Novel thienopyrimidine derivatives as dual EGFR and VEGFR-2 inhibitors: design, synthesis, anticancer activity and effect on cell cycle profile

Mghwary A.E.-S.Gedawy E.M.Kamal A.M.Abuel-Maaty S.M.Department of Pharmaceutical Organic ChemistryFaculty of PharmacyCairo UniversityCairoEgypt; Department of Pharmaceutical ChemistryFaculty of Pharmacy and Pharmaceutical IndustriesBadr University in Cairo BUCCairoEgypt; Department of Organic ChemistryFaculty of PharmacyOctober University for Modern Science and Arts (MSA)CairoEgypt2020-01-092020-01-09201914756366https://doi.org/10.1080/14756366.2019.1593160PubMed ID 30919701https://t.ly/y6MXyScopusAim: 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.Englishanticancer activityapoptosisdesignEGFRsynthesisThieno[2,3-d]pyrimidinesvandetanibVEGFR-23 [(6,7,8,9 tetrahydro 5h cyclohepta[4,5]thieno[2,3 d]pyrimidin 4 yl)oxy]aniline4 (2 chlorophenoxy) 6,7,8,9 tetrahydro 5h cyclohepta[4,5]thieno[2,3 d]pyrimidine4 (4 bromophenoxy) 6,7,8,9 tetrahydro 5h cyclohepta[4,5]thieno[2,3 d]pyrimidine4 (4 chloro 3 methylphenoxy) 6,7,8,9 tetrahydro 5h cyclohepta[4,5]thieno[2,3 d]pyrimidine4 (4 chlorophenoxy) 6,7,8,9 tetrahydro 5h cyclohepta[4,5]thieno[2,3 d]pyrimidine4 (4 fluorophenoxy) 6,7,8,9 tetrahydro 5h cyclohepta[4,5]thieno[2,3 d]pyrimidine4 (4 methoxyphenoxy) 6,7,8,9 tetrahydro 5h cyclohepta[4,5]thieno[2,3 d]pyrimidine4 (4 nitrophenoxy) 6,7,8,9 tetrahydro 5h cyclohepta[4,5]thieno[2,3 d]pyrimidine4 (4 tolyloxy) 6,7,8,9 tetrahydro 5h cyclohepta[4,5]thieno[2,3 d]pyrimidine4 (o tolyloxy) 6,7,8,9 tetrahydro 5h cyclohepta[4,5]thieno[2,3 d]pyrimidine4 [(6,7,8,9 tetrahydro 5h cyclohepta[4,5]thieno[2,3 d]pyrimidin 4 yl)amino]benzenesulfonamide4 [(6,7,8,9 tetrahydro 5h cyclohepta[4,5]thieno[2,3 d]pyrimidin 4 yl)oxy]anilineantineoplastic agentdoxorubicinepidermal growth factor receptorepidermal growth factor receptor kinase inhibitorerlotinibgefitiniblapatinibn (4 methylpyrimidin 2 yl) 4 [(6,7,8,9 tetrahydro 5h cyclohepta[4,5]thieno[2,3 d]pyrimidin 4 yl)amino]benzenesulfonamiden (pyrimidin 2 yl) 4 [(6,7,8,9 tetrahydro 5h cyclohepta[4,5] thieno[2,3 d]pyrimidin 4 yl)amino]benzenesulfonamidepyrimidine derivativeunclassified drugvandetanibvasculotropin receptor 2vasculotropin receptor 2 inhibitorantineoplastic agentEGFR protein, humanepidermal growth factor receptorKDR protein, humanprotein kinase inhibitorpyrimidine derivativethienopyrimidinevasculotropin receptor 2antineoplastic activityapoptosisArticlecarbon nuclear magnetic resonancecell cyclecell cycle arrestcell cycle G2 phasecell cycle M phasechlorinationcontrolled studydrug designdrug synthesiselemental analysisenzyme inhibitionheatinghumanhuman cellIC50MCF-7 cell lineMTT assaynucleophilicitypriority journalproton nuclear magnetic resonancereaction analysissubstitution reactionantagonists and inhibitorscell cyclecell proliferationchemical structurechemistrydose responsedrug effectdrug screeningmetabolismmolecular dockingstructure activity relationsynthesisAntineoplastic AgentsApoptosisCell CycleCell ProliferationDose-Response Relationship, DrugDrug Screening Assays, AntitumorErbB ReceptorsHumansMCF-7 CellsMolecular Docking SimulationMolecular StructureProtein Kinase InhibitorsPyrimidinesStructure-Activity RelationshipVascular Endothelial Growth Factor Receptor-2Novel thienopyrimidine derivatives as dual EGFR and VEGFR-2 inhibitors: design, synthesis, anticancer activity and effect on cell cycle profileArticlehttps://doi.org/10.1080/14756366.2019.1593160PubMed ID 30919701