Design, Synthesis and Cytotoxicity Screening of New Thiazole Derivatives as Potential Anticancer Agents through VEGFR-2 Inhibition

Z-configurated isomers are kinetically preferred molecules. Compounds with Z-configuration are contained in many natural products, biologically active compounds and as synthons for organic synthesis. Two series of new thiazole-based analogs were synthesized from appropriate starting materials hydrazinecarbothioamide derivatives (Z)-2a,b to be evaluated for their inhibitory activity towards VEGFR-2. The prepared thiazole compounds 3a-5b were screened for their cytotoxic potency against the MDA-MB-231 breast cancer cell line and their percentage inhibition against VEGFR-2. Compound 4d exhibited good VEGFR-2 inhibitory activity. A DNA flow cytometry analysis was conducted, and compound 4d demonstrated cell cycle arrest at the G1 and G2/M phases of the cell cycle profile and an apoptosis-inducing effect by increasing the percentage of pre-G1 phase. Compound 4d was further evaluated for its apoptosis-inducing effect by studying the effect on mitochondrial membrane potential (MMP) and p53 activation. It was found to boost the level of p53 and reduce the level of MMP compared with the untreated control cells.

Automated summary

Z-configurated isomers are preferred molecules with significant applications in natural products, biologically active compounds, and organic synthesis. In this study, new thiazole analogs were synthesized and evaluated for their inhibitory activity against breast cancer cells and VEGFR-2. Compound 4d showed strong VEGFR-2 inhibitory activity and induced apoptosis through cell cycle arrest.