发现比格利尼杂合体作为凋亡机器中新型的半胱天冬酶-9 激活剂：亲脂性，分子对接研究，对血管生成基因和 miR-21 表达水平的影响。
Discovery of the Biginelli hybrids as novel caspase-9 activators in apoptotic machines: Lipophilicity, molecular docking study, influence on angiogenesis gene and miR-21 expression levels.
机构信息
Department of Chemistry, Faculty of Science, University of Kragujevac, Radoja Domanovića 12, 34000 Kragujevac, Serbia.
Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Hajduk Veljkova 3, 21000 Novi Sad, Serbia.
出版信息
Bioorg Chem. 2019 May;86:569-582. doi: 10.1016/j.bioorg.2019.02.026. Epub 2019 Feb 12.
In order to investigate potential therapeutically agents, novel products of Biginelli reaction (4a-l) were synthesized and exposed to cytotoxic and caspase activities, angiogenesis, cell cycle distribution, gene and microRNA expression levels, lipophilicity assessment and docking study. Among the twelve novel compounds (4a-l) evaluated for the cytotoxic activity, five of them (4c, 4d, 4f, 4k and 4l) that showed excellent activity on the tested cell lines (HeLa, LS174 and A549) were selected for further evaluation. Interestingly, compound 4f has up to three times higher selectivity index (SI) towards cancer cells than cisplatin (on HeLa, LS174 and A549 SI = 18.2, 13.5 and 11.2, respectively). The obtained results from cell cycle distribution and caspase activity indicate that tested compounds (4c, 4d, 4f, 4k and 4l) promoted caspase-9 activation, implicated in the intrinsic pathway of apoptosis. Lipophilicity of 4a-l was determinate by using reversed-phase high-performance liquid chromatography.
为了研究潜在的治疗药物，我们合成了比格利内利反应（4a-l）的新型产物，并对其细胞毒性、半胱天冬酶活性、血管生成、细胞周期分布、基因和 microRNA 表达水平、脂溶性评估和对接研究进行了评估。在对十二种新型化合物（4a-l）进行细胞毒性活性评价中，其中五种化合物（4c、4d、4f、4k 和 4l）对测试的细胞系（HeLa、LS174 和 A549）表现出优异的活性，被选中进行进一步评估。有趣的是，化合物 4f 在 HeLa、LS174 和 A549 细胞系中对癌细胞的选择性指数（SI）比顺铂高 3 倍（SI = 18.2、13.5 和 11.2）。从细胞周期分布和半胱天冬酶活性获得的结果表明，测试化合物（4c、4d、4f、4k 和 4l）促进了半胱天冬酶-9 的激活，这与细胞凋亡的内在途径有关。通过反相高效液相色谱法测定了 4a-l 的脂溶性。
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