HDAC抑制剂Belinostat类似物的研究以及氧化吲哚螺四氢呋喃环衍生物的合成

发布时间：2018-09-08 12:26

【摘要】：癌症是一种直接危害人类生命健康的严重性疾病。而HDAC抑制剂则是近年来临床验证的癌症治疗的理想药物。因此,开发新型的抑癌效果好、毒副作用小的组蛋白去乙酰化酶抑制剂新药在药物研发和临床医药领域有着重要意义。本文设计并合成了具备抗肿瘤活性的组蛋白去乙酰化酶抑制剂贝利斯他的类似物,步骤简单,原料廉价易得,所得化合物也有着良好的广谱抑酶活性。在各种天然产物和已知药物分子中,有三分之一的有机化合物是杂环化合物。其中,螺环氧化吲哚化合物也是许多天然产物的核心骨架,而且具有很好的生物活性。因此,以绿色环保的方法合成氧化吲哚螺环化合物在天然产物化学和药物化学领域有着重要意义。本文一步合成了氧化吲哚螺四氢呋喃环为核心骨架的一系列化合物,所用方法简单环保,无有机溶剂参与反应。本论文第一部分对组蛋白去乙酰化酶抑制剂进行了简要概述,并阐述了国内外对于此类化合物的结构设计以及活性探索的研究现状,总结了这类化合物的结构与活性的相互影响,并且借鉴了前人的研究为本文的路线设计提供了创新思路。同时本部分综述了含氧螺环的天然产物和化学药物,对合成氧化吲哚螺四氢呋喃环衍生物的方法进行了概述,分析此类反应中的优缺点,为本文的内容提供借鉴。本论文第二部分介绍了组蛋白去乙酰化酶抑制剂贝利斯他的类似物的合成路线方法。通过廉价易得的原料,经过较少的步骤合成了目标化合物,并列举出其抗肿瘤活性。本文第三部分介绍了使用α-异戊烯基化的靛红衍生物作为底物,通过一步反应来合成氧化吲哚螺四氢呋喃环衍生物的反应。在反应中,以绿色无毒的水取代其他有机溶剂为反应溶剂,经甲磺酸催化一步生成氧化吲哚螺四氢呋喃环衍生物,并提出了可能机理。所有目标产物的结构均经1H NMR、13C NMR、HRMS测试,部分化合物的结构通过单晶X-ray衍射证实。
[Abstract]:Cancer is a serious disease that directly endangers human life and health, and HDAC inhibitors are the ideal drugs for cancer treatment which have been clinically verified in recent years. Therefore, it is of great significance to develop new histone deacetylase inhibitors with good anti-cancer effect and low toxicity and side effects in drug research and development and clinical medicine. The analogues of histone deacetylase inhibitor Bellistat with antitumor activity were synthesized. The steps were simple, the raw materials were cheap and easy to obtain, and the obtained compounds also had good broad-spectrum inhibitory enzymes activities. Among the natural products and known drug molecules, one third of the organic compounds were heterocyclic compounds. Indole compounds are also the core skeleton of many natural products and have very good biological activities. Therefore, the synthesis of indole spiro-oxides by green environmental protection method is of great significance in the field of natural product chemistry and pharmaceutical chemistry. In this paper, a series of complexes with indole spiro-tetrahydrofuran ring as the core skeleton were synthesized in one step. The first part of this paper gives a brief overview of histone deacetylase inhibitors, and describes the structure design and activity of these compounds at home and abroad, summarizes the interaction between the structure and activity of these compounds, and draw lessons from it. At the same time, this part summarizes the natural products and chemical drugs of oxygen-containing spiral rings, summarizes the synthetic methods of indole spiro-tetrahydrofuran ring derivatives, analyzes the advantages and disadvantages of such reactions, and provides reference for the content of this paper. The second part of this paper introduces the synthesis of indole spiro-tetrahydrofuran ring derivatives. The synthetic routes of histone deacetylase inhibitor Bellista analogues are described. The target compounds are synthesized in fewer steps from cheap and readily available raw materials and their antitumor activities are enumerated. In the third part of this paper, the indirubin derivatives with a-isopentenyl group are introduced as substrates to synthesize oxidation by one-step reaction. The reaction of indole spiral tetrahydrofuran ring derivatives. In the reaction, green and non-toxic water was used to replace other organic solvents as the reaction solvent, and one-step synthesis of indole spiral tetrahydrofuran ring derivatives catalyzed by methanesulfonic acid was carried out. The possible mechanism was proposed. The structures of all the target products were determined by 1H NMR, 13C NMR and HRMS. It was confirmed by single crystal X-ray diffraction.
【学位授予单位】：江苏师范大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O626

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