一類靶向USP15抑制的四氫-β-咔啉類化合物的發(fā)現(xiàn)及活性研究
發(fā)布時(shí)間：2019-07-06 08:42
【摘要】：泛素化是蛋白質(zhì)高效和高度選擇性降解的過(guò)程,同時(shí)該過(guò)程為可逆過(guò)程,其逆向過(guò)程稱之為去泛素化,主要由去泛素化酶調(diào)控。泛素特異性蛋白酶是去泛素化酶的一種。研究報(bào)道,泛素特異性蛋白酶15(USP15)可以通過(guò)去泛素化TGFβ受體從而促進(jìn)TGFβ信號(hào)通路的表達(dá),進(jìn)而促進(jìn)腫瘤的生長(zhǎng)和轉(zhuǎn)移。例如膠質(zhì)瘤細(xì)胞中USP15的缺失使腫瘤體積變小,暗示著USP15可以作為治療腫瘤的一個(gè)靶點(diǎn),因此USP15抑制劑具有廣闊的應(yīng)用前景。而目前并沒(méi)有報(bào)道特異性靶向USP15的抑制劑,只有對(duì)所有DUBs幾乎都有抑制作用的廣譜抑制劑PR-619。本論文旨在發(fā)現(xiàn)一類特異性靶向USP15的抑制劑。我們之前的研究發(fā)現(xiàn)一類新穎結(jié)構(gòu)的四氫-β-咔啉類化合物能夠抑制TGFβ信號(hào)通路的活性,從而具有抗腫瘤增殖和遷移的作用。而USP15可通過(guò)去泛素化TGFβ受體促進(jìn)TGFβ信號(hào)通路的表達(dá),于是我們很自然地設(shè)想此類化合物是否具有抑制USP15的作用?所以我們對(duì)這類化合物進(jìn)行了USP15酶活篩選,發(fā)現(xiàn)部分化合物對(duì)USP15具有較好的酶活抑制作用,并且個(gè)別化合物與PR-619保持相當(dāng)?shù)囊种谱饔盟�。通過(guò)初步的構(gòu)效關(guān)系分析,我們發(fā)現(xiàn)在四氫-β-咔啉吲哚中苯環(huán)上引入醇胺類取代基和氨基酸殘基有利于提高活性,因此我們計(jì)劃引入更多的此類取代基探討結(jié)構(gòu)和活性的關(guān)系,并獲得了一部分活性和PR-619相似的化合物。我們接著對(duì)這些化合物的特異性進(jìn)行了分析,發(fā)現(xiàn)這些化合物相比PR-619具有較好的特異性。根據(jù)化合物對(duì)USP15抑制活性與結(jié)構(gòu)的關(guān)系,我們總結(jié)了如下構(gòu)效關(guān)系：四氫-β-咔啉環(huán)上5-位取代沒(méi)有6-,7-,8-位三個(gè)位置有優(yōu)勢(shì),而6-,7-,8-位三個(gè)位置取代的活性相似；取代基電子效應(yīng)無(wú)益于活性的提高；醇胺類取代基利于活性提高,且直鏈結(jié)構(gòu)比支鏈結(jié)構(gòu)有優(yōu)勢(shì),其中的O原子至關(guān)重要,不可缺失；氨基酸殘基有利于活性提高,但氨基酸必須為α氨基酸；酰胺鍵結(jié)構(gòu)不可倒換,否則活性會(huì)消失。
[Abstract]:Ubiquitin is a highly efficient and highly selective degradation process of proteins. At the same time, the process is reversible. Its reverse process is called de-ubiquitin, which is mainly regulated by deubiquitin enzyme. Ubiquitin specific protease is a kind of deubiquitin enzyme. It has been reported that ubiquitin specific protease 15 (USP15) can promote the expression of TGF 尾 signaling pathway by deubiquitin TGF 尾 receptor, thus promoting tumor growth and metastasis. For example, the deletion of USP15 in glioma cells makes the tumor smaller, suggesting that USP15 can be used as a target for the treatment of tumors, so USP15 inhibitors have broad application prospects. At present, no specific inhibitor of USP15 has been reported, only PR-619., a broad-spectrum inhibitor that has inhibitory effect on almost all DUBs. The purpose of this paper is to find a class of specific targeting inhibitors of USP15. Our previous studies have found that a class of novel tetrahydro-尾-carbene compounds can inhibit the activity of TGF 尾 signaling pathway and thus have the effect of anti-tumor proliferation and migration. USP15 can promote the expression of TGF 尾 signaling pathway by deubiquitin TGF 尾 receptor, so we naturally imagine whether these compounds have the effect of inhibiting USP15. Therefore, we screened the USP15 enzyme activity of these compounds, and found that some compounds had good inhibitory effect on USP15, and some compounds maintained the same inhibitory level as PR-619. Through the preliminary structure-activity relationship analysis, we found that the introduction of alkylamines and amino acid residues into the benzene ring of tetrahydro-尾-carbalin indole was beneficial to improve the activity. therefore, we plan to introduce more such substitutes to explore the relationship between structure and activity, and obtain some compounds with similar activity to PR-619. We then analyzed the specificity of these compounds and found that these compounds have better specificity than PR-619. According to the relationship between the inhibitory activity of compounds to USP15 and the structure, we summarized the structure-activity relationship as follows: there was no 5-position substitution on the tetrahydro-尾-carborin ring, there were no 6 position substitution, 7 position substitution, 8-position substitution activity was similar, and the electron effect of the substitution group was not beneficial to the improvement of the activity, and the structure-activity relationship of the compounds was summarized as follows: there was no 5-position substitution on the tetrahydro-尾-carborin ring, and there were no advantages at the 8-position substitution position. Alcoholamines are beneficial to the improvement of activity, and the straight chain structure is superior to the branch chain structure, in which the O atom is very important and can not be deleted; the amino acid residues are beneficial to the improvement of activity, but the amino acids must be 偽 amino acids; the amide bond structure can not be reversed, otherwise the activity will disappear.
