Chen Zhong, Geng Da-Wei, Yuan Tang-Bo, Yu Chen, Cai Da-Wei, Yin Yong, Shen Qiang
Department of Orthopaedics, Shanghai General Hospital of Nanjing Medical University, Shanghai, China; Department of Orthopaedics, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China.
Department of Orthopaedics, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China.
Bioorg Med Chem Lett. 2025 Jan 1;115:130031. doi: 10.1016/j.bmcl.2024.130031. Epub 2024 Nov 16.
Novel N-substituent diphenylamine derivatives as tubulin inhibitors targeting colchicine-binding site have been designed based on structural simplification and structural fusing strategy. Most designed compounds exhibited the moderate or potent antiproliferative activities against five cancer cell lines. Among them, compound 4k displayed the significant selectivity for osteosarcoma cells MG-63 and U2OS with the IC value of 0.08-0.14 μM. Further investigations verified 4k could inhibit tubulin polymerization by targeting colchicine binding site. Meanwhile, compound 4k not only effectively induced tumor cell cycle arrest at the G2/M phase, but also slightly induced cell apoptosis. These results indicated that N-substituent of diphenylamine derivatives are deserved for further development as tubulin colchicine binding site inhibitors.
基于结构简化和结构融合策略，设计了新型N-取代二苯胺衍生物作为靶向秋水仙碱结合位点的微管蛋白抑制剂。大多数设计的化合物对五种癌细胞系表现出中等或强效的抗增殖活性。其中，化合物4k对骨肉瘤细胞MG-63和U2OS表现出显著的选择性，IC值为0.08-0.14μM。进一步研究证实4k可通过靶向秋水仙碱结合位点抑制微管蛋白聚合。同时，化合物4k不仅有效地诱导肿瘤细胞周期停滞在G2/M期，还轻微诱导细胞凋亡。这些结果表明二苯胺衍生物的N-取代基作为微管蛋白秋水仙碱结合位点抑制剂值得进一步开发。
