Sakineh Dadashpour1,2, Tuba Tϋylϋ Kϋçϋkkılınç3, Beyza Ayazgök3, Seyed Jalal Hosseinimehr4, Ann M Chippindale5, Alireza Foroumadi6, Hamid Irannejad1. 1. Department of Medicinal Chemistry, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran. 2. Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran. 3. Department of Biochemistry, Faculty of Pharmacy, Hacettepe University, Sihhiye, Ankara 06100, Turkey. 4. Department of Radiopharmacy, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran. 5. Department of Chemistry, University of Reading, Whiteknights, Reading, Berks RG6 6AD, UK. 6. Department of Medicinal Chemistry, Faculty of Pharmacy and The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.
Abstract
Aim: Mesenchymal-epithelial transition factor (c-Met)/HGF overactivation is involved in diverse human cancers. Materials & methods: Herein, we report the synthesis and biological evaluation of thiomethylpyridine-linked triazolotriazines as c-Met kinase inhibitors. Results: Compounds 10b and 11e were more potent than crizotinib on HepG2 cells with IC50 values of 0.74 and 0.71 μM in the MTT assay, respectively. Interestingly, all of the target compounds displayed IC50 values in the range of 3.9-11.1 nM in the c-Met kinase inhibition assay which were lower than the value for crizotinib (11.1 nM). Conclusion: Target compound 10b can be considered as a leading drug candidate due to its lower IC50 values than crizotinib in both HGF-induced proliferation and c-Met kinase inhibition assays.
Aim: Mesenchymal-epithelial transition factor (c-Met)/HGF overactivation is involved in diverse humancancers. Materials & methods: Herein, we report the synthesis and biological evaluation of thiomethylpyridine-linked triazolotriazines as c-Met kinase inhibitors. Results: Compounds 10b and 11e were more potent than crizotinib on HepG2 cells with IC50 values of 0.74 and 0.71 μM in the MTT assay, respectively. Interestingly, all of the target compounds displayed IC50 values in the range of 3.9-11.1 nM in the c-Met kinase inhibition assay which were lower than the value for crizotinib (11.1 nM). Conclusion: Target compound 10b can be considered as a leading drug candidate due to its lower IC50 values than crizotinib in both HGF-induced proliferation and c-Met kinase inhibition assays.