【學(xué)位授予單位】：華東師范大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R96
本文編號(hào)：2510904
[Abstract]:Ubiquitin is a highly efficient and highly selective degradation process of proteins. At the same time, the process is reversible. Its reverse process is called de-ubiquitin, which is mainly regulated by deubiquitin enzyme. Ubiquitin specific protease is a kind of deubiquitin enzyme. It has been reported that ubiquitin specific protease 15 (USP15) can promote the expression of TGF 尾 signaling pathway by deubiquitin TGF 尾 receptor, thus promoting tumor growth and metastasis. For example, the deletion of USP15 in glioma cells makes the tumor smaller, suggesting that USP15 can be used as a target for the treatment of tumors, so USP15 inhibitors have broad application prospects. At present, no specific inhibitor of USP15 has been reported, only PR-619., a broad-spectrum inhibitor that has inhibitory effect on almost all DUBs. The purpose of this paper is to find a class of specific targeting inhibitors of USP15. Our previous studies have found that a class of novel tetrahydro-尾-carbene compounds can inhibit the activity of TGF 尾 signaling pathway and thus have the effect of anti-tumor proliferation and migration. USP15 can promote the expression of TGF 尾 signaling pathway by deubiquitin TGF 尾 receptor, so we naturally imagine whether these compounds have the effect of inhibiting USP15. Therefore, we screened the USP15 enzyme activity of these compounds, and found that some compounds had good inhibitory effect on USP15, and some compounds maintained the same inhibitory level as PR-619. Through the preliminary structure-activity relationship analysis, we found that the introduction of alkylamines and amino acid residues into the benzene ring of tetrahydro-尾-carbalin indole was beneficial to improve the activity. therefore, we plan to introduce more such substitutes to explore the relationship between structure and activity, and obtain some compounds with similar activity to PR-619. We then analyzed the specificity of these compounds and found that these compounds have better specificity than PR-619. According to the relationship between the inhibitory activity of compounds to USP15 and the structure, we summarized the structure-activity relationship as follows: there was no 5-position substitution on the tetrahydro-尾-carborin ring, there were no 6 position substitution, 7 position substitution, 8-position substitution activity was similar, and the electron effect of the substitution group was not beneficial to the improvement of the activity, and the structure-activity relationship of the compounds was summarized as follows: there was no 5-position substitution on the tetrahydro-尾-carborin ring, and there were no advantages at the 8-position substitution position. Alcoholamines are beneficial to the improvement of activity, and the straight chain structure is superior to the branch chain structure, in which the O atom is very important and can not be deleted; the amino acid residues are beneficial to the improvement of activity, but the amino acids must be 偽 amino acids; the amide bond structure can not be reversed, otherwise the activity will disappear.
【學(xué)位授予單位】：華東師范大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R96
【相似文獻(xiàn)】
相關(guān)碩士學(xué)位論文 前1條
1 童為光;一類靶向USP15抑制的四氫-β-咔啉類化合物的發(fā)現(xiàn)及活性研究[D];華東師范大學(xué);2014年
，本文編號(hào)：2510904
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