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.

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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.

Full Text link: https://t.ly/y6MXy

Date issued: 2019

Scientific Journal Rankings: Click Here

Doi: https://doi.org/10.1080/14756366.2019.1593160 PubMed ID 30919701

Publisher: Taylor and Francis Ltd

Series Info: Journal of Enzyme Inhibition and Medicinal Chemistry
34

Type: Article

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

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.