基于结构的组蛋白去乙酰化酶和甲基转移酶双靶点抑制剂的设计、合成和活性研究
发布时间：2019-03-19 13:48
【摘要】：目的:组蛋白去乙酰化酶和组蛋白甲基转移酶是和多种癌症相关的两个关键靶点酶,研究发现多靶点抗癌药物不仅可以提高治疗效果,而且可以避免多种药物联合用药时可能产生的相互作用,降低副作用,在癌症治疗方面具有重要意义。本实验研究目的是设计合成一些新型双靶点抗癌化合物,可以同时抑制两个靶点蛋白的活性。不仅可以达到治疗癌症的目的,而且为多靶点药物的开发研究提供基础。方法:首先,在化合物设计方面采用药效团拼合的方法去设计双靶点抗癌化合物。其次,在合成化合物路线方面通过借鉴文献以及查阅Scifinder的方法来设计化合物合成的路线。再次,在后期的生物活性检测方面,运用抗增殖毒性实验、In Cell-western以及酶活性研究来检测化合物的毒性以及对于靶点酶的抑制作用。最后本文应用计算机辅助技术来研究化合物的成药性以及和与靶点蛋白结构的结合模式。结果:本文运用药效团拼合的原理,基于靶点组蛋白甲基转移酶抑制剂BIX-01294的母核喹唑啉双环和组蛋白去乙酰化酶抑制剂伏立诺他Vorinostat改造,成功设计了三个系列的目标化合物。通过借鉴文献以及查阅Scifinder,根据化合物的结构特点,成功设计出五条合成路线。化合物分别以2,4-二氯-6,7-二甲氧基喹唑啉和4-甲氧基-2-氨基苯甲酸等为原料,成功合成了23个目标化合物,所有的全新中间体和目标化合物经过了1H-NMR和13C-NMR的结构验证。对于化合物的后期活性测试实验,经过细胞抗增殖毒性实验、In Cell-western以及酶活性研究结果显示,化合物QZ-8(14)表现出良好的生物活性筛选结果,细胞抗增殖实验中,QZ-8(14)对于肿瘤细胞(MDA-MB-231、MCF-7、A549、HCT-8)的EC50值分别约为10μM、37μM、36μM、73μM左右;对于HDAC的IC50只有6μM左右;在In Cell-western实验中对于G9a的IC50只有7μM左右。通过生物活性实验筛选出来的化合物QZ-8(14)经过计算机辅助药物设计软件Discovery Studio的ADME预测功能的预测结果,成药性良好;运用Schr?dinger Suite软件把QZ-8(14)与蛋白晶体结构精密分子对接研究结果表明,化合物QZ-8(14)和双靶点的结合模式都非常好,可以和双靶点蛋白之间产生良好的相互作用。结论:本研究运用药效团拼合原理成功设计了一批组蛋白去乙酰化酶和组蛋白甲基转移酶双靶点抑制的目标化合物,经过借鉴文献及Scifinder等资料成功合成了23个全新的目标化合物,合成出的目标化合物通过初步的生物活性筛选,化合物QZ-8(14)表现出较好的药理活性。药物成药性测试和分子对接研究表明,化合物QZ-8(14)表现出较好的成药性预测结果以及分子间的相互作用。
[Abstract]:Objective: histone deacetylase and histone methyltransferase are two key target enzymes related to various cancers. Moreover, it can avoid the possible interaction and reduce the side effects, which is of great significance in the treatment of cancer. The aim of this study is to design and synthesize some novel double target anticancer compounds, which can inhibit the activity of two target proteins at the same time. It can not only achieve the purpose of cancer treatment, but also provide a basis for the development of multi-target drugs. Methods: firstly, two-target anticancer compounds were designed by the combination of pharmacophore in the design of compounds. Secondly, the synthetic route of compound is designed by referring to the literature and referring to the method of Scifinder. Thirdly, in the later biological activity detection, anti-proliferation toxicity test, In Cell-western and enzyme activity study were used to detect the toxicity of the compounds and their inhibition to target enzymes. Finally, computer-aided techniques were used to study the formation of compounds and their binding patterns to target protein structures. Results: based on the principle of combination of pharmacodynamics groups, the target histone methyltransferase inhibitor, BIX-01294, was modified with quinazoline binicyclic and Volinostat Vorinostat, an inhibitor of histone deacetylase, in the parent nucleus of the target histone methyltransferase inhibitor (HMTI). Three series of target compounds have been designed successfully. Five synthetic routes were successfully designed by referring to the literature and referring to Scifinder, according to the structural characteristics of the compounds. Using 2,4-dichloro-6,7-dimethoxy-quinazoline and 4-methoxy-2-aminobenzoic acid as raw materials, 23 target compounds were synthesized successfully. All the new intermediates and target compounds were confirmed by 1H-NMR and 13C-NMR. The results of cell anti-proliferation toxicity test, In Cell-western and enzyme activity study showed that compound QZ-8 (14) showed good biological activity screening results. In the cell anti-proliferation test, the results of cell anti-proliferation test showed that QZ-8 (14) showed good biological activity. The EC50 values of QZ-8 (14) for tumor cells (MDA-MB-231,MCF-7,A549,HCT-8) were about 10 渭 M, 37 渭 M, 36 渭 M and 73 渭 M, respectively. The IC50 for HDAC is only about 6 渭 M, and the IC50 for G9a is only about 7 渭 M for In Cell-western experiment. The compounds QZ-8 _ (14) screened by bioactivity experiment were predicted by the ADME prediction function of the computer-aided drug design software Discovery Studio, and the results showed that the drug-forming properties of the compounds were good. The docking of QZ-8 _ (14) with protein crystal structure by Schr?dinger Suite software shows that the binding mode of QZ-8 _ (14) and double target is very good, and the results show that the binding mode of QZ-8 _ (14) with protein crystal structure is very good. It can interact well with double target proteins. Conclusion: in this study, a series of target compounds of histone deacetylase and histone methyltransferase were successfully designed by using the principle of combination of pharmacophore groups, and the two targets of histone deacetylase and histone methyltransferase were successfully designed. Twenty-three new target compounds were successfully synthesized by reference to literature and Scifinder, and the target compounds were screened by preliminary biological activity. The compounds QZ-8 (14) showed good pharmacological activity. The results of drug formation test and molecular docking showed that compound QZ-8 (14) showed good prediction results and intermolecular interaction.
