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  3. Novel nicotinoyl pyrazoline derivates bearing N-methyl indole moiety as antitumor agents: Design, synthesis and evaluation

Novel nicotinoyl pyrazoline derivates bearing N-methyl indole moiety as antitumor agents: Design, synthesis and evaluation

  • Eur J Med Chem. 2018 Aug 5:156:722-737. doi: 10.1016/j.ejmech.2018.07.044.
Kun Chen 1,  Ya-Liang Zhang 2,  Jing Fan 3,  Xiang Ma 3,  Ya-Juan Qin 4,  Hai-Liang Zhu 5
Affiliations

Affiliations

  • 1 The Joint Research Center of Guangzhou University and Keele Univeristy for Gene Interference and Application, School of Life Science, Guangzhou University, Guangzhou, 510006, People's Republic of China. Electronic address: Kchennju@hotmail.com.
  • 2 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, People's Republic of China.
  • 3 The Joint Research Center of Guangzhou University and Keele Univeristy for Gene Interference and Application, School of Life Science, Guangzhou University, Guangzhou, 510006, People's Republic of China.
  • 4 Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, People's Republic of China. Electronic address: yjqin@njmu.edu.cn.
  • 5 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, People's Republic of China. Electronic address: zhuhl@nju.edu.cn.
PMID: 30041136 DOI: 10.1016/j.ejmech.2018.07.044
Abstract

In the present work, twenty-five nicotinoyl pyrazoline derivates bearing N-methyl indole moiety have been designed and synthesized. The biological evaluation of these compounds as tubulin assembly inhibitors revealed that most of them were potential antitumor agents. Among them, compound 28 exhibited most potency against Cancer cell line panels (GI50 = 29-90 nM for HeLa, HepG2 and MCF-7 cells) without toxicity to non-tumor cells (CC50 > 300 μM for 293 T cell), bound to the colchicine site of tubulin and displayed excellent inhibitory activity in tubulin assembly assay (IC50 = 1.6 μM, better than CA-4). Molecular dynamics simulation was carried out to validate the docking pose of compound 28 with tubulin crystalline. Further investigation on HepG2 and HeLa cells demonstrated that compound 28 could cause mitosis arrest to G2/M phase, and subsequently induced cell Apoptosis. The efficiency in vivo of compound 28 was also evaluated on HeLa-Xenograft nude mice, and the relative tumor inhibition ration was up to 61.52% without noticeable weight loss and tissue damage (examined by H&E staining), which was comparable to CA-4 (inhibited 59.92%). In brief, compound 28 is a promising candidate for tumor therapy as tubulin assembly inhibitor.

Keywords

Cell cycle arrest; Molecular dynamics; Nicotinoyl pyrazoline; Tubulin assembly inhibition; Xenograft model.

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