield in varied culture conditions,suggested most gene clusters are silent.Efforts for mining the cryptic gene clusters in P.dangeardii,including epigenetic regulation and one-strain-many-compounds(OSMAC)approach were failed probably due to the high yield of rubratoxins.A metabolic shunting strategy by deleting the key gene for rubratoxins biosynthesis combining with optimization of culture condition successfully activated multiple silent genes encoding for other polyketide synthases(PKSs),and led to the trace compounds detectable.As a result,a total of 23 new compounds including azaphilone monomers,dimers,turimers with unprecedented polycyclic bridged heterocycle and spiral structures,as well as siderophores were identified.Some compounds showed significant cytotoxicities,anti-inflammatory or antioxidant activities.The attractive dual PKS s gene clusters for azaphilones biosynthesis were mined by bioinformatic analysis and overexpression of a pathway specific transcription factor.Our work therefor provides an efficient approach to mine the chemical diversity of endophytic fungi.展开更多
基金supported by the National Natural Science Foundation of China(No.82260692)Guangxi Natural Science Foundation(No.2024GXNSFFA010004)+2 种基金Bagui Youth Talent Development ProgramHigh-Level Talent Training Project Foundation of Guangxi University of Chinese Medicine(Nos.202407 and 2022C038)the Innovation Project of Guangxi Graduate Education(No.YCSW2025457)。
文摘This study identified six novel azaphilones,isochromophilones G-L(1-6),and three novel biosynthetically related congeners(7-9)from Diaporthe sp.SCSIO 41011.The structures and absolute configurations were elucidated through comprehensive spectroscopic analyses combined with experimental and calculated electronic circular dichroism(ECD)spectra.Significantly,three highly oxygenated azaphilones contain an acetyl group at the terminal chain(4)or linear conjugated polyenoid moieties(5 and 6),which occur infrequently in the azaphilone family.Additionally,several compounds demonstrated inhibition of lipopolysaccharide(LPS)-induced nuclear factor kappa-B(NF-κB)activation in RAW 264.7 macrophages at 20μmol·L^(-1).The novel compound(1)effectively inhibited receptor activator of NF-κB ligand(RANKL)-induced osteoclast differentiation without exhibiting cytotoxicity in bone marrow and RAW264.7 macrophages,indicating its potential as a promising lead compound for osteolytic disease treatment.This research presents the first documented evidence of azaphilone derivatives as inhibitors of RANKL-induced osteoclastogenesis.
基金This research was funded by the National Natural Science Foundation of China(Nos.U20A2001,21877133)the National Key R&D Program of China(No.2019YFC0312501)+3 种基金the Key-Area Research and Development Program of Guangdong Province(No.2020B1111030005)the Key Project of Natural Science Foundation of Guangdong Province(No.2016A030311026)the Fundamental Research Funds for the Central Universities(No.20ykjc04)We acknowledge the IARC,SYSU for support towards IR and LC-MS equipment.We also thank SCSIO for generous support towards ECD equipment and X-ray single crystal diffractometer.
文摘Co-culturing the mangrove endophytic fungus Penicillium sclerotiorum THSH-4 with Penicillium sclerotiorum ZJHJJ-18 in PDB medium resulted in the production of nine new azaphilones derivatives,peniazaphilones A—I(1-9),and six known azaphilones derivatives(10-15).Their structures were elucidated by analysis of detailed spectroscopic data,single-crystal X-ray diffraction,ECD spectra,^(13)C NMR calculation and DP4+analysis.It is noteworthy that compound 1 with an isoquinoline quinone moiety,was isolated from natural source for the first time.Besides,compound 2 is the third reported phenylhydrazone derivative from fungi.In the bioactivity assays,compounds 1,12,14 and 15(IC_(50)=4.71-17.64μmol/L)exhibited potent inhibition of LPS-induced NO release from RAW264.7 without obvious cytotoxicity within 50μmol/L compared to the positive control indomethacin(IC_(50)=35.27μmol/L).Moreover,compounds 1 and 13 displayed moderate to strong cytotoxicity to A549 and MDA-MB-435,with IC_(50) values in the range of 6.84-14.63μmol/L.Together compound 1 showed moderate broad-spectrum antibacterial activity.
基金supported by National Natural Science Foundation of China[grant number:32272288].
文摘Monascus azaphilone pigments(MonAzPs)are beneficial secondary metabolites secreted by Monascus spp.,which have great potentials to be used in industrial fields besides food industry.But there is very little knowledge about their regulatory mechanism,which limits the large-scale production and utilization of MonAzPs.In this study,we firstly studied the effect on MonAzPs production by inhibiting and enhancing histone deacetylase gene hos2(Mrhos2)expression in Monascus ruber.UPLC detection revealed that inactivation of Mrhos2 dramatically decreased MonAzPs production,while overexpression of Mrhos2 significantly increased MonAzPs production.Transcriptional level analysis shows Mrhos2 regulates expression of MonAzPs biosynthesis genes.Immunoaffinity enrichment assisted mass spectrometry assay reveals deletion of Mrhos2 perturbs lysine acetylation of enzymes in the metabolic pathway of acetyl-CoA and malonyl-CoA.Collectively,transcription activation and protein acetylation modification mediated by MrHos2 are involved in regulating the MonAzPs production,and MrHos2 can be used as a target to increase MonAzPs production.
基金This work was co-financed by National Natural Science Foundation of China(81121062,21132004,90813036,and 81172948),MOE(NCET-10-0477)Jiangsu Provincial Government(BK2009010).
文摘Three new azaphilone compounds,isochromophilones X-XII(1-3),together with two known ones sclerotioramine(4)and isochromophilone VI(5)were isolated from the cultures of an endophytic fungus Diaporthe sp.The structures were elucidated by extensive HRESIMS and NMR spectroscopic analyses.All compounds were tested for their cytotoxicities against five human cancer cell lines by MTT method,among which compound 1 showed moderate inhibitory effects on these cell lines.This was the first report of azaphilones isolated from Diaporthe sp.
基金supported financially by the National Key Research and Development Program of China(2018YFA0901900)the CAMS Innovation Fund for Medical Sciences(CIFMS,2016-I2M-1-010,2017-I2M-4-004)+1 种基金Fundamental Research Funds for the Central Universities(2017PT35001)supported by the Drug Innovation Major Project(2018ZX09711001-008-001)
文摘Endophytic fungi are promising producers of bioactive small molecules.Bioinformatic analysis of the genome of an endophytic fungus Penicillium dangeardii revealed 43 biosynthetic gene clusters,exhibited its strong ability to produce numbers of secondary metabolites.However,this strain mainly produce rubratoxins alone with high yield in varied culture conditions,suggested most gene clusters are silent.Efforts for mining the cryptic gene clusters in P.dangeardii,including epigenetic regulation and one-strain-many-compounds(OSMAC)approach were failed probably due to the high yield of rubratoxins.A metabolic shunting strategy by deleting the key gene for rubratoxins biosynthesis combining with optimization of culture condition successfully activated multiple silent genes encoding for other polyketide synthases(PKSs),and led to the trace compounds detectable.As a result,a total of 23 new compounds including azaphilone monomers,dimers,turimers with unprecedented polycyclic bridged heterocycle and spiral structures,as well as siderophores were identified.Some compounds showed significant cytotoxicities,anti-inflammatory or antioxidant activities.The attractive dual PKS s gene clusters for azaphilones biosynthesis were mined by bioinformatic analysis and overexpression of a pathway specific transcription factor.Our work therefor provides an efficient approach to mine the chemical diversity of endophytic fungi.
