Elgammal Walid E, Elkady Hazem, Yousef Reda G, Eldehna Wagdy M, Husein Dalal Z, Amin Fatma G, Alsfouk Bshra A, Elkaeed Eslam B, Eissa Ibrahim H, Metwaly Ahmed M
Chemistry Department, Faculty of Science, Al-Azhar University Nasr City 11884, Cairo Egypt.
Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University Cairo 11884 Egypt
RSC Adv. 2025 May 7;15(18):14477-14498. doi: 10.1039/d5ra01223f. eCollection 2025 Apr 28.
Vascular endothelial growth factor receptor-2 (VEGFR-2) is a key regulator of tumor angiogenesis and has become an important target in anticancer drug development. In this study, novel nicotinamide-thiadiazol hybrids were synthesized and evaluated for their anti-breast cancer potential through VEGFR-2 inhibition. The compounds were assessed for their cytotoxicity against MDA-MB-231 and MCF-7 cell lines. Among the nicotinamide-thiadiazol hybrids, 7a exhibited the most potent anticancer activity, with IC values of 4.64 ± 0.3 μM in MDA-MB-231 and 7.09 ± 0.5 μM in MCF-7, showing comparable efficacy to sorafenib. VEGFR-2 inhibition assays confirmed strong inhibitory potential with an IC of 0.095 ± 0.05 μM. cell cycle analysis indicated that 7a induced S-phase arrest, while apoptosis assays demonstrated a substantial increase in late apoptotic cells (44.01%). Other mechanistic studies further confirmed the activation of the intrinsic apoptotic pathway, as evidenced by caspase-3 activation (8.2-fold), Bax upregulation (6.9-fold), and Bcl-2 downregulation (3.68-fold). Computational studies, including molecular docking and 200 ns molecular dynamics (MD) simulations, confirmed the stable interaction of 7a with VEGFR-2, showing binding affinities comparable to sorafenib. Further validation through MM-GBSA, ProLIF, PCAT, and FEL analyses reinforced its strong binding capability. Additionally, ADMET predictions suggested favorable pharmacokinetic properties, including good absorption, high plasma protein binding, and non-CYP2D6 inhibition. Moreover, toxicity analysis classified 7a as non-mutagenic and non-carcinogenic, with a lower predicted toxicity than sorafenib. Finally, density functional theory (DFT) calculations highlighted the structural stability and reactivity of 7a, further supporting its potential as a VEGFR-2 inhibitor. These findings suggest that 7a is a promising VEGFR-2 inhibitor with significant anticancer potential, favorable pharmacokinetics, and an improved safety profile. Further preclinical studies and structural modifications are warranted to optimize its therapeutic potential.
血管内皮生长因子受体-2（VEGFR-2）是肿瘤血管生成的关键调节因子，已成为抗癌药物研发的重要靶点。在本研究中，合成了新型烟酰胺-噻二唑杂化物，并通过抑制VEGFR-2评估其抗乳腺癌潜力。评估了这些化合物对MDA-MB-231和MCF-7细胞系的细胞毒性。在烟酰胺-噻二唑杂化物中，7a表现出最强的抗癌活性，在MDA-MB-231细胞中的IC值为4.64±0.3μM，在MCF-7细胞中的IC值为7.09±0.5μM，显示出与索拉非尼相当的疗效。VEGFR-2抑制试验证实其具有强大的抑制潜力，IC值为0.095±0.05μM。细胞周期分析表明7a诱导S期阻滞，而凋亡试验显示晚期凋亡细胞大幅增加（44.01%）。其他机制研究进一步证实了内源性凋亡途径的激活，表现为半胱天冬酶-3激活（8.2倍）、Bax上调（6.9倍）和Bcl-2下调（3.68倍）。包括分子对接和200纳秒分子动力学（MD）模拟在内的计算研究证实了7a与VEGFR-2的稳定相互作用，显示出与索拉非尼相当的结合亲和力。通过MM-GBSA、ProLIF、PCAT和FEL分析进一步验证，强化了其强大的结合能力。此外，ADMET预测表明其具有良好的药代动力学性质，包括良好的吸收、高血浆蛋白结合率和非CYP2D6抑制作用。此外，毒性分析将7a归类为非诱变和非致癌物质，预测毒性低于索拉非尼。最后，密度泛函理论（DFT）计算突出了7a的结构稳定性和反应性，进一步支持了其作为VEGFR-2抑制剂的潜力。这些发现表明7a是一种有前景的VEGFR-2抑制剂，具有显著的抗癌潜力、良好的药代动力学性质和改善的安全性。有必要进行进一步的临床前研究和结构修饰以优化其治疗潜力。
