新型含金刚烷结构缺氧诱导因子-1抑制剂的合成及抗肿瘤活性研究

发布时间：2018-06-01 19:13

本文选题：金刚烷 + 缺氧诱导因子-1　；参考：《长春工业大学》2016年硕士论文

【摘要】：在肿瘤细胞缺氧的情况下,缺氧诱导因子-1(HIF-1)具有关键的调节作用,使肿瘤细胞顺应缺氧的环境。目前,缺氧诱导因子-1是抗肿瘤药物研究的重要靶点。已经发现了很多缺氧诱导因子-1抑制剂。其中,一些含金刚烷结构的化合物可以作为缺氧诱导因子-1抑制剂。1.对化合物3-(4-羟苯基)金刚烷-1-羧酸的羧基部分和酚羟基部分进行结构修饰,合成了一类新型的含金刚烷结构单元的3-(4-羟苯基)金刚烷-1-羧酸衍生物9个,在合成这类化合物的过程中,合成了10个重要的中间体化合物。2.以化合物4-(1-金刚烷基)苯酚为骨架,对其苯酚环进行结构修饰,合成了新型的包含金刚烷结构单元的4-(1-金刚烷基)苯酚衍生物4个,在合成这类化合物的过程中,合成了7个中间体化合物。3.另外,以1-金刚烷羧酸为原料探究了具有金刚烷结构单元的金刚烷羧酸衍生物的合成方法及实验条件。化合物的结构是由核磁氢谱、碳谱、红外光谱及质谱确定的。利用荧光素酶报告基因的方法,检测了这些化合物作为缺氧诱导因子-1抑制剂的潜能,得到了一些对缺氧诱导因子-1有抑制作用的抑制剂。并且,大部分合成的化合物在可以有效抑制缺氧诱导因子-1活性的浓度下,没有明显的细胞毒性。对合成的化合物进行了结构活性分析。在缺氧的条件下,具有吲哚基团含金刚烷结构单元的化合物20a可以作为肝癌细胞中缺氧诱导因子-1有效的抑制剂。而且,细胞毒性非常小(IC50=0.02μM)。这些化合物的合成可能会给新的抗肿瘤药物的研发提供一些有价值的信息。
[Abstract]:Hypoxia-inducible factor-1 (HIF-1) plays a key role in regulating tumor cells to adapt to anoxic environment. At present, hypoxia-inducible factor-1 is an important target of anti-tumor drugs. A number of hypoxia inducible factor-1 inhibitors have been identified. Among them, some compounds with adamantane structure can be used as anoxic inducible factor-1 inhibitor. In this paper, the carboxyl and phenolic hydroxyl parts of the compound 3-O4-hydroxyphenyl) adamantine-1-carboxylic acid were modified, and a new class of derivatives of 3-O4-hydroxyphenyl) adamantine-1-carboxylic acid containing adamantane structure unit was synthesized. In the process of synthesizing these compounds, ten important intermediates. 2. 2 were synthesized. In this paper, the structure of the phenol ring was modified by the structure modification of the phenol ring of the compound 4-O1-adamantyl) phenol. Four new derivatives of phenol containing the adamantane structure unit were synthesized. In the process of synthesizing these compounds, four new derivatives were synthesized. Seven intermediates were synthesized. In addition, the synthetic method and experimental conditions of adamantane carboxylic acid derivatives with adamantane structure unit were studied using 1-adamantane carboxylic acid as raw material. The structure of the compound is determined by nuclear magnetic hydrogen spectrum, carbon spectrum, infrared spectrum and mass spectrometry. Luciferase reporter genes were used to detect the potential of these compounds as inhibitors of hypoxia inducible factor-1 (HIF-1), and some inhibitors were obtained to inhibit hypoxia inducible factor-1 (HIF-1). Moreover, most of the synthesized compounds have no obvious cytotoxicity at the concentration that can effectively inhibit the activity of hypoxia inducible factor-1 (HIF-1). The structure and activity of the synthesized compounds were analyzed. Under hypoxia condition, compounds with indolyl group containing adamantane structure unit can be used as effective inhibitors of hypoxia inducible factor-1 in hepatocellular carcinoma cells for 20a. Moreover, the cytotoxicity of IC50 / 0.02 渭 MN was very small. The synthesis of these compounds may provide valuable information for the development of new anti-tumor drugs.
【学位授予单位】：长春工业大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R914.5;R96;O657.63

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