Key Laboratory of Natural Medicine and Immune-Engineering of Henan Province, Henan University Jinming Campus, Kaifeng 475004, Henan, China.
Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
Bioorg Chem. 2021 May;110:104793. doi: 10.1016/j.bioorg.2021.104793. Epub 2021 Mar 5.
Colchicine binding site inhibitors (CBSIs) hold great potential for the treatment of various tumors and they can overcome multidrug resistance which the existing tubulin inhibitors such as paclitaxel and vinorelbine are faced with. Herein, we report the design, synthesis and biological evaluation of a series of tetrahydro-quinoxaline derivatives as colchicine binding site inhibitors. All the synthesized compounds were evaluated for their in vitro antiproliferative activities against HT-29 and Hela cancer cell lines, and most of the target compounds demonstrated moderate to strong activities towards two tumor cell lines. In addition, the structure-activity relationships of these derivatives were also discussed. Among them, compounds 11a and 11b showed the most potent activities. Moreover, compound 11a inhibited the tubulin polymerization in both cell-free and cellular assays. Further profiling of compound 11a revealed that it arrested cell cycle in G2/M and induced cell apoptosis in a dose-dependent manner. Furthermore, molecular docking study proved that compound 11a acted on the colchicine binding site. Therefore, 11a is a promising candidate for the discovery of colchicine binding site inhibitors.
秋水仙碱结合位点抑制剂（CBSIs）在治疗各种肿瘤方面具有巨大的潜力，它们可以克服现有微管抑制剂（如紫杉醇和长春瑞滨）所面临的多药耐药性。本文报道了一系列四氢喹喔啉衍生物作为秋水仙碱结合位点抑制剂的设计、合成和生物学评价。所有合成的化合物都对 HT-29 和 Hela 癌细胞系进行了体外抗增殖活性评估，大多数目标化合物对两种肿瘤细胞系表现出中等至较强的活性。此外，还讨论了这些衍生物的构效关系。其中，化合物 11a 和 11b 表现出最强的活性。此外，化合物 11a 在无细胞和细胞测定中均能抑制微管聚合。对化合物 11a 的进一步分析表明，它以剂量依赖的方式将细胞周期阻滞在 G2/M 期并诱导细胞凋亡。此外，分子对接研究证明化合物 11a 作用于秋水仙碱结合位点。因此，11a 是发现秋水仙碱结合位点抑制剂的有前途的候选物。
