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

Shatha Hallal Al-Ziyadi; Ahmed H Halawa; Amany Belal; Nisreen Khalid Aref Albezrah; Ahmad J Obaidullah; Nashwa S Abdelshafi; Hossa F Al-Shareef; Ahmed B M Mehany; Saber M Hassan; Walid E Elgammal

doi:10.1021/acsomega.5c03503

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

ACS Omega. 2025 Aug 25;10(35):39772-39790. doi: 10.1021/acsomega.5c03503. eCollection 2025 Sep 9.

Affiliations

¹ Department of Obstetric & Gynecology/College of Medicine, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
² Chemistry Department, Faculty of Science (Boys), Al-Azhar University, P.O. Box 11884 Nasr City, Cairo, Egypt.
³ Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
⁴ Department of Obstetric & Gynecology. College of Medicine, Taif University, P.O. Box 11099, Taif 21944. Saudi Arabia.
⁵ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
⁶ Chemistry Department, Faculty of Education, Ain Shams University, Roxy, 11711 Cairo, Egypt.
⁷ Department of Chemistry, Faculty of Sciences, Umm Al-Qura University, P.O. Box 21955 Mecca, Makkah, Saudia Arabia.
⁸ Zoology Department, Faculty of Science (Boys), Al-Azhar University, Nasr City 11884, Cairo, Egypt.

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 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.

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.