2. Academic Validation
  3. Design and evaluation of novel N-substituent diphenylamine derivatives as tubulin colchicine binding site inhibitors

Design and evaluation of novel N-substituent diphenylamine derivatives as tubulin colchicine binding site inhibitors

  • Bioorg Med Chem Lett. 2025 Jan 1:115:130031. doi: 10.1016/j.bmcl.2024.130031.
Zhong Chen 1,  Da-Wei Geng 2,  Tang-Bo Yuan 2,  Chen Yu 2,  Da-Wei Cai 2,  Yong Yin 3,  Qiang Shen 4
Affiliations

Affiliations

  • 1 Department of Orthopaedics, Shanghai General Hospital of Nanjing Medical University, Shanghai, China; Department of Orthopaedics, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China.
  • 2 Department of Orthopaedics, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China.
  • 3 Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: yongyin@cpu.edu.cn.
  • 4 Department of Orthopaedics, Shanghai General Hospital of Nanjing Medical University, Shanghai, China. Electronic address: qiangshen1231@163.com.
PMID: 39557311 DOI: 10.1016/j.bmcl.2024.130031
Abstract

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 IC50 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.

Keywords

Antitumor; Colchicine-binding site; N-substituent of diphenylamine; Tubulin.

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