【学位授予单位】：天津医科大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R91;R914.5
本文编号：2443577
[Abstract]:Objective: histone deacetylase and histone methyltransferase are two key target enzymes related to various cancers. Moreover, it can avoid the possible interaction and reduce the side effects, which is of great significance in the treatment of cancer. The aim of this study is to design and synthesize some novel double target anticancer compounds, which can inhibit the activity of two target proteins at the same time. It can not only achieve the purpose of cancer treatment, but also provide a basis for the development of multi-target drugs. Methods: firstly, two-target anticancer compounds were designed by the combination of pharmacophore in the design of compounds. Secondly, the synthetic route of compound is designed by referring to the literature and referring to the method of Scifinder. Thirdly, in the later biological activity detection, anti-proliferation toxicity test, In Cell-western and enzyme activity study were used to detect the toxicity of the compounds and their inhibition to target enzymes. Finally, computer-aided techniques were used to study the formation of compounds and their binding patterns to target protein structures. Results: based on the principle of combination of pharmacodynamics groups, the target histone methyltransferase inhibitor, BIX-01294, was modified with quinazoline binicyclic and Volinostat Vorinostat, an inhibitor of histone deacetylase, in the parent nucleus of the target histone methyltransferase inhibitor (HMTI). Three series of target compounds have been designed successfully. Five synthetic routes were successfully designed by referring to the literature and referring to Scifinder, according to the structural characteristics of the compounds. Using 2,4-dichloro-6,7-dimethoxy-quinazoline and 4-methoxy-2-aminobenzoic acid as raw materials, 23 target compounds were synthesized successfully. All the new intermediates and target compounds were confirmed by 1H-NMR and 13C-NMR. The results of cell anti-proliferation toxicity test, In Cell-western and enzyme activity study showed that compound QZ-8 (14) showed good biological activity screening results. In the cell anti-proliferation test, the results of cell anti-proliferation test showed that QZ-8 (14) showed good biological activity. The EC50 values of QZ-8 (14) for tumor cells (MDA-MB-231,MCF-7,A549,HCT-8) were about 10 渭 M, 37 渭 M, 36 渭 M and 73 渭 M, respectively. The IC50 for HDAC is only about 6 渭 M, and the IC50 for G9a is only about 7 渭 M for In Cell-western experiment. The compounds QZ-8 _ (14) screened by bioactivity experiment were predicted by the ADME prediction function of the computer-aided drug design software Discovery Studio, and the results showed that the drug-forming properties of the compounds were good. The docking of QZ-8 _ (14) with protein crystal structure by Schr?dinger Suite software shows that the binding mode of QZ-8 _ (14) and double target is very good, and the results show that the binding mode of QZ-8 _ (14) with protein crystal structure is very good. It can interact well with double target proteins. Conclusion: in this study, a series of target compounds of histone deacetylase and histone methyltransferase were successfully designed by using the principle of combination of pharmacophore groups, and the two targets of histone deacetylase and histone methyltransferase were successfully designed. Twenty-three new target compounds were successfully synthesized by reference to literature and Scifinder, and the target compounds were screened by preliminary biological activity. The compounds QZ-8 (14) showed good pharmacological activity. The results of drug formation test and molecular docking showed that compound QZ-8 (14) showed good prediction results and intermolecular interaction.
【学位授予单位】：天津医科大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R91;R914.5
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