吲唑类组蛋白去乙酰化酶抑制剂的合成及抗肿瘤活性  

Synthesis and anti-tumor activity of histone deacetylase inhibitors based indazole scaffold

作　　者：韩潇[1] 曾慧君 陈慧琼 HAN Xiao;ZENG Hui-jun;CHEN Hui-qiong(Department of Medical Nursing,Changjiang Polytechnic,Wuhan 430074,China;Wuhan Inistitute for Food and Cosmetic Control,Wuhan 430012,China;Wuhan Aimin Pharmaceutical Limited Company,Ezhou 436070,China)

机构地区：[1]长江职业学院医药护理学院,湖北武汉430074 [2]武汉食品化妆品检验所,湖北武汉430012 [3]武汉爱民制药股份有限公司,湖北鄂州436070

出　　处：《化学研究与应用》2022年第5期1046-1053,共8页Chemical Research and Application

基　　金：湖北省教育厅项目(B2020429)资助;全国食品工业职业教育教学指导委员会2020年度教育教学改革与研究课题项目(SH390)资助。

摘　　要：为了得到HDAC抑制活性和抗癌活性更强的PXD-101衍生物,通过分子内缩合、Wittig等反应合成了四个含有吲唑基的PXD-101衍生物,并采用HDAC和CCK-8试剂盒评价其生物活性。结果显示,吲唑基团是一个药效团,能够增强PXD-101的抑酶活性以及抗肿瘤活性。其中化合物6d(IC_(50)=0.012±0.001μmol·L^(-1))对HDAC6展现出了最强的抑制剂活性,是阳性药物PXD-101(IC_(50)=0.076±0.021μmol·L^(-1))的6.3倍;同时化合物6d(IC_(50)=0.5±0.28μmol·L^(-1))对KB细胞也有最强的抑制活性,是PXD-101(IC_(50)=0.8±0.24μmol·L^(-1))的1.6倍。。To discover novel PXD-101 derivatives with higher HDAC inhibitory activity and antitumor potency,four PXD-101 derivatives cantaining indazole unit were synthesized via intramolecular condensation,Wittig reaction,and their activities were evaluated by HDAC and CCK-8 assay kits.The preliminary biological results showed that indazole group was a pharmacophore,which could enhance potency against HDAC and antitumor activity of PXD-101.Specifically,compound 6d(IC_(50)=0.012±0.001μmol·L^(-1))exhibited the most potent anti-HDAC6 activity,which was 6.3-fold more potent than PXD-101(IC_(50)=0.076±0.021μmol·L^(-1)).Moreover,the compound 6d(IC_(50)=0.5±0.28μmol·L^(-1))showed the greatest potency against KB,which was 1.6-fold more potent than PXD-101(IC_(50)=0.8±0.24μmol·L^(-1)).

关 键 词：吲唑 分子内缩合 WITTIG反应 HDAC抑制剂 抗肿瘤活性 

分 类 号：O625.6[理学—有机化学]