Design, synthesis, anticancer evaluation, and molecular modelling studies of novel tolmetin derivatives as potential VEGFR-2 inhibitors and apoptosis inducers.

Novel tolmetin derivatives to were designed, synthesised, and evaluated for antiproliferative activity by NCI (USA) against a panel of 60 tumour cell lines. The cytotoxic activity of the most active tolmetin derivatives and was examined against HL-60, HCT-15, and UO-31 tumour cell lines. Compound was found to be the most potent derivative against HL-60, HCT-15, and UO-31 cell lines with IC values of 10.32 ± 0.55, 6.62 ± 0.35, and 7.69 ± 0.41 µM, respectively. Molecular modelling studies of derivative towards the VEGFR-2 active site were performed. Compound displayed high inhibitory activity against VEGFR-2 (IC = 0.20 µM). It extremely reduced the HUVECs migration potential exhibiting deeply reduced wound healing patterns after 72 h. It induced apoptosis in HCT-15 cells (52.72-fold). This evidence was supported by an increase in the level of apoptotic caspases-3, -8, and -9 by 7.808-, 1.867-, and 7.622-fold, respectively. Compound arrested the cell cycle in the G0/G1 phase. Furthermore, the ADME studies showed that compound possessed promising pharmacokinetic properties.