Abd El-Haleem Akram H, Kassem Manar Abd El-Karim, Elnagar Mohamed R, Abbas Safinaz E-S, El Kerdawy Ahmed M, Farouk Ahmed K B A W
Pharmaceutical Chemistry Department, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, Sixth of October City, Giza 77, Egypt.
Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11823, Egypt.
ACS Med Chem Lett. 2024 Nov 25;15(12):2150-2157. doi: 10.1021/acsmedchemlett.4c00438. eCollection 2024 Dec 12.
New derivatives -, , -, -, , , , -, -, and were synthesized and evaluated for their VEGFR-2 inhibition. Compounds , , and showed remarkable enzyme inhibition IC = 57.1, 42.5, and 52.5 nM, respectively) relative to sorafenib (IC = 41.1 nM) and were assessed for their cytotoxicity versus HepG2, MCF-7, A549, HT-29, and PC3 cancer cell lines in addition to WI-38. Compound displayed nearly equipotent cytotoxicity against A549 and HT-29 (IC = 6.66 and 8.51 μM) compared to sorafenib (IC = 6.60 and 8.78 μM). Cell cycle analysis and apoptotic assay of in the HT-29 cell line showed cellular growth arrest at the G2/M phase in addition to the induction of apoptosis. Western blot analysis of compound revealed the deactivation of VEGFR-2. Moreover, a wound healing assay of showed inhibition of wound closure. Additionally, molecular modeling studies of compounds , , and were carried out.
合成了新的衍生物-、-、-、-、、、、-、-和，并对其VEGFR-2抑制活性进行了评估。相对于索拉非尼（IC = 41.1 nM），化合物、和表现出显著的酶抑制作用（IC分别为57.1、42.5和52.5 nM），并除了在WI-38细胞系中测试外，还对其针对HepG2、MCF-7、A549、HT-29和PC3癌细胞系的细胞毒性进行了评估。与索拉非尼（IC分别为6.60和8.78 μM）相比，化合物对A549和HT-29表现出几乎等效的细胞毒性（IC分别为6.66和8.51 μM）。对HT-29细胞系中的进行细胞周期分析和凋亡检测，结果显示除诱导凋亡外，细胞生长停滞于G2/M期。对化合物进行蛋白质免疫印迹分析显示VEGFR-2失活。此外，对进行伤口愈合检测显示伤口闭合受到抑制。另外，还对化合物、和进行了分子模拟研究。
