Synthesis and bioevaluation study of novel N-methylpicolinamide and thienopyrimidine derivatives as selectivity c-Met kinase inhibitors |
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Authors: | Linxiao Wang Shan Xu Xiuying Chen Xiaobo Liu Yongli Duan Dejia Kong Dandan Zhao Pengwu Zheng Qidong Tang Wufu Zhu |
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Institution: | 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 |
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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. |
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Keywords: | Thienopyrimidine Pyridazinone c-Met Bioevaluation |
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