Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University, New Dammeitta, Egypt.
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
Eur J Med Chem. 2019 Apr 15;168:315-329. doi: 10.1016/j.ejmech.2019.02.050. Epub 2019 Feb 22.
Two series of picolinamide derivatives bearing (thio)urea and dithiocarbamate moieties were designed and synthesized as VEGFR-2 kinase inhibitors. All the new compounds were screened for their cytotoxic activity against A549 cancer cell line and VEGFR-2 inhibitory activity. Compounds 7h, 9a and 9l showed potent inhibitory activity against VEGFR-2 kinase with IC values of 87, 27 and 94 nM, respectively in comparison to sorafenib (IC = 180 nM) as a reference. Compounds 7h, 9a and 9l were further screened for their antitumor activity against specific resistant human cancer cell lines from different origins (Panc-1, OVCAR-3, HT29 and 786-O cell lines) where compound 7h showed significant cell death in most of them. Multi-kinase inhibition assays were performed for the most potent VEGFR-2 inhibitors where compound 7h showed enhanced potency towards EGFR, HER-2, c-MET and MER kinases. Cell cycle analysis of A549 cells treated with 9a showed cell cycle arrest at G2/M phase and pro-apoptotic activity as indicated by annexin V-FITC staining.
设计并合成了两个系列的含有（硫）脲和二硫代氨基甲酸盐部分的吡啶甲酰胺衍生物，作为 VEGFR-2 激酶抑制剂。所有新化合物均针对 A549 癌细胞系的细胞毒性活性和 VEGFR-2 抑制活性进行了筛选。与索拉非尼（IC50=180nM）作为参比化合物相比，化合物 7h、9a 和 9l 对 VEGFR-2 激酶具有很强的抑制活性，IC50 值分别为 87、27 和 94nM。化合物 7h、9a 和 9l 进一步针对来自不同来源的特定耐药性人类癌细胞系（Panc-1、OVCAR-3、HT29 和 786-O 细胞系）进行了抗肿瘤活性筛选，其中化合物 7h 在大多数细胞系中表现出显著的细胞死亡。对最有效的 VEGFR-2 抑制剂进行了多激酶抑制测定，其中化合物 7h 对 EGFR、HER-2、c-MET 和 MER 激酶显示出增强的活性。用 9a 处理 A549 细胞的细胞周期分析表明，细胞周期在 G2/M 期停滞，并表现出促凋亡活性，如 Annexin V-FITC 染色所示。
