Shi Leilei, Zhou Jianfeng, Wu Jifeng, Cao Junya, Shen Yuemao, Zhou Hua, Li Xun
School of Pharmaceutical Sciences, Key Laboratory of Chemistry and Chemical Biology (Ministry of Education), Shandong University, Ji'nan, Shandong 250012, PR China.
School of Medicine and Pharmacy, Ocean University of China, Qingdao 266100, PR China.
Bioorg Med Chem. 2016 Apr 15;24(8):1840-52. doi: 10.1016/j.bmc.2016.03.008. Epub 2016 Mar 3.
Inhibition of VEGFR-2 kinase has been highlighted as one of the well-defined strategies to suppress tumor growth via blockade of angiogenesis. Guided by the principles of bioisosteric replacement and pharmacophoric fragment migration, a series of novel quinoxalinone derivates were designed, synthesized and evaluated for their VEGFR-2 inhibitory potencies. Among them, compounds 7c, 8b, 8c, 8e and 10b displayed antiangiogenic abilities via the in vitro tube formation assay (cellular level) and ex vivo rat aortic ring assay (tissue level) at a low concentration (0.1 μM). By means of in vivo zebrafish embryo model, two (Z)-3-(2-(pyridin-4-yl)vinyl)quinoxalinone derivates 8c and 8e showed significant antiangiogenesis effects, suggesting they have potentials to be developed into antiangiogenesis agents via further structural optimization. Moreover, these two compounds also demonstrated potent inhibition toward VEGFR-2 and B-raf kinases in a low concentration (1 μM). A possible interpretation of our evaluation result has been presented by a molecular docking study by docking representative compound 8c with VEGFR-2.
抑制VEGFR-2激酶已被视为通过阻断血管生成来抑制肿瘤生长的明确策略之一。以生物电子等排体替代和药效基团片段迁移原理为指导，设计、合成了一系列新型喹喔啉酮衍生物，并对其VEGFR-2抑制活性进行了评估。其中，化合物7c、8b、8c、8e和10b在低浓度（0.1 μM）下通过体外管形成试验（细胞水平）和离体大鼠主动脉环试验（组织水平）显示出抗血管生成能力。借助体内斑马鱼胚胎模型，两种（Z）-3-（2-（吡啶-4-基）乙烯基）喹喔啉酮衍生物8c和8e显示出显著的抗血管生成作用，表明它们有潜力通过进一步的结构优化开发成抗血管生成药物。此外，这两种化合物在低浓度（1 μM）下也对VEGFR-2和B-raf激酶表现出强效抑制作用。通过将代表性化合物8c与VEGFR-2对接的分子对接研究，对我们的评估结果给出了一种可能的解释。
