A concise and efficient method for the synthesis of novel 9,10-imethoxybenzo[6,7]oxepino[3,4-b]quinolin13(6H)-one and its derivatives 7a-p has been developed via the intramolecular Friedel-Crafts acylation reactions o...A concise and efficient method for the synthesis of novel 9,10-imethoxybenzo[6,7]oxepino[3,4-b]quinolin13(6H)-one and its derivatives 7a-p has been developed via the intramolecular Friedel-Crafts acylation reactions of 6,7-dimethoxy-2-(phenoxymethyl)quinoline-3-carboxylic acids 6a-p with polyphosphoric acid (PPA) as catalyst and solvent under mild conditions. The key intermediates 6a-p were prepared through the in situ formation of ethyl 6,7-dimethoxy-2-(phenoxymethyl)quinoline-3-carboxylates 5a-p followed by hydrolysis with aqueous ethanolic sodium hydroxide solution. The novel synthetic method has the advantages of good yields, easy work-up, and environmentally friendly character, which may provide a novel highly efficient process for making quinoline and related azaheterocycle libraries.展开更多
Objective:Esophageal squamous cell carcinoma(ESCC)has high morbidity and mortality rates worldwide.Cancer stem cells(CSCs)may cause tumor initiation,metastasis,and recurrence and are also responsible for chemotherapy ...Objective:Esophageal squamous cell carcinoma(ESCC)has high morbidity and mortality rates worldwide.Cancer stem cells(CSCs)may cause tumor initiation,metastasis,and recurrence and are also responsible for chemotherapy and radiotherapy failures.Myeloid-derived suppressor cells(MDSCs),in contrast,are known to be involved in mediating immunosuppression.Here,we aimed to investigate the mechanisms of interaction of CSCs and MDSCs in the tumor microenvironment.Methods:ESCC tissues and cell lines were evaluated.Neural precursor cell expressed,developmentally downregulated 9(NEDD9)was knocked down and overexpressed by lentiviral transfection.Quantitative PCR,Western blot,immunohistochemistry,cell invasion,flow cytometry,cell sorting,multiplex chemokine profiling,and tumor growth analyses were performed.Results:Microarray analysis revealed 10 upregulated genes in esophageal CSCs.Only NEDD9 was upregulated in CSCs using the sphere-forming method.NEDD9 expression was correlated with tumor invasion(P=0.0218),differentiation(P=0.0153),and poor prognosis(P=0.0373).Additionally,NEDD9 was required to maintain the stem-like phenotype.Screening of chemokine expression in ESCC cells with NEDD9 overexpression and knockdown showed that NEDD9 regulated C-X-C motif chemokine ligand 8(CXCL8)expression via the ERK pathway.CXCL8 mediated the recruitment of MDSCs induced by NEDD9 in vitro and in vivo.MDSCs promoted the stemness of ESCC cells through NEDD9 via the Notch pathway.Conclusions:As a marker of ESCC,NEDD9 maintained the stemness of ESCC cells and regulated CXCL8 through the ERK pathway to recruit MDSCs into the tumor,suggesting NEDD9 as a therapeutic target and novel prognostic marker for ESCC.展开更多
目的探讨2型糖尿病(T2DM)患者血清中基质细胞衍生因子-1(SDF-1)和基质金属蛋白酶-9(MMP-9)的变化及意义。方法测定120例T2DM患者和30例健康对照者血清中SDF-1和MMP-9的水平、血管内皮祖细胞(EPCs)的数量和其表面CXCR4的表达率。糖尿病...目的探讨2型糖尿病(T2DM)患者血清中基质细胞衍生因子-1(SDF-1)和基质金属蛋白酶-9(MMP-9)的变化及意义。方法测定120例T2DM患者和30例健康对照者血清中SDF-1和MMP-9的水平、血管内皮祖细胞(EPCs)的数量和其表面CXCR4的表达率。糖尿病患者分单纯糖尿病组和血管病变组。结果 SDF-1水平和EPCs数量在对照组、单纯糖尿病组、血管病变组中依次下降(P<0.05 or 0.01);MMP-9水平在对照组、单纯糖尿病组和血管病变组中依次增高(P<0.01);CXCR4表达率单纯糖尿病组较对照组和血管病变组升高(P<0.05 or 0.01),血管病变组较对照组降低(P<0.05);SDF-1与MMP-9呈负相关(r=-0.223,P<0.05),与EPCs呈正相关(r=0.224,P<0.05);MMP-9与EPCs呈负相关(r=-0.215,P<0.05)。结论 T2DM患者SDF-1/CXCR4轴与EPCs的数量及功能密切相关,MMP-9通过降低SDF-1水平可能是其促进血管病变的机制之一。展开更多
