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  3. Discovery of novel N-benzylbenzamide derivatives as tubulin polymerization inhibitors with potent antitumor activities

Discovery of novel N-benzylbenzamide derivatives as tubulin polymerization inhibitors with potent antitumor activities

  • Eur J Med Chem. 2021 Apr 15:216:113316. doi: 10.1016/j.ejmech.2021.113316.
Huajian Zhu 1,  Wenlong Li 1,  Wen Shuai 1,  Yang Liu 1,  Limei Yang 1,  Yuchen Tan 1,  Tiandong Zheng 1,  Hong Yao 1,  Jinyi Xu 1,  Zheying Zhu 2,  Dong-Hua Yang 3,  Zhe-Sheng Chen 3,  Shengtao Xu 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China.
  • 2 Division of Molecular Therapeutics & Formulation, School of Pharmacy, The University of Nottingham, University Park Campus, Nottingham NG7 2RD, UK.
  • 3 College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, New York, 11439, United States.
  • 4 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China. Electronic address: cpuxst@cpu.edu.cn.
PMID: 33676300 DOI: 10.1016/j.ejmech.2021.113316
Abstract

A series of novel N-benzylbenzamide derivatives were designed and synthesized as tubulin polymerization inhibitors. Among fifty-one target compounds, compound 20b exhibited significant antiproliferative activities with IC50 values ranging from 12 to 27 nM against several Cancer cell lines, and possessed good plasma stability and satisfactory physicochemical properties. Mechanism studies demonstrated that 20b bound to the colchicine binding site and displayed potent anti-vascular activity. Notably, the corresponding disodium phosphate 20b-P exhibited an excellent safety profile with the LD50 value of 599.7 mg/kg (i.v. injection), meanwhile, it significantly inhibited tumor growth and decreased microvessel density in liver Cancer cell H22 allograft mouse model without obvious toxicity. Collectively, 20b and 20b-P are novel promising anti-tubulin agents with more druggable properties and deserve to be further investigated for Cancer therapy.

Keywords

Anti-vascular; Antitumor; Druggability; N-benzylbenzamide; Tubulin inhibitors.

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