Eissa Ibrahim H, Elgammal Walid E, Mahdy Hazem A, Zara Susi, Carradori Simone, Husein Dalal Z, Alharthi Maymounah N, Ibrahim Ibrahim M, Elkaeed Eslam B, Elkady Hazem, Metwaly Ahmed M
Department of Pharmaceutical Medicinal Chemistry & Drug Design, Faculty of Pharmacy (Boys), Al-Azhar University Cairo 11884 Egypt
Chemistry Department, Faculty of Science, Al-Azhar University Nasr City Cairo 11751 Egypt.
RSC Adv. 2024 Nov 6;14(48):35505-35519. doi: 10.1039/d4ra04158e. eCollection 2024 Nov 4.
This study aims to investigate the potential of designed 2,3-dihydro-1,3,4-thiadiazole derivatives as anti-proliferative agents targeting VEGFR-2, utilizing a multidimensional approach combining and analyses.
The synthesized derivatives were evaluated for their inhibitory effects on MCF-7 and HepG2 cancer cell lines. Additionally, VEGFR-2 inhibition was assessed. Further investigations into the cellular mechanisms were conducted to elucidate the effects of 20b (-(4-(()-1-((()-5-Acetyl-3-(-tolyl)-1,3,4-thiadiazol-2(3)-ylidene)hydrazono) ethyl) phenyl) benzamide) on cell cycle arrest and apoptosis induction. Furthermore, computational investigations, including molecular docking, MD simulations, DFT calculations, MM-GBSA, PCAT, and ADMET predictions were conducted.
Compound 20b emerged as a standout candidate with significantly lower IC values of 0.05 μM and 0.14 μM for MCF-7 and HepG2 cell lines, respectively. It exhibited notable VEGFR-2 inhibition (0.024 μM), surpassing the efficacy of sorafenib (0.041 μM). Compound 20b demonstrated cancer-specific targeting potential with a high selectivity index in normal WI-38 cells (IC 0.19 μM). Mechanistic studies revealed its ability to arrest the cell cycle of MCF-7 cells and induce apoptosis (total apoptosis 34.47%, early apoptosis 18.48%, and late apoptosis 15.99%), supported by upregulated caspase-8 (3.42-fold) and caspase-9 (5.44-fold) expression. Additionally, 20b arrested the cell cycle of MCF-7 cells at the %G0-G1 phase. Computational investigations provided insights into its molecular interactions with VEGFR-2, contributing to the rational design and understanding of its pharmacological profile.
Compound 20b presents as a promising anti-proliferative agent targeting VEGFR-2. Also, this comprehensive investigation underscores the potential of 2,3-dihydro-1,3,4-thiadiazole derivatives as promising candidates for further development in anti-cancer research.
本研究旨在利用结合多种分析方法的多维方法，研究设计的2,3 - 二氢 - 1,3,4 - 噻二唑衍生物作为靶向血管内皮生长因子受体2（VEGFR - 2）的抗增殖剂的潜力。
评估合成衍生物对MCF - 7和HepG2癌细胞系的抑制作用。此外，评估VEGFR - 2抑制情况。对细胞机制进行进一步研究，以阐明20b（-（4 - （（（（- 1 - （（（- 5 - 乙酰基 - 3 - （对甲苯基）- 1,3,4 - 噻二唑 - 2（3H）- 亚基）肼基）乙基）苯基）苯甲酰胺）对细胞周期阻滞和凋亡诱导的影响。此外，还进行了包括分子对接、分子动力学模拟、密度泛函理论计算、分子力学/广义玻恩表面面积计算、主成分分析和药物代谢及毒性预测在内的计算研究。
化合物20b成为突出候选物，对MCF - 7和HepG2细胞系的IC值分别显著低至0.05 μM和0.14 μM。它表现出显著的VEGFR - 2抑制作用（0.024 μM），超过了索拉非尼（0.041 μM）的疗效。化合物20b在正常WI - 38细胞（IC 0.19 μM）中具有高选择性指数，显示出癌症特异性靶向潜力。机制研究表明其能够使MCF - 7细胞的细胞周期停滞并诱导凋亡（总凋亡率34.47%，早期凋亡率18.48%，晚期凋亡率15.99%），这由半胱天冬酶 - 8（3.42倍）和半胱天冬酶 - 9（5.44倍）表达上调所支持。此外，20b使MCF - 7细胞的细胞周期停滞在G0 - G1期。计算研究为其与VEGFR - 2的分子相互作用提供了见解，有助于合理设计并理解其药理特性。
化合物20b是一种有前景的靶向VEGFR - 2的抗增殖剂。此外，这项全面研究强调了2,3 - 二氢 - 1,3,4 - 噻二唑衍生物作为抗癌研究中进一步开发的有前景候选物的潜力。
