Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmacy, Shandong University, Ji'nan, Shandong 250012, PR China.
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmacy, Shandong University, Ji'nan, Shandong 250012, PR China.
Bioorg Chem. 2019 Jul;88:102938. doi: 10.1016/j.bioorg.2019.102938. Epub 2019 Apr 20.
Bcl-2 family proteins play a vital role for cancer cell in escaping apoptosis, and small-molecule anti-apoptotic Bcl-2 protein inhibitors have been developed as new anticancer therapies. In current study, a series of substituted 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were developed based on the lead compound 1 (K = 5.2 µM against Bcl-2 protein). The fluorescence polarization assays suggested that active compounds possessed potent binding affinities to both Bcl-2 and Mcl-1 protein, but had minor or no binding affinities to Bcl-X protein. MTT assays showed that these compounds had certain anti-proliferative activities against cancer cells. Furthermore, it was found that active compound 11t could induce cell apoptosis and caspase-3 activation in a dose-dependent manner in Jurkat cells.
Bcl-2 家族蛋白在癌细胞逃避细胞凋亡中起着至关重要的作用，因此，小分子抗凋亡 Bcl-2 蛋白抑制剂已被开发为新的抗癌疗法。在本研究中，基于先导化合物 1（对 Bcl-2 蛋白的 K = 5.2 µM），开发了一系列取代的 1,2,3,4-四氢异喹啉-3-羧酸衍生物。荧光偏振测定表明，活性化合物对 Bcl-2 和 Mcl-1 蛋白均具有很强的结合亲和力，但对 Bcl-X 蛋白几乎没有结合亲和力。MTT 测定表明，这些化合物对癌细胞具有一定的抗增殖活性。此外，研究发现活性化合物 11t 可在 Jurkat 细胞中以剂量依赖的方式诱导细胞凋亡和 caspase-3 激活。
