2. Academic Validation
  3. Design, synthesis and anticancer properties of isocombretapyridines as potent colchicine binding site inhibitors

Design, synthesis and anticancer properties of isocombretapyridines as potent colchicine binding site inhibitors

  • Eur J Med Chem. 2020 Jul 1;197:112308. doi: 10.1016/j.ejmech.2020.112308.
Wen Shuai 1,  Xinnan Li 1,  Wenlong Li 1,  Feijie Xu 1,  Lixue Lu 1,  Hong Yao 1,  Limei Yang 1,  Huajian Zhu 1,  Shengtao Xu 2,  Zheying Zhu 3,  Jinyi 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 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China. Electronic address: [email protected].
  • 3 Division of Molecular Therapeutics & Formulation, School of Pharmacy, The University of Nottingham, University Park Campus, Nottingham NG7 2RD, UK, UK.
  • 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: [email protected].
PMID: 32339853 DOI: 10.1016/j.ejmech.2020.112308
Abstract

A series of novel isocombretapyridines were designed and synthesized based on a lead compound isocombretastatin A-4 (isoCA-4) by replacing 3,4,5-trimethoxylphenyl with substituent pyridine nucleus. The MTT assay results showed that compound 20a possessed the most potent activities against all tested cell lines with IC50 values at nanomolar concentration ranges. Moreover, 20a inhibited tubulin polymerization at a micromolar level and also displayed potent anti-vascular activity in vitro. Further mechanistic studies were conducted to demonstrate that compound 20a could bind to the colchicine site of tubulin,and disrupte the cell microtubule networks, induce G2/M phase arrest, promote Apoptosis and depolarize mitochondria of K562 cells in a dose-dependent manner. Notably, 20a exhibited more potent tumor growth inhibition activity with 68.7% tumor growth inhibition than that of isoCA-4 in H22 allograft mouse model without apparent toxicity. The present results suggested that compound 20a may serve as a promising potent microtubule-destabilizing agent candidate for the development of therapeutics to treat Cancer.

Keywords

Anti-vascular; Antitumor; Colchicine binding site; Isocombretapyridines; Tubulin inhibitors.

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