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 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.
Highlights
Protein kinases have a crucial role in signal transduction pathways that mediate several cellular functions1
epidermal growth factor receptor (EGFR)-signaling pathways stimulate vascular endothelial growth factor (VEGF)8 which is considered as the key inducer of tumor angiogenesis
Angiogenesis is the process of blood vessel formation that starts with dilatation and increase in the vascular permeability of the existing capillaries and venules
Summary
Protein kinases have a crucial role in signal transduction pathways that mediate several cellular functions. EGFR-signaling pathways stimulate vascular endothelial growth factor (VEGF) which is considered as the key inducer of tumor angiogenesis. Binding of VEGF with VEGFR-2 stimulates signaling pathways (p38MAPK, PI3K/Akt) that mediate several cellular functions such as proliferation, migration, survival and vascular permeability for the tumor cell and promotes angiogenesis. It has been demonstrated that VEGFR-2 are highly expressed in cancer cells especially endothelial cells. It has been demonstrated that VEGFR-2 are highly expressed in cancer cells especially endothelial cells11 Both glycoproteins, EGFR and VEGFR-2 are closely related; inhibition of EGFR decreasing the expression of VEGF, whereas targeting of VEGFR-2 potentiate the anticancer activity of EGFR inhibitors. Several EGFR/VEGFR-2 dual inhibitors have been discovered, such as vandetanib
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Journal of Enzyme Inhibition and Medicinal Chemistry
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
