本文關(guān)鍵詞： 1 2-苯并異噻唑-3-酮 CaspaSe-3 抑制劑 細(xì)胞凋亡　出處：《天津科技大學(xué)》2014年碩士論文　論文類型：學(xué)位論文

【摘要】：細(xì)胞凋亡,又稱細(xì)胞程序性死亡,是組織發(fā)育和體內(nèi)平衡重要的生理過程。細(xì)胞異常凋亡會(huì)引起很多疾病,例如老年癡呆、帕金森、亨廷頓舞蹈癥,細(xì)胞凋亡被認(rèn)為是針對(duì)此類疾病的重要靶點(diǎn)。Caspase家族在細(xì)胞凋亡的啟動(dòng)和執(zhí)行過程中起到重要作用,尤其是作為效應(yīng)因子的Caspase-3,在細(xì)胞凋亡模型中的不同信號(hào)通路都起到至關(guān)重要的作用。因此,Caspase-3被認(rèn)為是治療細(xì)胞凋亡異常類疾病的潛在治療靶點(diǎn)。本實(shí)驗(yàn)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-酮對(duì)Caspase-3有很好的抑制作用,同時(shí)報(bào)道了一系列具有高度親和性的Caspase-3抑制劑,其半數(shù)抑制率達(dá)到31 nmol/L。通過分子對(duì)接研究發(fā)現(xiàn)了這一類抑制劑只能填充入S1,S2,S3口袋,在S4口袋并沒有氫鍵形成。而通過對(duì)比已報(bào)道的抑制劑的共晶結(jié)構(gòu)發(fā)現(xiàn),S4口袋是比較重要的。因此,進(jìn)一步的工作希望通過延長(zhǎng)小分子化合物的長(zhǎng)度使其與蛋白分子更好的結(jié)合。本論文中共合成30個(gè)1,2-苯并異噻唑-3-酮類衍生物,其中28個(gè)為未見文獻(xiàn)報(bào)道的新化合物。對(duì)這些化合物進(jìn)行體外酶水平活性評(píng)估,包括對(duì)Caspase-3和Caspase-7的抑制作用。大部分化合物對(duì)Caspase-3的抑制作用達(dá)到納摩級(jí)別,其中化合物5j對(duì)Caspase-3的抑制活性達(dá)到1.15 nmol/L。在此基礎(chǔ)上,對(duì)化合物進(jìn)行細(xì)胞水平上的生物評(píng)價(jià)的結(jié)果表明化合物5t對(duì)喜樹堿誘導(dǎo)的Jurkat T細(xì)胞的凋亡表現(xiàn)很好的保護(hù)作用。為了進(jìn)一步了解化合物的抑制作用,對(duì)化合物5j和13a進(jìn)行了分子對(duì)接研究。通過對(duì)比5j和13a分子對(duì)接模型,可以看出通過引入苯環(huán)-雜環(huán)的雙環(huán)結(jié)構(gòu)來(lái)延長(zhǎng)分子長(zhǎng)度,提高了小分子化合物與蛋白分子的親和力,能夠改善抑制活性。這一點(diǎn)正好與之前的預(yù)想相吻合。此外,由于之前合成的一系列抑制劑水溶性不好,本課題的另一個(gè)目的是提高這一類化合物的水溶性,其中化合物5a-5f、5t、9、13水溶性有很大改善,為進(jìn)一步的細(xì)胞活性和動(dòng)物模型方面研究提供可能。
[Abstract]:Apoptosis, also known as programmed cell death, is an important physiological process in tissue development and balance in vivo. Abnormal apoptosis can cause many diseases, such as Alzheimer's disease, Parkinson's disease and Huntington's disease. Apoptosis is considered to be an important target for this disease. Caspase family plays an important role in the initiation and implementation of apoptosis, especially as an effector of Caspase-3. Different signaling pathways play a crucial role in the apoptosis model. Caspase-3 is considered to be a potential therapeutic target for the treatment of apoptosis-like diseases. 2-benzoisothiazole-3-one has a good inhibitory effect on Caspase-3, and a series of Caspase-3 inhibitors with high affinity have been reported. Its half inhibition rate was 31 nmol / L. by molecular docking study, it was found that this kind of inhibitor could only be filled into the S1 / S2 / S3 pocket. There is no hydrogen bond formation in the S4 pocket, and it is important to compare the eutectic structure of the inhibitors reported. Further work was carried out to improve the binding of small molecular compounds to protein molecules by lengthening their length. In this paper, 30 1h2benzoisothiazole-3-one derivatives were synthesized. 28 of them were new compounds which had not been reported in the literature. The enzyme activity of these compounds was evaluated in vitro. The inhibition of most compounds on Caspase-3 reached the Nama level, including the inhibition of Caspase-3 and Caspase-7. The inhibitory activity of compound 5j on Caspase-3 reached 1.15 nmol / L on this basis. The results of biological evaluation of the compounds at the cell level showed that the compound 5t could induce camptothecin induced Jurkat. The apoptosis of T cells showed a good protective effect. In order to further understand the inhibitory effect of compounds. The molecular docking of compounds 5j and 13a was studied. By comparing the molecular docking models of 5j and 13a, we can see that the molecular length can be prolonged by introducing the double ring structure of benzene-heterocyclic. It improves the affinity of small molecular compounds to protein molecules and improves the inhibitory activity. This is exactly as expected. In addition, a series of previously synthesized inhibitors are not water-soluble. Another purpose of this paper is to improve the water solubility of this kind of compounds, in which the water solubility of compound 5a-5f5 TX 913 has been greatly improved. It provides the possibility for further study on cell activity and animal model.
【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】：2014
【分類號(hào)】：R914;O626

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