Discovery of thinopyrimidine-triazole conjugates as c-Met targeting and apoptosis inducing agents |
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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, PR China;1. Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University In Egypt, Cairo, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, 11562 Cairo, Egypt;1. Chemistry Department, Faculty of Education, Alexandria University, 21526 Alexandria, Egypt;2. Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt;3. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt;1. Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, International Joint Research Center for Intelligent Biosensor Technology and Health, College of Chemistry, Central China Normal University, Wuhan, 430079, PR China;2. Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, Jiangsu Simcere Pharmaceutical Co. Ltd, Nanjing, 210042, PR China;1. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China;2. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China |
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| Abstract: | Five series of N-methylpicolinamide moiety and thienopyrimidine moiety bearing triazole (21–26, 27–34, 35–41, 42–47 and 48–54) were designed and synthesized. And all the target compounds were evaluated for the IC50 values against three cancer cell lines (A549, HepG2 and MCF-7) and some selected compounds (43, 49 and 52) were further evaluated for the activity against c-Met, Flt-3, VEGFR-2, c-Kit and EGFR kinases. Moreover, SARs and docking studies indicated that thieno3,2-d]pyrimidine bearing triazole moiety was privileged structure for the activity. Especially, the Cl atom on the 4-C position of aryl group showed the best activity. The most promising compound 49 showed 3.7–5.4-fold more activity than the lead drug Foretinib against A549, HepG2 and MCF-7 cell lines, with the IC50 values of 0.9 ± 0.1 µM, 0.5 ± 0.1 µM and 1.1 ± 0.2 µM, respectively. And The experiments of enzyme-based showed that 49 inhibitor the c-Met selectively, with the IC50 values of 16 nM, which showed equal activity to Foretinib (14 nM). What’s more, According to the result of AO single staining and Annexin V/PI staining, it's claimed that the 49 could induce late apoptosis of HepG2 cells and by a concentration-dependent manner. |
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| Keywords: | Thienopyrimidine Triazole c-Met Antitumor activity Docking study Apoptosis |
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