Novel thienopyrimidine derivatives as dual EGFR and VEGFR-2 inhibitors: design, synthesis, anticancer activity and effect on cell cycle profile.
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 IC50 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.
['Mghwary|Aml E-S|AE|', 'Gedawy|Ehab M|EM|', 'Kamal|Aliaa M|AM|', 'Abuel-Maaty|Suzan M|SM|']
D000970:Antineoplastic Agents D017209:Apoptosis D002453:Cell Cycle D049109:Cell Proliferation D004305:Dose-Response Relationship, Drug D004354:Drug Screening Assays, Antitumor D066246:ErbB Receptors D006801:Humans D061986:MCF-7 Cells D062105:Molecular Docking Simulation D015394:Molecular Structure D047428:Protein Kinase Inhibitors D011743:Pyrimidines D013329:Structure-Activity Relationship D040301:Vascular Endothelial Growth Factor Receptor-2
EGFR VEGFR-2 design synthesis anticancer activity apoptosis Thieno[2,3-d]pyrimidines vandetanib