The bacterial trialkyl-substituted aromatic polyketides are structurally featured with the unusual aromatic core in the middle of polyketide chain such as TM-123(1),veramycin A(2),NFAT-133(3)and benwamycin I(4),which ...The bacterial trialkyl-substituted aromatic polyketides are structurally featured with the unusual aromatic core in the middle of polyketide chain such as TM-123(1),veramycin A(2),NFAT-133(3)and benwamycin I(4),which were discovered from Streptomyces species and demonstrated with antidiabetic and immunosuppressant activities.Though the biosynthetic pathway of 1-3 was reported as a type I polyketide synthase(PKS),the PKS assembly line was interpreted inconsistently,and it remains a mystery how the compound 3 was generated.Herein,the PKS assembly logic of 1-4 was revised by site-mutagenetic analysis of the PKS dehydratase domains.Based on gene deletion and complementation,the putative P450 monooxygenase nftE1 and metallo-beta-lactamase(MBL)fold hydrolase nftF1 were verified as essential genes for the biosynthesis of 1-4.The absence of nftE1 led to abolishment of 1-4 and accumulation of new products(5-8).Structural elucidation reveals 5-8 as the non-aromatic analogs of 1,suggesting the NftE1-catalyzed aromatic core formation.Deletion of nftF1 resulted in disappearance of 3 and 4 with the compounds 1 and 2 unaffected.As a rare MBL-fold hydrolase from type I PKSs,NftF1 potentially generates the compound 3 through two strategies:catalyze premature chain-offloading as a trans-acting thioesterase or hydrolyze the lactone-bond of compound 1 as an esterase.展开更多
Dear Editor,Glioblastoma(GBM)is one of the most fatal brain tumors.Current first-line post-surgery regimens for GBM including radiotherapy and temozolomide(TMZ)chemotherapy show very limited efficacy.1,2 Novel therape...Dear Editor,Glioblastoma(GBM)is one of the most fatal brain tumors.Current first-line post-surgery regimens for GBM including radiotherapy and temozolomide(TMZ)chemotherapy show very limited efficacy.1,2 Novel therapeutic approaches for GBM patients are urgently needed.Natural products are important sources for drug discovery,especially in the field of cancer treatment.3 We previously isolated stellettin B(STELB)(Fig.1a)from marine sponge(Jaspis stellifera)and reported the remarkable and specific anticancer activities.Recently,a series of stellettins has been totally synthesized and the core chemical structure has been indicated.4 However,the specific mechanism and its role in regulating tumor biology remain largely unknown.展开更多
Four new chlorinated carbazole alkaloids,chlocarbazomycins(CCBs)A-D,were isolated from sponge associated bacterium Streptomyces diacarni LHW51701.Their structures were elucidated via spectroscopic techniques(including...Four new chlorinated carbazole alkaloids,chlocarbazomycins(CCBs)A-D,were isolated from sponge associated bacterium Streptomyces diacarni LHW51701.Their structures were elucidated via spectroscopic techniques(including HRESIMS,ID&2D NMR),and X-ray crystallographic analysis.Structurally,the 4-chloro coupled with 3-methoxyl substituents in the tricycle nucleus of CCBs A-D and the A/-methoxyl group of CCB-D are rare in naturally occurred tricyclic carbazole alkaloids.Moreover,CCBs A-D do not bear the typical Cl poro-alkyl and C2 meto-methyl side chains of bacterial tricycle carbazoles,suggesting a novel mechanism of aromatic ring formation in biosynthesis.The biological evaluation showed that CCB-C possessed inhibitory activities against pathogenic microorganisms including methicillin-resistant Staphylococcus aureus(MRSA),Mycobacterium smegmatis,Bacillus mycoides,and Candida albicans.展开更多
Piericidins are a large family of bacterialα-pyridone antibiotics with antitumor activities such as their anti-renal carcinoma activity exhibited recently in nude mice.The backbones of piericidins are derived fromβ,...Piericidins are a large family of bacterialα-pyridone antibiotics with antitumor activities such as their anti-renal carcinoma activity exhibited recently in nude mice.The backbones of piericidins are derived fromβ,δ-diketo carboxylic acids,which are offloaded from a modular polyketide synthase(PKS)and putatively undergo a carbonyl amidation beforeα-pyridone ring formation.The tailoring modifications to theα-pyridone structure mainly include the verified hydroxylation and O-methylation of the C-4′position and an unidentified C-5′O-methylation.Here,we describe a piericidin producer,terrestrial Streptomyces