Four prenylated flavonoids compounds 1-4,named sinopodophyllines A-D,and a flavonoid glycoside(compound 13),sinopodophylliside A,together with 19 known compounds(compounds 5-12 and 14-24) were isolated from the fruits...Four prenylated flavonoids compounds 1-4,named sinopodophyllines A-D,and a flavonoid glycoside(compound 13),sinopodophylliside A,together with 19 known compounds(compounds 5-12 and 14-24) were isolated from the fruits of Sinopodophyllum hexandrum.The structures of new compounds were elucidated by extensive spectroscopic analysis,including HRESIMS,1D and 2D NMR.Compounds 1-6,9-11,and 14-17 were tested for their cytotoxicity against human breast-cancer T47 D,MCF-7 and MDA-MB-231 cells in vitro,and compounds 2,5,6,10 and 11 showed significant cytotoxicity(IC50 values < 10 μmol·L^(-1))against T47 D cells.展开更多
Twenty prenylated flavonoids 1-20 were synthesized by glycoside hydrolysis, dehydrogenation, selective O-methylation, O-prenylation and Claisen rearrangement reaction, from abundant and inexpensive natural flavonoids ...Twenty prenylated flavonoids 1-20 were synthesized by glycoside hydrolysis, dehydrogenation, selective O-methylation, O-prenylation and Claisen rearrangement reaction, from abundant and inexpensive natural flavonoids naringin, hespiredin, quercetin and myricetin. Among them, 1-7, 10-15 and 17-20 are novel compounds, the natural product 3,3＇,4＇,7-tetramethoxy-8-prenyl-5-hydroxy flavonoid（16） was synthesized in a high yield. Their antiprolirative activities were evaluated in vitro on a panel of three human cancer cell lines（HeLa, HCC1954 and SK-OV-3）. The results show that most of the target compounds displayed moderate to potent antiprolirative activities against the three cancer cells with half maximal inhibitory concentration（ICs0） values from 0.49 μmol/L to 95.07 μmol/L. Among them, 3′,4′,7-trimethoxyl-5-hydroxyl-8-prenyl flavonoid（12） exhibited the strongest antiprolirative activity against the three cancer cells mentioned above with IC50 values of 0.91-7.08 μmol/L. 3′,7-Dimethoxy-5-O- prenyl flavone（6） and 3′,4′,7-trimethoxy-5-O-prenyl flavone（10） showed selective antiproliferative activity against HCC1954 cells with TC50 value of 0 49 and 5 .32μmol/L, respectively.展开更多
8-Prenylnaringenin(8-PN)is a valuable medical phytoestrogen,which is a precursor to many prenylated flavonoids.How-ever,the availability of 8-PN is limited by inefficient prenyltransferases(PTs)and inadequate substrat...8-Prenylnaringenin(8-PN)is a valuable medical phytoestrogen,which is a precursor to many prenylated flavonoids.How-ever,the availability of 8-PN is limited by inefficient prenyltransferases(PTs)and inadequate substrate precursor levels in microbial chassis.First,six PTs from different sources and their truncated cognates were expressed in a(2S)-naringenin producing strain.Only SfN8DT-1 derived from Sophora flavescens and its truncated cognate,tSfN8DT-1,could synthe-size 8-PN.Second,tSfN8DT-1 was engineered by multiple sequence alignment and a mutant tSfN8DT-1^(Q12E)with greater catalytic activity was obtained.Third,key genes,tHMGR and IDI1,of the mevalonate(MVA)pathway were overexpressed using a copy number combinatorial strategy,which greatly improved 8-PN titer by 368.75%.Fourth,a predicted structure of tSfN8DT-1^(Q12E)was used for molecular docking and virtual saturation mutagenesis.Two key residues,P229 and N305,were identified and saturation mutagenesis on these two sites resulted in an improved mutant N305M.The best-performing mutant,tSfN8DT-1^(Q12EN305M),produced 49.35±0.05 mg/L(5.57±0.01 mg/g DCW)8-PN in a shaking flask.Finally,101.40±2.55 mg/L of 8-PN was obtained in a 5-L bioreactor,which is the greatest titer reported to date for 8-PN.This study combined metabolic engineering and protein engineering methods to enhance precursor supplements and improve the catalytic ability of SfN8DT-1.The production of 8-PN in Saccharomyces cerevisiae was greatly increased through these methods,which may provide a feasible strategy for the biosynthesis of prenylated flavonoids.展开更多
Bioactive natural polymethoxyflavones 1―6 and their vinyl ether derivatives 7―15 were synthesized by bromination,aromatic nucleophilic substitution,methylation,benzyl protection,Friedel-Crafts acetylation,aldol cond...Bioactive natural polymethoxyflavones 1―6 and their vinyl ether derivatives 7―15 were synthesized by bromination,aromatic nucleophilic substitution,methylation,benzyl protection,Friedel-Crafts acetylation,aldol condensation,cyclization,DDQ dehydrogenation,regioselective demethylation,debenzylation and O-prenylation or O-farnesylation with resorcinol and appropriate substituted benzaldehydes as starting materials.Among them,compounds 7―15 are new compounds.Natural products 2―4 were firstly total synthesized.The syntheses of compounds 1,5 and 6 were efficiently improved by the new synthetic routes.The structures of all synthetic compounds were confirmed by NMR,IR spectra and MS.展开更多
基金supported by Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine(No.2010JZ-W-01)Ministry of Education,PRC,and National Key Technology R&D Program“New Drug Innovation”of China(Nos.2009ZX09308-004,2013ZX09103002-006)
文摘Four prenylated flavonoids compounds 1-4,named sinopodophyllines A-D,and a flavonoid glycoside(compound 13),sinopodophylliside A,together with 19 known compounds(compounds 5-12 and 14-24) were isolated from the fruits of Sinopodophyllum hexandrum.The structures of new compounds were elucidated by extensive spectroscopic analysis,including HRESIMS,1D and 2D NMR.Compounds 1-6,9-11,and 14-17 were tested for their cytotoxicity against human breast-cancer T47 D,MCF-7 and MDA-MB-231 cells in vitro,and compounds 2,5,6,10 and 11 showed significant cytotoxicity(IC50 values < 10 μmol·L^(-1))against T47 D cells.
