Discovery of thieno[2,3-d]pyrimidine-based derivatives as potent VEGFR-2 kinase inhibitors and anti-cancer agents

Bioorg Chem. 2021 Apr 27;112:104947. doi: 10.1016/j.bioorg.2021.104947. Online ahead of print.ABSTRACTVascular endothelial growth factor-2 (VEGFR-2) is considered one of the most important factors in tumor angiogenesis, and consequently a number of anticancer therapeutics have been developed to inhibit VEGFR-2 signaling. Accordingly, eighteen derivatives of thieno[2,3-d]pyrimidines having structural characteristics similar to VEGFR-2 inhibitors were designed and synthesized. Anticancer activities of the new derivatives were assessed against three human cancer cell lines (HCT-116, HepG2, and MCF-7) using MTT. Sorafenib was used as positive control. Compounds 17c-i, and 20b showed excellent anticancer activities against HCT-116 and HepG2 cell lines, while compounds 17i and 17g was found to be active against MCF-7 cell line. Compound 17f exhibited the highest cytotoxic activities against the examined cell lines, HCT-116 and HepG2, with IC50 values of 2.80 ± 0.16 and 4.10 ± 0.45 µM, respectively. Aiming at exploring the mechanism of action of these compounds, the most active cytotoxic derivatives were in vitro tested for their VEGFR-2 inhibitory activity. Compound 17f showed high activity against VEGFR-2 with an IC50 value of 0.23 ± 0.03 µM, that is equal to that of reference, sorafenib (IC50 = 0.23 ± 0.04 µM). Molecular docking studies also were performed to investigate the possible binding interactions of the target compounds with the active sites of VEGFR-2. The synthes...
Source: Bioorganic Chemistry - Category: Chemistry Authors: Source Type: research