【摘要】：目的:組蛋白去乙�；负徒M蛋白甲基轉移酶是和多種癌癥相關的兩個關鍵靶點酶,研究發(fā)現(xiàn)多靶點抗癌藥物不僅可以提高治療效果,而且可以避免多種藥物聯(lián)合用藥時可能產(chǎn)生的相互作用,降低副作用,在癌癥治療方面具有重要意義。本實驗研究目的是設計合成一些新型雙靶點抗癌化合物,可以同時抑制兩個靶點蛋白的活性。不僅可以達到治療癌癥的目的,而且為多靶點藥物的開發(fā)研究提供基礎。方法:首先,在化合物設計方面采用藥效團拼合的方法去設計雙靶點抗癌化合物。其次,在合成化合物路線方面通過借鑒文獻以及查閱Scifinder的方法來設計化合物合成的路線。再次,在后期的生物活性檢測方面,運用抗增殖毒性實驗、In Cell-western以及酶活性研究來檢測化合物的毒性以及對于靶點酶的抑制作用。最后本文應用計算機輔助技術來研究化合物的成藥性以及和與靶點蛋白結構的結合模式。結果:本文運用藥效團拼合的原理,基于靶點組蛋白甲基轉移酶抑制劑BIX-01294的母核喹唑啉雙環(huán)和組蛋白去乙酰化酶抑制劑伏立諾他Vorinostat改造,成功設計了三個系列的目標化合物。通過借鑒文獻以及查閱Scifinder,根據(jù)化合物的結構特點,成功設計出五條合成路線。化合物分別以2,4-二氯-6,7-二甲氧基喹唑啉和4-甲氧基-2-氨基苯甲酸等為原料,成功合成了23個目標化合物,所有的全新中間體和目標化合物經(jīng)過了1H-NMR和13C-NMR的結構驗證。對于化合物的后期活性測試實驗,經(jīng)過細胞抗增殖毒性實驗、In Cell-western以及酶活性研究結果顯示,化合物QZ-8(14)表現(xiàn)出良好的生物活性篩選結果,細胞抗增殖實驗中,QZ-8(14)對于腫瘤細胞(MDA-MB-231、MCF-7、A549、HCT-8)的EC50值分別約為10μM、37μM、36μM、73μM左右;對于HDAC的IC50只有6μM左右;在In Cell-western實驗中對于G9a的IC50只有7μM左右。通過生物活性實驗篩選出來的化合物QZ-8(14)經(jīng)過計算機輔助藥物設計軟件Discovery Studio的ADME預測功能的預測結果,成藥性良好;運用Schr?dinger Suite軟件把QZ-8(14)與蛋白晶體結構精密分子對接研究結果表明,化合物QZ-8(14)和雙靶點的結合模式都非常好,可以和雙靶點蛋白之間產(chǎn)生良好的相互作用。結論:本研究運用藥效團拼合原理成功設計了一批組蛋白去乙�；负徒M蛋白甲基轉移酶雙靶點抑制的目標化合物,經(jīng)過借鑒文獻及Scifinder等資料成功合成了23個全新的目標化合物,合成出的目標化合物通過初步的生物活性篩選,化合物QZ-8(14)表現(xiàn)出較好的藥理活性。藥物成藥性測試和分子對接研究表明,化合物QZ-8(14)表現(xiàn)出較好的成藥性預測結果以及分子間的相互作用。
[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.
【學位授予單位】：天津醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R91;R914.5

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