基金Supported by the National Natural Science Foundation of China（Nos.J1210040, 21173074）.
文摘Twenty prenylated flavonoids 1-20 were synthesized by glycoside hydrolysis, dehydrogenation, selective O-methylation, O-prenylation and Claisen rearrangement reaction, from abundant and inexpensive natural flavonoids naringin, hespiredin, quercetin and myricetin. Among them, 1-7, 10-15 and 17-20 are novel compounds, the natural product 3,3＇,4＇,7-tetramethoxy-8-prenyl-5-hydroxy flavonoid（16） was synthesized in a high yield. Their antiprolirative activities were evaluated in vitro on a panel of three human cancer cell lines（HeLa, HCC1954 and SK-OV-3）. The results show that most of the target compounds displayed moderate to potent antiprolirative activities against the three cancer cells with half maximal inhibitory concentration（ICs0） values from 0.49 μmol/L to 95.07 μmol/L. Among them, 3′,4′,7-trimethoxyl-5-hydroxyl-8-prenyl flavonoid（12） exhibited the strongest antiprolirative activity against the three cancer cells mentioned above with IC50 values of 0.91-7.08 μmol/L. 3′,7-Dimethoxy-5-O- prenyl flavone（6） and 3′,4′,7-trimethoxy-5-O-prenyl flavone（10） showed selective antiproliferative activity against HCC1954 cells with TC50 value of 0 49 and 5 .32μmol/L, respectively.
基金supported by the National Key Research and Development Program of China(2019YFA0904800)the National Science Fund for Excellent Young Scholars(21822806)the National Natural Science Foundation of China(21908078).
文摘8-Prenylnaringenin(8-PN)is a valuable medical phytoestrogen,which is a precursor to many prenylated flavonoids.How-ever,the availability of 8-PN is limited by inefficient prenyltransferases(PTs)and inadequate substrate precursor levels in microbial chassis.First,six PTs from different sources and their truncated cognates were expressed in a(2S)-naringenin producing strain.Only SfN8DT-1 derived from Sophora flavescens and its truncated cognate,tSfN8DT-1,could synthe-size 8-PN.Second,tSfN8DT-1 was engineered by multiple sequence alignment and a mutant tSfN8DT-1^(Q12E)with greater catalytic activity was obtained.Third,key genes,tHMGR and IDI1,of the mevalonate(MVA)pathway were overexpressed using a copy number combinatorial strategy,which greatly improved 8-PN titer by 368.75%.Fourth,a predicted structure of tSfN8DT-1^(Q12E)was used for molecular docking and virtual saturation mutagenesis.Two key residues,P229 and N305,were identified and saturation mutagenesis on these two sites resulted in an improved mutant N305M.The best-performing mutant,tSfN8DT-1^(Q12EN305M),produced 49.35±0.05 mg/L(5.57±0.01 mg/g DCW)8-PN in a shaking flask.Finally,101.40±2.55 mg/L of 8-PN was obtained in a 5-L bioreactor,which is the greatest titer reported to date for 8-PN.This study combined metabolic engineering and protein engineering methods to enhance precursor supplements and improve the catalytic ability of SfN8DT-1.The production of 8-PN in Saccharomyces cerevisiae was greatly increased through these methods,which may provide a feasible strategy for the biosynthesis of prenylated flavonoids.
基金Supported by the Science & Technology Planning Project of Hunan Province,China (No.2011FJ3214)
文摘Bioactive natural polymethoxyflavones 1―6 and their vinyl ether derivatives 7―15 were synthesized by bromination,aromatic nucleophilic substitution,methylation,benzyl protection,Friedel-Crafts acetylation,aldol condensation,cyclization,DDQ dehydrogenation,regioselective demethylation,debenzylation and O-prenylation or O-farnesylation with resorcinol and appropriate substituted benzaldehydes as starting materials.Among them,compounds 7―15 are new compounds.Natural products 2―4 were firstly total synthesized.The syntheses of compounds 1,5 and 6 were efficiently improved by the new synthetic routes.The structures of all synthetic compounds were confirmed by NMR,IR spectra and MS.
