Novel thienopyrimidine derivatives as dual EGFR and VEGFR-2 inhibitors: design, synthesis, anticancer activity and effect on cell cycle profile
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Date
2019
Authors
Mghwary A.E.-S.
Gedawy E.M.
Kamal A.M.
Abuel-Maaty S.M.
Journal Title
Journal ISSN
Volume Title
Type
Article
Publisher
Taylor and Francis Ltd
Series Info
Journal of Enzyme Inhibition and Medicinal Chemistry
34
34
Scientific Journal Rankings
Abstract
Aim: Design and synthesis of thienopyrimidine derivatives as dual EGFR and VEGFR-2 inhibitors.Material and methods: A series of novel 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidine derivatives with different substituents on C-4 position was synthesized and evaluated for their anticancer activity against MCF-7 cell line. EGFR, VEGFR-2 inhibitory assay, the cell cycle analysis and apoptosis induction ability of the most potent compound 5f were evaluated.Results: Most of the compounds showed moderate to significant anticancer activity. Compound 5f exhibited the most potent anticancer activity being 1.73- and 4.64-folds more potent than erlotinib and doxorubicin, respectively. Compound 5f showed potent EGFR inhibitory activity being 1.18-folds more potent than reference standard erlotinib and it also showed good VEGFR-2 inhibitory activity at the micromolar level with IC 50 value 1.23��M. Compound 5f caused induction of cell cycle arrest at G2/M phase and accumulation of cells in pre-G1 phase. Compound 5f induced cellular apoptosis. � 2019, � 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
Description
Scopus
Keywords
anticancer activity, apoptosis, design, EGFR, synthesis, Thieno[2,3-d]pyrimidines, vandetanib, VEGFR-2, 3 [(6,7,8,9 tetrahydro 5h cyclohepta[4,5]thieno[2,3 d]pyrimidin 4 yl)oxy]aniline, 4 (2 chlorophenoxy) 6,7,8,9 tetrahydro 5h cyclohepta[4,5]thieno[2,3 d]pyrimidine, 4 (4 bromophenoxy) 6,7,8,9 tetrahydro 5h cyclohepta[4,5]thieno[2,3 d]pyrimidine, 4 (4 chloro 3 methylphenoxy) 6,7,8,9 tetrahydro 5h cyclohepta[4,5]thieno[2,3 d]pyrimidine, 4 (4 chlorophenoxy) 6,7,8,9 tetrahydro 5h cyclohepta[4,5]thieno[2,3 d]pyrimidine, 4 (4 fluorophenoxy) 6,7,8,9 tetrahydro 5h cyclohepta[4,5]thieno[2,3 d]pyrimidine, 4 (4 methoxyphenoxy) 6,7,8,9 tetrahydro 5h cyclohepta[4,5]thieno[2,3 d]pyrimidine, 4 (4 nitrophenoxy) 6,7,8,9 tetrahydro 5h cyclohepta[4,5]thieno[2,3 d]pyrimidine, 4 (4 tolyloxy) 6,7,8,9 tetrahydro 5h cyclohepta[4,5]thieno[2,3 d]pyrimidine, 4 (o tolyloxy) 6,7,8,9 tetrahydro 5h cyclohepta[4,5]thieno[2,3 d]pyrimidine, 4 [(6,7,8,9 tetrahydro 5h cyclohepta[4,5]thieno[2,3 d]pyrimidin 4 yl)amino]benzenesulfonamide, 4 [(6,7,8,9 tetrahydro 5h cyclohepta[4,5]thieno[2,3 d]pyrimidin 4 yl)oxy]aniline, antineoplastic agent, doxorubicin, epidermal growth factor receptor, epidermal growth factor receptor kinase inhibitor, erlotinib, gefitinib, lapatinib, n (4 methylpyrimidin 2 yl) 4 [(6,7,8,9 tetrahydro 5h cyclohepta[4,5]thieno[2,3 d]pyrimidin 4 yl)amino]benzenesulfonamide, n (pyrimidin 2 yl) 4 [(6,7,8,9 tetrahydro 5h cyclohepta[4,5] thieno[2,3 d]pyrimidin 4 yl)amino]benzenesulfonamide, pyrimidine derivative, unclassified drug, vandetanib, vasculotropin receptor 2, vasculotropin receptor 2 inhibitor, antineoplastic agent, EGFR protein, human, epidermal growth factor receptor, KDR protein, human, protein kinase inhibitor, pyrimidine derivative, thienopyrimidine, vasculotropin receptor 2, antineoplastic activity, apoptosis, Article, carbon nuclear magnetic resonance, cell cycle, cell cycle arrest, cell cycle G2 phase, cell cycle M phase, chlorination, controlled study, drug design, drug synthesis, elemental analysis, enzyme inhibition, heating, human, human cell, IC50, MCF-7 cell line, MTT assay, nucleophilicity, priority journal, proton nuclear magnetic resonance, reaction analysis, substitution reaction, antagonists and inhibitors, cell cycle, cell proliferation, chemical structure, chemistry, dose response, drug effect, drug screening, metabolism, molecular docking, structure activity relation, synthesis, Antineoplastic Agents, Apoptosis, Cell Cycle, Cell Proliferation, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, ErbB Receptors, Humans, MCF-7 Cells, Molecular Docking Simulation, Molecular Structure, Protein Kinase Inhibitors, Pyrimidines, Structure-Activity Relationship, Vascular Endothelial Growth Factor Receptor-2