Probing structural requirements for thiazole-based mimetics of sunitinib as potent VEGFR-2 inhibitors†

Abstract

Novel thiazole analogs 3a, 3b, 4, 5, 6a–g, 8a, 8b, 9a–c, 10a–d and 11 were designed and synthesized as molecular mimetics of sunitinib. In vitro antitumor activity of the obtained compounds was investigated against HepG2, HCT-116, MCF-7, HeP-2 and HeLa cancer cell lines. The obtained data showed that compounds 3b and 10c are the most potent members toward HepG2, HCT-116, MCF-7 and HeLa cells. Moreover, compounds 3a, 3b, 6g, 8a and 10c were assessed for their in vitro VEGFR-2 inhibitory activity. Results proved that compound 10c exhibited outstanding VEGFR-2 inhibition (IC₅₀ = 0.104 μM) compared to sunitinib. Compound 10c paused the G0–G1 phase of the cell cycle in HCT-116 and MCF-7 cells and the S phase in HeLa cells. Additionally, compound 10c elevated caspase-3/9 levels in HCT-116 and HeLa cells, leading to cancer cell death via apoptosis. Furthermore, compound 10c showed a significant reduction in tumor volume in Swiss albino female mice as an in vivo breast cancer model. Docking results confirmed the tight binding interactions of compound 10c with the VEGFR-2 binding site, with its binding energy surpassing that of sunitinib. In silico PK studies predicted compound 10c to have good oral bioavailability and a good drug score with low human toxicity risks.