新型烷酰胺、苯磺酰胺类HDAC抑制剂的设计、合成及初步生物活性研究

发布时间：2018-03-10 14:33

本文选题：组蛋白去乙酰化酶　切入点：组蛋白去乙酰化酶抑制剂　出处：《中国海洋大学》2013年硕士论文　论文类型：学位论文

【摘要】：组蛋白去乙酰化酶(Histone deacetylase,HDACs)是近些年研究较多的肿瘤相关的分子靶标之一,与肿瘤发生、发展和转移以及肿瘤组织的新生血管生成密切相关。组蛋白去乙酰化酶抑制剂(Histone deacetylase inhibitors,HDACIs)是以HDACs为靶点而开发的抗肿瘤药物,它们能引起细胞周期的阻断和肿瘤细胞选择性的凋亡,在体外和动物体内都具有明显抗肿瘤作用。迄今为止,已有两个HDAC抑制剂(SAHAFK228)被美国食品药品监督管理局(FDA)批准用于治疗皮肤T细胞淋巴瘤。因此,开发高效、低毒、选择性强的HDAC抑制剂已成为抗肿瘤药物的重要研究领域之一。MS-275是一种亚型选择性的HDAC抑制剂,其化学结构为苯甲酰胺类化合物,其口服在动物体内具有显著的抗癌活性且毒性较低,目前该药物正在美国进行白血病及实体瘤的临床Ⅱ期研究。本论文以MS-275为先导化合物,根据现有的同类药物的构效关系、结构优化改造及临床进展等研究信息,结合传统药物设计方法设计合成两个不同系列的衍生物,以期获得具有自主知识产权的系列HDAC抑制剂。设计的第1类系列化合物是将MS-275的连接链进行变换,用脂肪直链取代其芳香链,酶抑制区保留了邻苯二胺的结构,表面识别区用系列(杂)芳基替代MS-275的柔性基团以得到不同的化合物；之后在第1类结构基础上改造,把Ⅰ类的脂肪直链变为脂肪环,以测定环状基团对药物抗肿瘤活性的影响。第Ⅱ类系列化合物用苯磺酰胺取代苯甲酰胺,同样在表面识别区用系列(杂)芳基进行替代,同时设计合成了除苯磺酰胺外与MS-275完全相同的化合物151,以其考察吸电子效应更强的磺酰基基团对于其活性的影响。本文共合成了烷酰胺及苯磺酰胺两个系列26个新的目标化合物,采用SRB的方法,选择1株前列腺癌细胞PC3为模型,对第Ⅰ系列化合物的抗肿瘤活性进行初步评价,结果表明它们并无明显的抗肿瘤细胞株增殖的能力,推测与连接链的芳香基团缺失有关；同样选择前列腺癌细胞PC3为模型,对第Ⅱ系列目标化合物进行初步的活性评价,显示化合物148和151其具有一定的抑制肿瘤细胞增殖的活性,分子水平的抑制机制的探讨正在进行中。本论文为进一步寻找高效低毒的非羟肟酸类HDAC抑制剂提供了一定的研究基础。
[Abstract]:Histone deacetylase (histone deacetylase HDACs) is one of the molecular targets associated with tumorigenesis in recent years. Histone deacetylase inhibitors (HDACIsa), a histone deacetylase inhibitor, is an antitumor drug developed with HDACs as a target, which can block cell cycle and induce selective apoptosis of tumor cells. To date, two HDAC inhibitors, SAHAFK228, have been approved by the U.S. Food and Drug Administration for the treatment of cutaneous T-cell lymphoma. The highly selective HDAC inhibitors have become one of the important research fields of antitumor drugs. MS-275 is a subtype-selective HDAC inhibitor with the chemical structure of benzoamide compounds. The drug has significant anticancer activity and low toxicity in animals. At present, the drug is currently being studied in the United States for clinical stage II of leukemia and solid tumors. In this paper, MS-275 is used as a lead compound, according to the structure-activity relationship of existing similar drugs. Based on the information of structural optimization and clinical progress, two different series of derivatives were designed and synthesized in combination with traditional drug design methods. In order to obtain a series of HDAC inhibitors with independent intellectual property rights, the first series of compounds were designed to transform the chain of MS-275 to replace its aromatic chain with straight chain of fat, and the inhibitory region of enzyme retained the structure of o-phenylenediamine. The surface recognition zone replaces the flexible groups of MS-275 with a series of (hetero) aryl groups to obtain different compounds, and then transforms the straight chain of type I fat into a fatty ring on the basis of the first type structure. In order to determine the effect of cyclic groups on the antitumor activity of the drug. Class II compounds were substituted by benzamide with benzenesulfonamide and substituted by series (hetero) aryl groups in the surface recognition area. At the same time, the compound 151which is identical to MS-275 except benzenesulfonamide was designed and synthesized. In order to investigate the influence of the more electron-absorbing groups on its activity, 26 series of alkanamide and benzenesulfonamide were synthesized in this paper. New target compounds, Using SRB method, a prostate cancer cell line PC3 was selected as a model to evaluate the antitumor activity of the first series of compounds. The results showed that they had no obvious ability of anti-tumor cell proliferation. The preliminary activity evaluation of the target compounds of the second series showed that compounds 148 and 151had a certain activity of inhibiting the proliferation of tumor cells, which was related to the deletion of aromatic groups in the ligand chain, and the prostate cancer cell line PC3 was also selected as the model to evaluate the activity of the target compounds of the second series. The mechanism of inhibition at molecular level is in progress. This paper provides a basis for further searching for high efficiency and low toxicity non-hydroxamic acid HDAC inhibitors.
【学位授予单位】：中国海洋大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R91;R914.5

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