1. Novel thienopyrimidine derivatives as dual EGFR and VEGFR-2 inhibitors: design, synthesis, anticancer activity and effect on cell cycle profile.
- Author
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Mghwary AE, Gedawy EM, Kamal AM, and Abuel-Maaty SM
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Apoptosis drug effects, Cell Cycle drug effects, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, ErbB Receptors antagonists & inhibitors, ErbB Receptors metabolism, Humans, MCF-7 Cells, Molecular Docking Simulation, Molecular Structure, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Pyrimidines chemical synthesis, Pyrimidines chemistry, Structure-Activity Relationship, Vascular Endothelial Growth Factor Receptor-2 metabolism, Antineoplastic Agents pharmacology, Protein Kinase Inhibitors pharmacology, Pyrimidines pharmacology, Vascular Endothelial Growth Factor Receptor-2 antagonists & inhibitors
- 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 µM. 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.- Published
- 2019
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