含吲哚的吡唑并[3,4-d]嘧啶衍生物的设计合成及其生物活性研究  

Design, Synthesis and Biological Activity of Pyrazolo[3,4-d]pyrimidine Derivatives Containing Indole Moiety

作　　者：孙晓阳 冯思冉 董金娇 冯佳佳 刘振明[3] 宋亚丽 乔晓强 Sun Xiaoyang;Feng Siran;Dong Jinjiao;Feng Jiajia;Liu Zhenming;Song Yali;Qiao Xiaoqiang(Key Laboratory of Pharmaceutical Quality Control of Hebei Province,College of Pharmacetical Sciences,Hebei University,Baoding,Hebei 071000;National Drug Clinical Trial Institution,Cangzhou Central Hospital,Cangzhou,Hebei 061000;Drug Design Center,State Key Laboratory of Natural and Biomimetic Drugs,School of Pharmaceutical Sciences,Peking University,Beijing 100191;Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education,Hebei University,Baoding,Hebei 071000)

机构地区：[1]河北大学药学院河北省药物质量分析控制重点实验室,河北保定071000 [2]沧州市中心医院国家药物临床试验机构,河北沧州061000 [3]北京大学药学院天然药物及仿生药物国家重点实验室药物设计中心,北京100191 [4]河北大学药物化学与分子诊断教育部重点实验室,河北保定071000

出　　处：《有机化学》2020年第2期391-397,共7页Chinese Journal of Organic Chemistry

基　　金：河北省自然科学基金(No.B2018201269);河北省高等学校科学技术研究项目(No.ZD2019060);国家自然科学基金(No.21675039);河北省青年拔尖人才资助项目.

摘　　要：利用药物设计中的生物活性基团拼接原理,设计合成了13个含吲哚的吡唑并[3,4-d]嘧啶衍生物.目标化合物均经核磁共振氢谱(1H NMR)、核磁共振碳谱(13C NMR)和高分辨质谱仪(HRMS)进行了结构确证.对4株肿瘤细胞(HeLa、MGC-803、MCF-7、BEL-7404)的体外抗增殖活性实验结果表明,目标化合物均表现出一定的抗肿瘤活性,MCF-7、MGC-803肿瘤细胞株敏感度高于HeLa和BEL-7404.其中, 6-[(6-甲氧羰基吲哚-3-基)硫基]-1-苯基-吡唑并[3,4-d]嘧啶-4-酮(5m)表现出较好的体外肿瘤抑制活性,对MCF-7、MGC-80和HeLa细胞的IC50均小于30μmol·L^-1,对MCF-7的IC50值为(4.02±0.92)μmol·L^-1,优于对照药物依托泊苷(10.1±0.62μmol·L^-1)和羟喜树碱(5.93±0.56μmol·L^-1).拓扑异构酶抑制实验结果表明,此类化合物对TopoII有选择性抑制活性,所有化合物对TopoⅡ表现出不同程度抑制活性,对Topo Ⅰ未表现出抑制活性.Based on the combination principle in drug design, thirteen pyrazolo[3,4-d]pyrimidine derivatives containing indole moiety were designed and synthesized. The target compounds were confirmed by 1 H NMR, 13 C NMR and HRMS. Their in vitro cytotoxicity against four human cancer cell lines(HeLa、MGC-803、MCF-7、BEL-7404) has been investigated and most of the tested compounds displayed moderate antiproliferative activity. Especially, compound 5 m exhibited the highest level of antiproliferative activity with an IC50 value <30 μmol·L^-1 for HeLa, MGC-803 and MCF-7. IC50 value of methyl 3-((4-oxo-1-phenyl-4,5-dihydro-1 H-pyrazolo[3,4-d]pyrimidin-6-yl)thio)-1 H-indole-6-carboxylate(5 m) to MCF-7 was(4.02±0.92) μmol·L^-1, which was better than etoposide(10.1±0.62 μmol·L^-1) and camptothecin(5.93±0.56 μmol·L^-1). Further b iological evaluation of these compounds suggested that these compounds showed selective inhibitory activity against Topo Ⅱ as a possible intracellular target, and all compounds didn’t show inhibitory activity against Topo Ⅰ.

关 键 词：吲哚 吡唑并[3 4-d]嘧啶 抗肿瘤 拓扑异构酶 分子对接 

分 类 号：O626[理学—有机化学] TQ463.5[理学—化学]