Design and synthesis of thiadiazoles as anticancer, apoptotic, and VEGFR-2 inhibitors.

Abstract

Background: Vascular endothelial growth factor receptor (VEGFR-2) inhibitors are critical in cancer therapy due to their role in suppressing tumor angiogenesis. Herein, we report a new series of thiadiazole-based derivatives as potential VEGFR-2 inhibitors with promising anticancer activity.

Methods: The synthesized compounds were evaluated for anti-proliferative activity against human cancer cell lines (HCT-116, MCF-7, and HepG-2), and WI-38 as normal cells. Sorafenib was used as a reference drug. VEGFR-2 inhibitory activity was determined, followed by cell cycle analysis, apoptosis assays, Q-RT-PCR analysis, and wound-healing assays. In silico molecular docking was conducted to explore binding interactions.

Results: Among the tested compounds, 13b exhibited potent anti-proliferative activity (IC₅₀: 3.98-11.81 µM) and strong VEGFR-2 inhibition (IC₅₀: 41.51 nM), surpassing sorafenib (IC₅₀: 53.32 nM). Cell cycle analysis revealed that 13b induced G2/M phase arrest in MCF-7 cells. Apoptosis levels increased from 2% to 52%, accompanied by a > 12-fold rise in the Bax/Bcl-2 ratio and activation of caspase-8/9. Additionally, 13b significantly suppressed MCF-7 cell migration, with only 5.28% wound closure. In silico studies confirmed its strong VEGFR-2 binding interactions.

Conclusion: Thiadiazole-based derivatives, particularly compound 13b, exhibit potent VEGFR-2 inhibition, anti-proliferative effects, apoptosis induction, and anti-migratory activity, supporting their potential as promising anticancer agents.