本文關(guān)鍵詞：苯并異噻唑酮類saspse-3抑制劑的合成及評價　出處：《天津科技大學》2015年碩士論文　論文類型：學位論文

  更多相關(guān)文章： 1 2-苯并異噻唑-3-酮 Caspase-3抑制劑 細胞凋亡 分子對接 酰胺

【摘要】：細胞凋亡,即細胞程序性死亡,是組織發(fā)育和體內(nèi)平衡重要的生理過程。許多疾病的發(fā)病機理與細胞的異常凋亡有關(guān),caspase家族參與細胞凋亡的整個過程,其中caspase-3蛋白酶是細胞凋亡執(zhí)行者,在細胞凋亡過程中起了關(guān)鍵作用。許多危害人類健康的功能紊亂疾病都與caspase-3的異常激活有關(guān),因此caspase-3被認為是一種有應(yīng)用價值的藥物開發(fā)靶標,對caspase-3抑制劑的探索成了研究熱點。本實驗室在前期研究中通過高通量篩選發(fā)現(xiàn)1,2-苯并異噻唑-3-酮可以作為caspase-3抑制劑的先導化合物,并合成了一系列含脲結(jié)構(gòu)的化合物。然而在細胞實驗中,脲類衍生物溶解性和膜透性差的缺點被暴露。為了提高水溶性和膜透性,通過結(jié)構(gòu)修飾我們現(xiàn)在把脲類基團改變成酰胺基團并合成了一個新系列的N-酰基取代的苯并異噻唑-3-酮酰胺類衍生物。本文合成了36個1,2-苯并異噻唑-3-酮酰胺類衍生物,經(jīng)鑒定其中35個為未見文獻報道的新化合物。合成的酰胺類衍生物通過體外caspase-3和caspase-7酶活水平測試確定它們的抑制活性。除化合物11、14以及35外合成的化合物對caspase-3和caspase-7的抑制作用都達到納摩級,對caspase-3的抑制活性主要與碳鏈的長度有關(guān),其中化合物24和25分別對caspase-3和-7的抑制活性達到34.9 nmol/L和51.9nmol/L。在此基礎(chǔ)上,在細胞凋亡模型喜樹堿誘導的JurkatT細胞中,化合物24和25的抗細胞凋亡活性被評估,并表現(xiàn)出很好的細胞保護作用。為了進一步了解化合物的抑制作用,對活性最差的化合物11和最好的化合物24進行了分子對接模擬。通過化合物分子結(jié)構(gòu)在caspase-3活性位點鍵和模型解釋了活性高低的原因�？傊�,相比文獻報道的脲類衍生物,1,2-苯并異噻唑-3-酮酰胺類衍生物的水溶性和膜透性有很大改善,為下一步的動物模型方面研究了重要的研究基礎(chǔ)。
[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.
【學位授予單位】：天津科技大學
【學位級別】：碩士
【學位授予年份】：2015
【分類號】：TQ460.1;O626

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