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

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.