State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
Department of Organic Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, and School of Chemistry and Pharmacy, Guangxi Normal University, Guilin 541004, PR China.
Bioorg Chem. 2019 Mar;83:380-390. doi: 10.1016/j.bioorg.2018.10.027. Epub 2018 Oct 23.
A series of novel quinazolines as tubulin inhibitors occupying three zones of colchicine domain have been designed and synthesized inspired by the recently disclosed crystal structure of verubulin analogue 6 with tubulin. Among the newly synthesized compounds, 19c showed noteworthy potency against K562, HepG2, KB, HCT-8 and MDB-MB-231 cancer cells. In vitro microtubule polymerization assays identified 19c as a potent tubulin assembly inhibitor, the binding mode of which with tubulin was confirmed by molecular modeling studies to occupy three zones of tubulin domain. Furthermore, 19c disrupted the intracellular microtubule network, caused G2/M phase arrest, induced cell apoptosis and depolarized mitochondria of K562 cells. 19c also reduced the cell migration and disrupted the capillary-like tube formation of human umbilical vein endothelial cells (HUVECs). Importantly, 19c significantly and dose dependently inhibited tumor growth in H22 liver cancer xenograft mouse model. All these results suggested that 19c deserves further research as a novel and potential anti-tubulin agent for the treatment of cancers.
受最近公开的与微管蛋白结合的长春瑞滨类似物 6 的晶体结构的启发，设计并合成了一系列新型喹唑啉类化合物，作为占据秋水仙碱结构域三个区域的微管蛋白抑制剂。在所合成的新化合物中，化合物 19c 对 K562、HepG2、KB、HCT-8 和 MDB-MB-231 癌细胞表现出显著的活性。体外微管聚合实验鉴定出 19c 是一种有效的微管蛋白组装抑制剂，其与微管蛋白的结合模式通过分子建模研究得到证实，可占据微管蛋白结构域的三个区域。此外，19c 破坏了细胞内的微管网络，导致 G2/M 期停滞，诱导细胞凋亡和 K562 细胞线粒体去极化。19c 还减少了细胞迁移并破坏了人脐静脉内皮细胞（HUVEC）的毛细血管样管状形成。重要的是，19c 显著且剂量依赖性地抑制了 H22 肝癌异种移植小鼠模型中的肿瘤生长。所有这些结果表明，19c 值得进一步研究，作为一种新型潜在的抗微管蛋白药物，用于癌症治疗。
