摘要/Abstract

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30 μmol·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±0.62 μmol·L^-1）和羟喜树碱（5.93±0.56 μmol·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Topo II表现出不同程度抑制活性，对Topo I未表现出抑制活性.
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
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 ¹H NMR, ¹³C 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 5m 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-1H-pyrazolo[3,4-d]pyrimidin-6-yl)thio)-1H-indole-6-carboxylate (5m) 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 biological 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.
Key words: indole, pyrazolo[3,4-d]pyrimidine, anticancer, topoisomerase, molecular docking


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