本文關(guān)鍵詞：苯并異噻唑酮類(lèi)saspse-3抑制劑的合成及評(píng)價(jià)　出處：《天津科技大學(xué)》2015年碩士論文　論文類(lèi)型：學(xué)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(xì)胞凋亡 分子對(duì)接 酰胺

【摘要】：細(xì)胞凋亡,即細(xì)胞程序性死亡,是組織發(fā)育和體內(nèi)平衡重要的生理過(guò)程。許多疾病的發(fā)病機(jī)理與細(xì)胞的異常凋亡有關(guān),caspase家族參與細(xì)胞凋亡的整個(gè)過(guò)程,其中caspase-3蛋白酶是細(xì)胞凋亡執(zhí)行者,在細(xì)胞凋亡過(guò)程中起了關(guān)鍵作用。許多危害人類(lèi)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(rèn)為是一種有應(yīng)用價(jià)值的藥物開(kāi)發(fā)靶標(biāo),對(duì)caspase-3抑制劑的探索成了研究熱點(diǎn)。本實(shí)驗(yàn)室在前期研究中通過(guò)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(dǎo)化合物,并合成了一系列含脲結(jié)構(gòu)的化合物。然而在細(xì)胞實(shí)驗(yàn)中,脲類(lèi)衍生物溶解性和膜透性差的缺點(diǎn)被暴露。為了提高水溶性和膜透性,通過(guò)結(jié)構(gòu)修飾我們現(xiàn)在把脲類(lèi)基團(tuán)改變成酰胺基團(tuán)并合成了一個(gè)新系列的N-�；〈谋讲愢邕�-3-酮酰胺類(lèi)衍生物。本文合成了36個(gè)1,2-苯并異噻唑-3-酮酰胺類(lèi)衍生物,經(jīng)鑒定其中35個(gè)為未見(jiàn)文獻(xiàn)報(bào)道的新化合物。合成的酰胺類(lèi)衍生物通過(guò)體外caspase-3和caspase-7酶活水平測(cè)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(duì)caspase-3和caspase-7的抑制作用都達(dá)到納摩級(jí),對(duì)caspase-3的抑制活性主要與碳鏈的長(zhǎng)度有關(guān),其中化合物24和25分別對(duì)caspase-3和-7的抑制活性達(dá)到34.9 nmol/L和51.9nmol/L。在此基礎(chǔ)上,在細(xì)胞凋亡模型喜樹(shù)堿誘導(dǎo)的JurkatT細(xì)胞中,化合物24和25的抗細(xì)胞凋亡活性被評(píng)估,并表現(xiàn)出很好的細(xì)胞保護(hù)作用。為了進(jìn)一步了解化合物的抑制作用,對(duì)活性最差的化合物11和最好的化合物24進(jìn)行了分子對(duì)接模擬。通過(guò)化合物分子結(jié)構(gòu)在caspase-3活性位點(diǎn)鍵和模型解釋了活性高低的原因�？傊�,相比文獻(xiàn)報(bào)道的脲類(lèi)衍生物,1,2-苯并異噻唑-3-酮酰胺類(lèi)衍生物的水溶性和膜透性有很大改善,為下一步的動(dòng)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(xué)位授予單位】：天津科技大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2015
【分類(lèi)號(hào)】：TQ460.1;O626

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