Faculty of Pharmacy, Department of Pharmaceutical Organic Chemistry, Cairo University, Cairo, Egypt.
Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Badr University in Cairo (BUC), Badr City, Egypt.
J Enzyme Inhib Med Chem. 2021 Dec;36(1):922-939. doi: 10.1080/14756366.2021.1901089.
Novel tolmetin derivatives to were designed, synthesised, and evaluated for antiproliferative activity by NCI (USA) against a panel of 60 tumour cell lines. The cytotoxic activity of the most active tolmetin derivatives and was examined against HL-60, HCT-15, and UO-31 tumour cell lines. Compound was found to be the most potent derivative against HL-60, HCT-15, and UO-31 cell lines with IC values of 10.32 ± 0.55, 6.62 ± 0.35, and 7.69 ± 0.41 µM, respectively. Molecular modelling studies of derivative towards the VEGFR-2 active site were performed. Compound displayed high inhibitory activity against VEGFR-2 (IC = 0.20 µM). It extremely reduced the HUVECs migration potential exhibiting deeply reduced wound healing patterns after 72 h. It induced apoptosis in HCT-15 cells (52.72-fold). This evidence was supported by an increase in the level of apoptotic caspases-3, -8, and -9 by 7.808-, 1.867-, and 7.622-fold, respectively. Compound arrested the cell cycle in the G0/G1 phase. Furthermore, the ADME studies showed that compound possessed promising pharmacokinetic properties.
新型托美汀衍生物 被设计、合成，并由美国国家癌症研究所 (NCI) 针对 60 种肿瘤细胞系进行了抗增殖活性评估。对最活跃的托美汀衍生物 和 对 HL-60、HCT-15 和 UO-31 肿瘤细胞系的细胞毒性活性进行了检查。发现化合物 对 HL-60、HCT-15 和 UO-31 细胞系的活性最强，IC 值分别为 10.32 ± 0.55、6.62 ± 0.35 和 7.69 ± 0.41µM。对衍生物 对 VEGFR-2 活性位点的分子建模研究表明。化合物 对 VEGFR-2 具有高抑制活性（IC = 0.20µM）。它极大地降低了 HUVEC 的迁移潜力，在 72 小时后表现出明显减少的伤口愈合模式。它诱导 HCT-15 细胞凋亡（52.72 倍）。这一证据得到了凋亡半胱氨酸蛋白酶-3、-8 和 -9 水平分别增加 7.808、1.867 和 7.622 倍的支持。化合物 将细胞周期阻滞在 G0/G1 期。此外，ADME 研究表明，化合物 具有有前途的药代动力学特性。
