柔性侧链对吨酮识别DNA方式的调控作用

发布时间：2018-02-22 11:12

本文关键词： 吨酮 DNA作用抗肿瘤活性拓扑异构酶抑制剂　出处：《河北大学》2014年硕士论文　论文类型：学位论文

【摘要】：恶性肿瘤已成为严重危害人类健康的主要疾病。随着分子肿瘤学的发展，人类对恶性肿瘤发生、发展的机制逐步清晰。抗肿瘤药物的研发理念也发生了重大转变—由传统抗肿瘤药物转向靶向抗肿瘤药物。DNA及其相关酶是抗肿瘤药物的重要作用靶点，设计开发以DNA及其相关酶为靶点的抗肿瘤药物极具发展前景。本工作选择了具有良好生物和药理活性的吨酮作为先导，合成了一系列带有氨基侧链的吨酮衍生物，并利用光谱技术、凝胶电泳分析、PCR实验等方法系统地研究了它们和双螺旋DNA的结合方式、结合强度以及对细胞增殖的影响与其侧链结构因素等的关系。结果表明，柔性氨基侧链的引入调控了化合物与DNA的结合方式和强度，并且不同的氨基侧链可能改变化合物的极性，使化合物对肿瘤细胞增殖的抑制呈现出一定的差异。其中二甲胺基、吡咯烷基的引入显著增强了吨酮与DNA的结合强度，并明显提高了对肿瘤细胞的抑制能力。在此基础上，利用凝胶电泳检测了化合物对DNA拓扑异构酶(Topo)和Taq聚合酶活性的影响，结果显示，化合物对DNA拓扑异构酶(Topo)和Taq聚合酶没有抑制作用。此外，还检测并分析了课题组已有的抗肿瘤活性小分子CMCT、CMMT及51号硫色满酮衍生物对DNA拓扑异构酶的抑制作用和机理。结果表明，，CMCT和CMMT是Top I的毒剂，且CMCT抑制作用强于CMMT；51号对Top I几乎没有抑制作用。CMCT是Top II的毒剂。
[Abstract]:With the development of molecular oncology, malignant tumor has become a major disease of human health. The mechanism of development has gradually become clear. The concept of development of antitumor drugs has also undergone a major change-from traditional anti-tumor drugs to targeted anti-tumor drugs. DNA and its related enzymes are important targets of antitumor drugs. The design and development of antitumor drugs targeting DNA and its related enzymes are very promising. In this work, a series of tonone derivatives with amino side chain were synthesized by selecting tonone with good biological and pharmacological activities as the lead. The binding mode of double helix DNA and the relationship between the binding strength and the influence of cell proliferation on the side chain structure were systematically studied by means of spectral technique and gel electrophoresis analysis. The introduction of the flexible amino side chain regulates the binding mode and intensity of the compound to DNA, and different amino side chains may change the polarity of the compound, and the inhibition of the compound on the proliferation of tumor cells is different. The introduction of pyrrolidine significantly enhanced the binding strength of tonone to DNA and the inhibition of tumor cells. On this basis, the effects of the compounds on the activity of DNA topoisomerase (Topo) and Taq polymerase were detected by gel electrophoresis. The results showed that the compounds had no inhibitory effect on DNA topoisomerase (Topo) and Taq polymerase. In addition, the inhibitory effect and mechanism of CMMT and thiolone derivatives on DNA topoisomerase were detected and analyzed. The results showed that CMCT and CMMT were toxic agents of Top I. The inhibitory effect of CMCT was stronger than that of CMMT.51 had little inhibitory effect on Top I. CMCT was a toxic agent of Top II.
【学位授予单位】：河北大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R917

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