Development of New Thiadiazole Derivatives as VEGFR-2 Inhibitors With Anticancer and Proapoptotic Activities‏

Abstract

A series of thiadiazole-based derivatives were synthesized and evaluated for their potential as VEGFR-2 inhibitors and anticancer agents. Among them, compound 7b demonstrated significant cytotoxic activity against MCF-7 breast cancer cells, with an IC₅₀ value of 6.13 µM, surpassing that of the reference drug sorafenib (IC₅₀: 7.26 µM). Compound 7b also exhibited potent VEGFR-2 inhibition with an IC₅₀ of 40.65 nM, outperforming sorafenib (IC₅₀: 53.32 nM). Further investigation into the mechanism of action revealed that compound 7b induced significant changes in the cell-cycle distribution of MCF-7 cells, causing G1 arrest and delaying progression through the G2/M phase. Apoptosis analysis demonstrated that compound 7b primarily induced late apoptosis (55.90%) and necrosis (21.81%), with only 22.26% of cells remaining viable. Treatment with 7b increased the expression of the proapoptotic gene BAX (4.19 ± 0.34-fold) and suppressed the expression of the antiapoptotic gene Bcl-2 (0.38 ± 0.02-fold), resulting in a dramatic increase in the BAX/Bcl-2 ratio (11.03 ± 1.66-fold). Additionally, caspase-8 and caspase-9 levels were elevated by 2.99 ± 0.22-fold and 4.13 ± 0.11-fold, respectively, confirming activation of both intrinsic and extrinsic apoptotic pathways. In conclusion, compound 7b is a potent VEGFR-2 inhibitor with promising anticancer activity, demonstrating cytotoxicity, inhibition of cell migration, and induction of apoptosis in MCF-7 cells. These results suggest that compound 7b has the potential to be developed as a therapeutic agent for breast cancer treatment, warranting further in vivo and mechanistic studies.