Design, synthesis and biological evaluation of a novel tubulin inhibitor 7a3 targeting the colchicine binding site

European Journal of Medicinal Chemistry
Qinhuai LaiJinliang Yang

Abstract

Tubulin inhibitors that target the colchicine binding site continue to emerge as promising anticancer agents. In this study, based on the anti-proliferative activities, a novel tubulin inhibitor 7a3 targeting the colchicine binding site was designed, synthesized, and optimized from a series of novel cis-restricted pyrazole analogues of combretastatin A-4. The structure-activity relationships (SARs) of these newly synthesized compounds are summarized indicating that the methyl substituent at the N1 position and deamination were significantly important for the anti-proliferative efficacy. The optimized compound 7a3 exhibited the ability to arrest the cell cycle in the G2/M phase, induce cell apoptosis, and inhibit cell migration in tumour cells. The results of the immunofluorescence analysis using confocal microscopy and the tubulin polymerization assay revealed that tubulin assembly was disrupted by 7a3 in vitro. Furthermore, the targeting identification of 7a3 was illuminated by solving the crystal structure of 7a3 in complex with tubulin at a resolution of 3.2 Å (PDB code 5Z4U), which confirmed the result of molecular docking and further demonstrated that 7a3 binds to the site of colchicine. Moreover, the pharmacokinetic analy...Continue Reading

Citations

Jul 30, 2019·Expert Opinion on Therapeutic Patents·Kashif HaiderAhmed Kamal
Jan 18, 2020·Pharmaceuticals·Eavan C McLoughlin, Niamh M O'Boyle
Jan 21, 2021·Bioorganic & Medicinal Chemistry Letters·Ting ZhuSai-Yang Zhang
Dec 16, 2018·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Xiangping DengGuotao Tang

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