biostudies-literatureUnknown10(35)Al-Ziyadi SH<h4>Background</h4>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.<h4>Objective</h4>This study aimed to design, synthesize, and evaluate a novel series of sulfonamide derivatives as potential VEGFR-2 inhibitors with anticancer activity.<h4>Methods</h4>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.<h4>Results</h4>Among the tested compounds, <b>3a</b>, <b>6</b>, and <b>15</b> exhibited potent cytotoxicity against all cancer cell lines, with compound <b>6</b> 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 <b>15</b> exhibited the strongest VEGFR-2 inhibition (IC₅₀ = 0.0787 μM), while compound <b>3a</b> was the most potent EGFR inhibitor (IC₅₀ = 0.17 μM). Flow cytometry revealed that compounds <b>3a</b>, <b>6</b>, and <b>15</b> 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.<h4>Conclusion</h4>Compounds <b>3a</b>, <b>6</b>, and <b>15</b> represent promising VEGFR-2-targeting sulfonamides with potent, selective anticancer activity and favorable pharmacokinetic and safety profiles, warranting further development as lead candidates.ACS omega39772-39790https://www.ebi.ac.uk/biostudies/studies/S-EPMC12423892biostudies-literatureNovel Sulfonamide Derivatives as Anticancer Agents, VEGFR‑2 Inhibitors, and Apoptosis Triggers: Design, Synthesis, and Computational Studies.PMC12423892Hassan SMBelal AMehany ABMAl-Ziyadi SHAl-Shareef HFAbdelshafi NSElgammal WEAlbezrah NKAObaidullah AJHalawa AHfalseNovel Sulfonamide Derivatives as Anticancer Agents, VEGFR‑2 Inhibitors, and Apoptosis Triggers: Design, Synthesis, and Computational Studies.<h4>Background</h4>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.<h4>Objective</h4>This study aimed to design, synthesize, and evaluate a novel series of sulfonamide derivatives as potential VEGFR-2 inhibitors with anticancer activity.<h4>Methods</h4>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.<h4>Results</h4>Among the tested compounds, <b>3a</b>, <b>6</b>, and <b>15</b> exhibited potent cytotoxicity against all cancer cell lines, with compound <b>6</b> 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 <b>15</b> exhibited the strongest VEGFR-2 inhibition (IC₅₀ = 0.0787 μM), while compound <b>3a</b> was the most potent EGFR inhibitor (IC₅₀ = 0.17 μM). Flow cytometry revealed that compounds <b>3a</b>, <b>6</b>, and <b>15</b> 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.<h4>Conclusion</h4>Compounds <b>3a</b>, <b>6</b>, and <b>15</b> represent promising VEGFR-2-targeting sulfonamides with potent, selective anticancer activity and favorable pharmacokinetic and safety profiles, warranting further development as lead candidates.2025-01-01T00:00:00Z2025 Sep2026-06-01T23:32:52.418Z2026-05-24T03:07:07.121ZS-EPMC124238924094927610.1021/acsomega.5c03503