新型磺胺衍生物作为抗癌剂、VEGFR-2抑制剂和凋亡触发剂：设计、合成及计算研究
Novel Sulfonamide Derivatives as Anticancer Agents, VEGFR‑2 Inhibitors, and Apoptosis Triggers: Design, Synthesis, and Computational Studies.
作者信息
Al-Ziyadi Shatha Hallal, Halawa Ahmed H, Belal Amany, Albezrah Nisreen Khalid Aref, Obaidullah Ahmad J, Abdelshafi Nashwa S, Al-Shareef Hossa F, Mehany Ahmed B M, Hassan Saber M, Elgammal Walid E
机构信息
Department of Obstetric & Gynecology/College of Medicine, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
Chemistry Department, Faculty of Science (Boys), Al-Azhar University, P.O. Box 11884 Nasr City, Cairo, Egypt.
出版信息
ACS Omega. 2025 Aug 25;10(35):39772-39790. doi: 10.1021/acsomega.5c03503. eCollection 2025 Sep 9.
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, , , and exhibited potent cytotoxicity against all cancer cell lines, with compound showing IC 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 (IC > 69 μM), indicating favorable selectivity. Compound exhibited the strongest VEGFR-2 inhibition (IC = 0.0787 μM), while compound was the most potent EGFR inhibitor (IC = 0.17 μM). Flow cytometry revealed that compounds , , and 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 , , and represent promising VEGFR-2-targeting sulfonamides with potent, selective anticancer activity and favorable pharmacokinetic and safety profiles, warranting further development as lead candidates.
背景
血管内皮生长因子受体-2（VEGFR-2）在血管生成和肿瘤进展中起关键作用。靶向VEGFR-2仍然是抗癌药物开发的有效策略。
目的
本研究旨在设计、合成和评估一系列新型磺酰胺衍生物，作为具有抗癌活性的潜在VEGFR-2抑制剂。
方法
通过多步有机反应合成了一系列磺酰胺衍生物。通过光谱方法确认了它们的结构。使用MTT法评估了它们对HCT-116、HepG-2和MCF-7癌细胞系的体外抗增殖活性。通过对正常WI-38成纤维细胞的细胞毒性评估选择性。对显示出强效抗癌活性的化合物进一步检测其对VEGFR-2和EGFR激酶的抑制作用、细胞周期进程和凋亡诱导情况。分子对接和计算机辅助ADMET/毒性分析支持了药理学评估。
结果
在测试的化合物中，[具体化合物1]、[具体化合物2]和[具体化合物3]对所有癌细胞系均表现出强效细胞毒性，化合物[具体化合物1]对HCT-116、HepG-2和MCF-7的IC50值分别为3.53、3.33和4.31μM。这些化合物对WI-38细胞的细胞毒性最小（IC50>69μM），表明具有良好的选择性。化合物[具体化合物3]表现出最强的VEGFR-2抑制作用（IC50=0.0787μM），而化合物[具体化合物2]是最有效的EGFR抑制剂（IC50=0.17μM）。流式细胞术显示，化合物[具体化合物1]、[具体化合物2]和[具体化合物3]诱导G2/M期和G1期前停滞，并显著增强凋亡。对接研究表明与VEGFR-2有良好的结合相互作用。ADMET预测表明具有可接受的类药性和安全性。
结论
化合物[具体化合物1]、[具体化合物2]和[具体化合物3]代表了有前景的靶向VEGFR-2的磺酰胺类化合物，具有强效、选择性抗癌活性以及良好的药代动力学和安全性，值得作为先导候选物进一步开发。
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