2. Academic Validation
  3. Synthesis and bioevaluation study of novel N-methylpicolinamide and thienopyrimidine derivatives as selectivity c-Met kinase inhibitors

Synthesis and bioevaluation study of novel N-methylpicolinamide and thienopyrimidine derivatives as selectivity c-Met kinase inhibitors

  • Bioorg Med Chem. 2018 Jan 1;26(1):245-256. doi: 10.1016/j.bmc.2017.11.039.
Linxiao Wang 1,  Shan Xu 1,  Xiuying Chen 2,  Xiaobo Liu 1,  Yongli Duan 1,  Dejia Kong 1,  Dandan Zhao 1,  Pengwu Zheng 1,  Qidong Tang 3,  Wufu Zhu 4
Affiliations

Affiliations

  • 1 Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China.
  • 2 College of Pharmaceutical Sciences, Zhengzhou University, Key Laboratory of Advanced Drug Preparation Technologies, Zhengzhou University, Henan, Zhengzhou 450001, China.
  • 3 Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China. Electronic address: tangqidongcn@126.com.
  • 4 Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China. Electronic address: zhuwf@jxstnu.edu.cn.
PMID: 29203143 DOI: 10.1016/j.bmc.2017.11.039
Abstract

Four series of N-methylpicolinamide moiety and thienopyrimidine moiety bearing pyridazinone were designed and synthesized and evaluated for the IC50 values against three Cancer cell lines (A549, HepG2 and MCF-7) and some selected compounds were further evaluated for the activity against c-Met, Flt-3, VEGFR-2, c-Kit and EGFR kinases. Three compounds (35, 39 and 43) showed more active than positive control Foretinib against A549, HepG2 and MCF-7 cell lines. The most promising compound 43 showed superior activity against A549, HepG2 and MCF-7, with the IC50 values of 0.58 ± 0.15 µM, 0.47 ± 0.06 µM and 0.74 ± 0.12 µM, which were 3.73-5.39-fold more activity than Foretinib, respectively. The experiments of enzyme-based showed that 43 restrain the c-Met selectively, with the IC50 values of 16 nM, which showed equal activity to Foretinib (14 nM) and better than the compound 5 (90 nM). Moreover, AO and Annexin V/PI staining and docking studies were carried out.

Keywords

Bioevaluation; N-Methylpicolinamide; Pyridazinone; Thienopyrimidine; c-Met.

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