苯并异噻唑酮类saspse-3抑制剂的合成及评价

发布时间：2017-12-28 04:03

本文关键词：苯并异噻唑酮类saspse-3抑制剂的合成及评价　出处：《天津科技大学》2015年硕士论文　论文类型：学位论文

【摘要】：细胞凋亡,即细胞程序性死亡,是组织发育和体内平衡重要的生理过程。许多疾病的发病机理与细胞的异常凋亡有关,caspase家族参与细胞凋亡的整个过程,其中caspase-3蛋白酶是细胞凋亡执行者,在细胞凋亡过程中起了关键作用。许多危害人类健康的功能紊乱疾病都与caspase-3的异常激活有关,因此caspase-3被认为是一种有应用价值的药物开发靶标,对caspase-3抑制剂的探索成了研究热点。本实验室在前期研究中通过高通量筛选发现1,2-苯并异噻唑-3-酮可以作为caspase-3抑制剂的先导化合物,并合成了一系列含脲结构的化合物。然而在细胞实验中,脲类衍生物溶解性和膜透性差的缺点被暴露。为了提高水溶性和膜透性,通过结构修饰我们现在把脲类基团改变成酰胺基团并合成了一个新系列的N-酰基取代的苯并异噻唑-3-酮酰胺类衍生物。本文合成了36个1,2-苯并异噻唑-3-酮酰胺类衍生物,经鉴定其中35个为未见文献报道的新化合物。合成的酰胺类衍生物通过体外caspase-3和caspase-7酶活水平测试确定它们的抑制活性。除化合物11、14以及35外合成的化合物对caspase-3和caspase-7的抑制作用都达到纳摩级,对caspase-3的抑制活性主要与碳链的长度有关,其中化合物24和25分别对caspase-3和-7的抑制活性达到34.9 nmol/L和51.9nmol/L。在此基础上,在细胞凋亡模型喜树碱诱导的JurkatT细胞中,化合物24和25的抗细胞凋亡活性被评估,并表现出很好的细胞保护作用。为了进一步了解化合物的抑制作用,对活性最差的化合物11和最好的化合物24进行了分子对接模拟。通过化合物分子结构在caspase-3活性位点键和模型解释了活性高低的原因。总之,相比文献报道的脲类衍生物,1,2-苯并异噻唑-3-酮酰胺类衍生物的水溶性和膜透性有很大改善,为下一步的动物模型方面研究了重要的研究基础。
[Abstract]:Apoptosis, that is, programmed cell death, is an important physiological process in the development of tissue and balance in the body. The pathogenesis of many diseases is related to the abnormal apoptosis of cells. The caspase family is involved in the whole process of apoptosis. Caspase-3 protease is the executor of apoptosis and plays a key role in the process of cell apoptosis. Many functional disorders that are harmful to human health are related to abnormal activation of Caspase-3. Therefore, caspase-3 is considered to be a valuable drug development target, and the exploration of Caspase-3 inhibitors has become a research hotspot. In our previous studies, we found that 1,2- benzisothiazole -3- ketone can be used as a precursor of Caspase-3 inhibitors and synthesized a series of compounds containing urea structure. However, in cell experiments, the shortcomings of the solubility and poor membrane permeability of urea derivatives have been exposed. In order to improve water solubility and membrane permeability, we have changed the urea group to amide group through structural modification, and synthesized a new series of N- acyl substituted benzoisothiazole -3- ketone amide derivatives. 36 1,2- benzothiazolazole -3- ketone derivatives were synthesized in this paper, and 35 of them were identified as new compounds that were not reported in literature. The synthesized amide derivatives determine their inhibitory activity by testing the caspase-3 and caspase-7 enzyme activity levels in vitro. The inhibitory effect of compounds 11, 14 and 35 compounds of Caspase-3 and caspase-7 reached the level M. inhibitory activity against Caspase-3, the length of carbon chain and related compounds 24 and 25 respectively for caspase-3 and -7 inhibitory activity reached 34.9 nmol/L and 51.9nmol/L. On this basis, in the cell apoptosis model, camptothecin induced JurkatT cells, the anti apoptotic activities of compounds 24 and 25 were evaluated and showed good cytoprotection. In order to further understand the inhibitory effect of the compounds, the molecular docking simulation was carried out for the most active compounds 11 and the best compound 24. The cause of the activity was explained by the molecular structure of the compound in the caspase-3 active site key and model. In conclusion, compared with the reported urea derivatives, the water solubility and membrane permeability of 1,2- benzoisothiazole -3- ketone amide derivatives have been greatly improved, which has laid an important foundation for further research on animal models.
【学位授予单位】：天津科技大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：TQ460.1;O626

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