文摘A concise and efficient method for the synthesis of novel 9,10-imethoxybenzo[6,7]oxepino[3,4-b]quinolin13(6H)-one and its derivatives 7a-p has been developed via the intramolecular Friedel-Crafts acylation reactions of 6,7-dimethoxy-2-(phenoxymethyl)quinoline-3-carboxylic acids 6a-p with polyphosphoric acid (PPA) as catalyst and solvent under mild conditions. The key intermediates 6a-p were prepared through the in situ formation of ethyl 6,7-dimethoxy-2-(phenoxymethyl)quinoline-3-carboxylates 5a-p followed by hydrolysis with aqueous ethanolic sodium hydroxide solution. The novel synthetic method has the advantages of good yields, easy work-up, and environmentally friendly character, which may provide a novel highly efficient process for making quinoline and related azaheterocycle libraries.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.81602599,31400752,81771781,and U1804281)the National Key Research and Development Program of China(Grant No.2016YFC1303501)。
文摘Objective:Esophageal squamous cell carcinoma(ESCC)has high morbidity and mortality rates worldwide.Cancer stem cells(CSCs)may cause tumor initiation,metastasis,and recurrence and are also responsible for chemotherapy and radiotherapy failures.Myeloid-derived suppressor cells(MDSCs),in contrast,are known to be involved in mediating immunosuppression.Here,we aimed to investigate the mechanisms of interaction of CSCs and MDSCs in the tumor microenvironment.Methods:ESCC tissues and cell lines were evaluated.Neural precursor cell expressed,developmentally downregulated 9(NEDD9)was knocked down and overexpressed by lentiviral transfection.Quantitative PCR,Western blot,immunohistochemistry,cell invasion,flow cytometry,cell sorting,multiplex chemokine profiling,and tumor growth analyses were performed.Results:Microarray analysis revealed 10 upregulated genes in esophageal CSCs.Only NEDD9 was upregulated in CSCs using the sphere-forming method.NEDD9 expression was correlated with tumor invasion(P=0.0218),differentiation(P=0.0153),and poor prognosis(P=0.0373).Additionally,NEDD9 was required to maintain the stem-like phenotype.Screening of chemokine expression in ESCC cells with NEDD9 overexpression and knockdown showed that NEDD9 regulated C-X-C motif chemokine ligand 8(CXCL8)expression via the ERK pathway.CXCL8 mediated the recruitment of MDSCs induced by NEDD9 in vitro and in vivo.MDSCs promoted the stemness of ESCC cells through NEDD9 via the Notch pathway.Conclusions:As a marker of ESCC,NEDD9 maintained the stemness of ESCC cells and regulated CXCL8 through the ERK pathway to recruit MDSCs into the tumor,suggesting NEDD9 as a therapeutic target and novel prognostic marker for ESCC.
文摘目的探讨2型糖尿病(T2DM)患者血清中基质细胞衍生因子-1(SDF-1)和基质金属蛋白酶-9(MMP-9)的变化及意义。方法测定120例T2DM患者和30例健康对照者血清中SDF-1和MMP-9的水平、血管内皮祖细胞(EPCs)的数量和其表面CXCR4的表达率。糖尿病患者分单纯糖尿病组和血管病变组。结果 SDF-1水平和EPCs数量在对照组、单纯糖尿病组、血管病变组中依次下降(P<0.05 or 0.01);MMP-9水平在对照组、单纯糖尿病组和血管病变组中依次增高(P<0.01);CXCR4表达率单纯糖尿病组较对照组和血管病变组升高(P<0.05 or 0.01),血管病变组较对照组降低(P<0.05);SDF-1与MMP-9呈负相关(r=-0.223,P<0.05),与EPCs呈正相关(r=0.224,P<0.05);MMP-9与EPCs呈负相关(r=-0.215,P<0.05)。结论 T2DM患者SDF-1/CXCR4轴与EPCs的数量及功能密切相关,MMP-9通过降低SDF-1水平可能是其促进血管病变的机制之一。
