Dong Haiyang, Lu Lu, Song Xueting, Li Youkang, Zhou Jinguang, Xu Yungen, Zhang Yahong, Qi Jianguo, Liang Tingting, Wang Jianhong
Key Laboratory of Natural Medicine and Immune-Engineering of Henan Province, Henan University Jinming Campus Kaifeng 475004 Henan China
Huaihe Hospital of Henan University Kaifeng 475004 Henan China.
RSC Adv. 2023 Oct 16;13(43):30202-30216. doi: 10.1039/d3ra05720h. eCollection 2023 Oct 11.
Colchicine binding site inhibitors (CBSIs) are potential microtubule targeting agents (MTAs), which can overcome multidrug resistance, improve aqueous solubility and reduce toxicity faced by most MTAs. Novel tetrahydroquinoxaline sulfonamide derivatives were designed, synthesized and evaluated for their antiproliferative activities. The MTT assay results demonstrated that some derivatives exhibited moderate to strong inhibitory activities against HT-29 cell line. Among them, compound I-7 was the most active compound. Moreover, I-7 inhibited tubulin polymerization, disturbed microtubule network, disrupted the formation of mitotic spindle and arrested cell cycle at G2/M phase. However, I-7 didn't induce cell apoptosis. Furthermore, the prediction of ADME demonstrated that I-7 showed favorable physiochemical and pharmacokinetic properties. And the detailed molecular docking confirmed I-7 targeted the site of colchicine through hydrogen and hydrophobic interactions.
秋水仙碱结合位点抑制剂（CBSIs）是潜在的微管靶向剂（MTAs），其可以克服多药耐药性，提高水溶性并降低大多数MTAs面临的毒性。设计、合成了新型四氢喹喔啉磺酰胺衍生物，并对其抗增殖活性进行了评估。MTT法检测结果表明，一些衍生物对HT-29细胞系表现出中度至强抑制活性。其中，化合物I-7是活性最强的化合物。此外，I-7抑制微管蛋白聚合，扰乱微管网络，破坏有丝分裂纺锤体的形成并使细胞周期停滞在G2/M期。然而，I-7并未诱导细胞凋亡。此外，ADME预测表明I-7具有良好的理化性质和药代动力学性质。详细的分子对接证实I-7通过氢键和疏水相互作用靶向秋水仙碱位点。
