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

摘要

>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.