Synthesis, biological evaluation and molecular docking of benzimidazole grafted benzsulfamide-containing pyrazole ring derivatives as novel tubulin polymerization inhibitors

Bioorg Med Chem. 2019 Feb 1;27(3):502-515. doi: 10.1016/j.bmc.2018.12.031.

Yan-Ting Wang ¹, Tian-Qi Shi ², Hai-Liang Zhu ³, Chang-Hong Liu ⁴

Affiliations

1 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China; Department of Environmental Science & Engineering, Fudan University, Shanghai 200433, PR China.
2 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China.
3 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China. Electronic address: zhuhl@nju.edu.cn.
4 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China. Electronic address: chliu@nju.edu.cn.

PMID: 30606674 DOI: 10.1016/j.bmc.2018.12.031

Abstract

Tubulin-targeting drugs have increasingly become the focus of Anticancer drugs research. Twenty-five novel benzimidazole grafted benzsulfamide-containing pyrazole ring derivatives were synthesized and evaluated for bioactivity as potential tubulin polymerization inhibitors. Among them, compound 30 showed the most excellent inhibition against tubulin assembly (IC₅₀ = 1.52 μM) and in vitro growth inhibitory activity against a panel of four human Cancer cell lines (IC₅₀ = 0.15, 0.21, 0.33 and 0.17 μM, respectively for A549, Hela, HepG2 and MCF-7). It could also validly induce A549 cell Apoptosis, cause cell cycle arrest in G2/M phase and disrupt the cellular microtubule network. These results, along with molecular docking data, provided an important basis for further optimization of compound 30 as a potential Anticancer agent.

Keywords

Apoptosis; Benzimidazole; Benzsulfamide; Inhibition; Molecular docking; Pyrazole; Tubulin.

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