一类靶向USP15抑制的四氢-β-咔啉类化合物的发现及活性研究
发布时间：2019-07-06 08:42
【摘要】：泛素化是蛋白质高效和高度选择性降解的过程,同时该过程为可逆过程,其逆向过程称之为去泛素化,主要由去泛素化酶调控。泛素特异性蛋白酶是去泛素化酶的一种。研究报道,泛素特异性蛋白酶15(USP15)可以通过去泛素化TGFβ受体从而促进TGFβ信号通路的表达,进而促进肿瘤的生长和转移。例如胶质瘤细胞中USP15的缺失使肿瘤体积变小,暗示着USP15可以作为治疗肿瘤的一个靶点,因此USP15抑制剂具有广阔的应用前景。而目前并没有报道特异性靶向USP15的抑制剂,只有对所有DUBs几乎都有抑制作用的广谱抑制剂PR-619。本论文旨在发现一类特异性靶向USP15的抑制剂。我们之前的研究发现一类新颖结构的四氢-β-咔啉类化合物能够抑制TGFβ信号通路的活性,从而具有抗肿瘤增殖和迁移的作用。而USP15可通过去泛素化TGFβ受体促进TGFβ信号通路的表达,于是我们很自然地设想此类化合物是否具有抑制USP15的作用?所以我们对这类化合物进行了USP15酶活筛选,发现部分化合物对USP15具有较好的酶活抑制作用,并且个别化合物与PR-619保持相当的抑制作用水平。通过初步的构效关系分析,我们发现在四氢-β-咔啉吲哚中苯环上引入醇胺类取代基和氨基酸残基有利于提高活性,因此我们计划引入更多的此类取代基探讨结构和活性的关系,并获得了一部分活性和PR-619相似的化合物。我们接着对这些化合物的特异性进行了分析,发现这些化合物相比PR-619具有较好的特异性。根据化合物对USP15抑制活性与结构的关系,我们总结了如下构效关系：四氢-β-咔啉环上5-位取代没有6-,7-,8-位三个位置有优势,而6-,7-,8-位三个位置取代的活性相似；取代基电子效应无益于活性的提高；醇胺类取代基利于活性提高,且直链结构比支链结构有优势,其中的O原子至关重要,不可缺失；氨基酸残基有利于活性提高,但氨基酸必须为α氨基酸；酰胺键结构不可倒换,否则活性会消失。
[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 伪 amino acids; the amide bond structure can not be reversed, otherwise the activity will disappear.
【学位授予单位】：华东师范大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R96
本文编号：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 伪 amino acids; the amide bond structure can not be reversed, otherwise the activity will disappear.
【学位授予单位】：华东师范大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R96
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1 童为光;一类靶向USP15抑制的四氢-β-咔啉类化合物的发现及活性研究[D];华东师范大学;2014年
，本文编号：2510904
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