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Newly synthesized sulfonamide derivatives, particularly compounds 3a, 6, and 15, exhibit potent and selective anticancer activity by inhibiting VEGFR-2 and EGFR kinases and inducing apoptosis. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

August 25, 2025ACS Omega7 citationsOpen Access

Novel Sulfonamide Derivatives as Anticancer Agents, VEGFR-2 Inhibitors, and Apoptosis Triggers: Design, Synthesis, and Computational Studies

SAShatha Hallal Al-Ziyadi AHAhmed H. Halawa ABAmany Belal

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Abstract

Background: 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.Objective: This study aimed to design, synthesize, and evaluate a novel series of sulfonamide derivatives as potential VEGFR-2 inhibitors with anticancer activity.Methods: 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.Results: Among the tested compounds, 3a, 6, and 15 exhibited potent cytotoxicity against all cancer cell lines, with compound 6 showing IC 50 values of 3.53, 3.33, and 4.31 M against HCT-116, HepG-2, and MCF-7, respectively.These compounds showed minimal cytotoxicity against WI-38 cells (IC 50 > 69 M), indicating favorable selectivity.Compound 15 exhibited the strongest VEGFR-2 inhibition (IC 50 = 0.0787 M), while compound 3a was the most potent EGFR inhibitor (IC 50 = 0.17 M).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.Conclusion: 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.

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