conglobatus,which contains a piericidin biosynthetic gene cluster in two different loci.Deletion of the amidotransferase gene pieD resulted in the accumulation of two fatty acids that should be degraded from the nascent carboxylic acid released by the PKS,supporting the carbonyl amidation function of PieD duringα-pyridone ring formation.Deletion of the O-methyltransferase gene pieB1 led to the production of three piericidin analogues lacking C-5′O-methylation,therefore confirming that PieB1 specifically catalyses the tailoring modification.Moreover,bioactivity analysis of the mutant-derived products provided clues regarding the structure-function relationship for antitumor activity.The work addresses two previously unidentified steps involved in pyridyl pharmacophore formation during piericidin biosynthesis,facilitating the rational bioengineering of the biosynthetic pathway towards valuable antitumor agents.展开更多
Main observation and conclusion A divergent and novel protocol for the preparation of both pyrido[2,3,4-kl]acridine and pyrido[4,3,2-kl]acridine alkaloids was developed.This method featured the remote palladium-cataly...Main observation and conclusion A divergent and novel protocol for the preparation of both pyrido[2,3,4-kl]acridine and pyrido[4,3,2-kl]acridine alkaloids was developed.This method featured the remote palladium-catalyzed reductive cyclization with Mo(CO)_(6) as reductant.A wide range of substrates including three types of nitro arenes were tolerated and afforded corresponding products in good to excellent yields.展开更多
基金the National Natural Science Foundation of China(Nos.32070070,32211530074 and 31929001)the innovative research team of high-level local universities in Shanghai.H.D.thanks Royal Society-NSFC international exchange grant(IEC\NSFC\211349).
文摘The bacterial trialkyl-substituted aromatic polyketides are structurally featured with the unusual aromatic core in the middle of polyketide chain such as TM-123(1),veramycin A(2),NFAT-133(3)and benwamycin I(4),which were discovered from Streptomyces species and demonstrated with antidiabetic and immunosuppressant activities.Though the biosynthetic pathway of 1-3 was reported as a type I polyketide synthase(PKS),the PKS assembly line was interpreted inconsistently,and it remains a mystery how the compound 3 was generated.Herein,the PKS assembly logic of 1-4 was revised by site-mutagenetic analysis of the PKS dehydratase domains.Based on gene deletion and complementation,the putative P450 monooxygenase nftE1 and metallo-beta-lactamase(MBL)fold hydrolase nftF1 were verified as essential genes for the biosynthesis of 1-4.The absence of nftE1 led to abolishment of 1-4 and accumulation of new products(5-8).Structural elucidation reveals 5-8 as the non-aromatic analogs of 1,suggesting the NftE1-catalyzed aromatic core formation.Deletion of nftF1 resulted in disappearance of 3 and 4 with the compounds 1 and 2 unaffected.As a rare MBL-fold hydrolase from type I PKSs,NftF1 potentially generates the compound 3 through two strategies:catalyze premature chain-offloading as a trans-acting thioesterase or hydrolyze the lactone-bond of compound 1 as an esterase.
基金the National Natural Science Foundation of China(82073890,81673464,and 82061148017,to DK,22137006 and 82104054,to HW L)Fellowship of China Postdoctoral Science Foundation(2021M702464 to XP)Postgraduate Innovation Fund of 13th Five-Year comprehensive investment of Tianjin Medical University(YJSCX201806 to XP).SF295 cell line was kindly provided by the National Cancer Institute,National Institutes of Health,USA.We thank Dr.Xi Chen from Tianjin Key Laboratory of Ophthalmology and Visual Science,Tianjin Eye Institute,Tianjin Eye Hospital for assistance in spectrometry proteomics data analysis.
文摘Dear Editor,Glioblastoma(GBM)is one of the most fatal brain tumors.Current first-line post-surgery regimens for GBM including radiotherapy and temozolomide(TMZ)chemotherapy show very limited efficacy.1,2 Novel therapeutic approaches for GBM patients are urgently needed.Natural products are important sources for drug discovery,especially in the field of cancer treatment.3 We previously isolated stellettin B(STELB)(Fig.1a)from marine sponge(Jaspis stellifera)and reported the remarkable and specific anticancer activities.Recently,a series of stellettins has been totally synthesized and the core chemical structure has been indicated.4 However,the specific mechanism and its role in regulating tumor biology remain largely unknown.
