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

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.
Shatha Hallal Al-Ziyadi 1,  Ahmed H Halawa 2,  Amany Belal 3,  Nisreen Khalid Aref Albezrah 4,  Ahmad J Obaidullah 5,  Nashwa S Abdelshafi 6,  Hossa F Al-Shareef 7,  Ahmed B M Mehany 8,  Saber M Hassan 2,  Walid E Elgammal 2
Affiliations

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.
PMID: 40949276 DOI: 10.1021/acsomega.5c03503
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.

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