Novel Sulfonamide Derivatives as Anticancer Agents, VEGFR‑2 Inhibitors, and Apoptosis Triggers: Design, Synthesis,...

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a pivotal role in angiogenesis and tumor progression. Targeting VEGFR-2 remains a validated strategy for anticancer drug development.

This study aimed to design, synthesize, and evaluate a novel series of sulfonamide derivatives as potential VEGFR-2 inhibitors with anticancer activity.

A series of sulfonamide derivatives were synthesized through multistep organic reactions. Their structures were confirmed by spectroscopic methods. In vitro antiproliferative activity was evaluated against HCT-116, HepG-2, and MCF-7 cancer cell lines using MTT assays. Selectivity was assessed via cytotoxicity against normal WI-38 fibroblasts. Compounds showing potent anticancer activity were further examined for VEGFR-2 and EGFR kinase inhibition, cell cycle progression, and apoptosis induction. Molecular docking and in silico ADMET/toxicity analyses supported the pharmacological evaluation.

Among the tested compounds, 3a, 6, and 15 exhibited potent cytotoxicity against all cancer cell lines, with compound 6 showing IC₅₀ values of 3.53, 3.33, and 4.31 μM against HCT-116, HepG-2, and MCF-7, respectively. These compounds showed minimal cytotoxicity against WI-38 cells (IC₅₀ > 69 μM), indicating favorable selectivity. Compound 15 exhibited the strongest VEGFR-2 inhibition (IC₅₀ = 0.0787 μM), while compound 3a was the most potent EGFR inhibitor (IC₅₀ = 0.17 μM). Flow cytometry revealed that compounds 3a, 6, and 15 induced G2/M and Pre-G1 phase arrest and significantly enhanced apoptosis. Docking studies demonstrated favorable binding interactions with VEGFR-2. ADMET predictions suggested acceptable drug-likeness and safety profiles.

Compounds 3a, 6, and 15 represent promising VEGFR-2-targeting sulfonamides with potent, selective anticancer activity and favorable pharmacokinetic and safety profiles, warranting further development as lead candidates.