基金the National Key R&D Program of China(No.2019YFC0312501)the National Natural Science Foundation of China(No.31929001)+2 种基金the Special Project for Marine Economic Development(Six Major Marine Industries)of Guangdong Province Department of Natural Resources of Guangdong Province(No.[2020]039)the Construction Project of Shanghai Key Laboratory of Molecular Imaging(No.18DZ2260400)the Innovative Research Team of High-Level Local Universities in Shanghai,and the Taishan Scholar Project from Shandong Province to H.L.The authors are grateful to Ying Wu for QTOF mass analysis,Hong-Yan Liu for NMR analysis,and Prof.Meifeng Tao from School of Life Sciences and Biotechnology,Shanghai Jiao Tong University for kindly providing the indicator strains for bioactivity assay.
文摘Four new chlorinated carbazole alkaloids,chlocarbazomycins(CCBs)A-D,were isolated from sponge associated bacterium Streptomyces diacarni LHW51701.Their structures were elucidated via spectroscopic techniques(including HRESIMS,ID&2D NMR),and X-ray crystallographic analysis.Structurally,the 4-chloro coupled with 3-methoxyl substituents in the tricycle nucleus of CCBs A-D and the A/-methoxyl group of CCB-D are rare in naturally occurred tricyclic carbazole alkaloids.Moreover,CCBs A-D do not bear the typical Cl poro-alkyl and C2 meto-methyl side chains of bacterial tricycle carbazoles,suggesting a novel mechanism of aromatic ring formation in biosynthesis.The biological evaluation showed that CCB-C possessed inhibitory activities against pathogenic microorganisms including methicillin-resistant Staphylococcus aureus(MRSA),Mycobacterium smegmatis,Bacillus mycoides,and Candida albicans.
基金support from the National Natural Science Foundation of China(Nos.32070070,31929001,and 31800031)the Innovative Research Team of High-Level Local Universities in Shanghai。
文摘Piericidins are a large family of bacterialα-pyridone antibiotics with antitumor activities such as their anti-renal carcinoma activity exhibited recently in nude mice.The backbones of piericidins are derived fromβ,δ-diketo carboxylic acids,which are offloaded from a modular polyketide synthase(PKS)and putatively undergo a carbonyl amidation beforeα-pyridone ring formation.The tailoring modifications to theα-pyridone structure mainly include the verified hydroxylation and O-methylation of the C-4′position and an unidentified C-5′O-methylation.Here,we describe a piericidin producer,terrestrial Streptomyces conglobatus,which contains a piericidin biosynthetic gene cluster in two different loci.Deletion of the amidotransferase gene pieD resulted in the accumulation of two fatty acids that should be degraded from the nascent carboxylic acid released by the PKS,supporting the carbonyl amidation function of PieD duringα-pyridone ring formation.Deletion of the O-methyltransferase gene pieB1 led to the production of three piericidin analogues lacking C-5′O-methylation,therefore confirming that PieB1 specifically catalyses the tailoring modification.Moreover,bioactivity analysis of the mutant-derived products provided clues regarding the structure-function relationship for antitumor activity.The work addresses two previously unidentified steps involved in pyridyl pharmacophore formation during piericidin biosynthesis,facilitating the rational bioengineering of the biosynthetic pathway towards valuable antitumor agents.
基金This project is financially supported by the National Key Research and Development Program of China(No.2018YFC0310900)the National Natural Science Foundation of China(Nos.81903499 and 41729002)the Innovative Research Team of High-Level Local Universities in Shanghai(No.SSMU-ZLCX20180702).
文摘Main observation and conclusion A divergent and novel protocol for the preparation of both pyrido[2,3,4-kl]acridine and pyrido[4,3,2-kl]acridine alkaloids was developed.This method featured the remote palladium-catalyzed reductive cyclization with Mo(CO)_(6) as reductant.A wide range of substrates including three types of nitro arenes were tolerated and afforded corresponding products in good to excellent yields.