Marzouk Adel A, Abdel-Aziz Salah A, Abdelrahman Kamal S, Wanas Amira S, Gouda Ahmed M, Youssif Bahaa G M, Abdel-Aziz Mohamed
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Deraya University, Minia, Egypt.
Bioorg Chem. 2020 Sep;102:104090. doi: 10.1016/j.bioorg.2020.104090. Epub 2020 Jul 10.
A series of new 1,6-dihydropyrimidin-2-thiol derivatives (scaffold A) as VEGFR-2 inhibitors has been designed and synthesized. Compounds 3a, 3b, 3e and 4b have been selected for in vitro anticancer screening by the National Cancer Institute. Compound 3e showed remarkable anticancer activity against most of the cell lines tested, where a complete cell death against leukemia, non-small cell lung cancer, colon, CNS, melanoma, and breast cancer cell lines was observed. In vitro five dose tests showed that compound 3e had high activity against most of the tested cell lines with GI ranging from 19 to 100 μM and selectivity ratios ranging between 0.75 and 1.71 at the GI level. VEGFR-2-kinase was tested against 3a, 3b, 3e, 4b and sorafenib was used as a reference. Compounds 3a and 3e were the most potent analogues with IC values of 386.4 nM and 198.7 nM against VEGFR-2, respectively, in comparison to sorafenib (IC = 0.17 nM). The results of the docking study showed a good fitting of the new compounds to the active site of VEGFR-2 with binding free energies in the range of -9.80 to -11.25 kcal/mol compared to -12.12 kcal/mol for sorafenib. Compounds 4a-e with the hydroxyimino group had a higher affinity to VEGFR-2 than their parent derivatives 3a-e.
设计并合成了一系列新型1,6 - 二氢嘧啶 - 2 - 硫醇衍生物（支架A）作为血管内皮生长因子受体 - 2（VEGFR - 2）抑制剂。美国国立癌症研究所已选择化合物3a、3b、3e和4b进行体外抗癌筛选。化合物3e对大多数测试细胞系显示出显著的抗癌活性，观察到其对白血病、非小细胞肺癌、结肠癌、中枢神经系统癌、黑色素瘤和乳腺癌细胞系具有完全的细胞杀伤作用。体外五剂量试验表明，化合物3e对大多数测试细胞系具有高活性，其生长抑制率（GI）范围为19至100 μM，在GI水平下选择性比在0.75至1.71之间。针对3a、3b、3e、4b测试了VEGFR - 2激酶，并以索拉非尼作为对照。与索拉非尼（IC = 0.17 nM）相比，化合物3a和3e是最有效的类似物，对VEGFR - 2的IC值分别为386.4 nM和198.7 nM。对接研究结果表明，新化合物与VEGFR - 2的活性位点具有良好的契合度，结合自由能在 - 9.80至 - 11.25 kcal/mol范围内，而索拉非尼为 - 12.12 kcal/mol。带有羟基亚氨基的化合物4a - e对VEGFR - 2的亲和力高于其母体衍生物3a - e。
