Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, Hebei, 071002, China.
Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, Hebei, 071002, China.
Eur J Med Chem. 2020 Aug 15;200:112459. doi: 10.1016/j.ejmech.2020.112459. Epub 2020 May 21.
In order to develop potent anticaner agents, a novel series of 3-(1H-indol-3-yl)-2,3,3a,4-tetrahydrothiochromeno[4,3-c]pyrazole derivatives were synthesized. Structures of all compounds were confirmed. MTT assay has been employed to study antiproliferative activity of these compounds with four human cancer cell lines (MGC-803, Hela, MCF-7 and Bel-7404) and a normal cell line L929. Most of these compounds showed potential anticancer activity and low cytotoxicity on normal cell in vitro. 7d and 7f showed the best anticancer activity, whose IC value is 15.43 μM and 20.54 μM towards MGC-803, respectively. Most of them exhibited topoisomerase II selective inhibitory. Cleavage reaction assay and DNA unwinding assay showed that 7f was a nonintercalative Topo II catalytic inhibitor, which was consistent with the docking results. Laser scanning confocal microscopy system tracks the location of representative compounds 7d and 7f which can be abundantly entering the nucleus. In particular, the most potent compounds 7d and 7f were shown to be able to induce G2/M cell cycle arrest and apoptosis in MGC-803 cells.
为了开发有效的抗癌药物，我们合成了一系列新型的 3-(1H-吲哚-3-基)-2,3,3a,4-四氢噻吩并[4,3-c]吡唑衍生物。所有化合物的结构均已得到确认。采用 MTT 法研究了这些化合物对四种人癌细胞系（MGC-803、Hela、MCF-7 和 Bel-7404）和正常细胞系 L929 的增殖抑制活性。这些化合物大多数具有潜在的抗癌活性和低细胞毒性。化合物 7d 和 7f 对 MGC-803 的 IC 值分别为 15.43 μM 和 20.54 μM，显示出最好的抗癌活性。它们大多数表现出拓扑异构酶 II 选择性抑制作用。切割反应试验和 DNA 解链试验表明，化合物 7f 是一种非嵌入性拓扑异构酶 II 催化抑制剂，与对接结果一致。激光扫描共聚焦显微镜系统跟踪了代表性化合物 7d 和 7f 的位置，它们可以大量进入细胞核。特别是，最有效的化合物 7d 和 7f 能够诱导 MGC-803 细胞的 G2/M 细胞周期停滞和凋亡。
