含吲哚或异喹啉DNA靶向分子合成及活性研究

发布时间：2018-06-01 13:12

本文选题：抗肿瘤 + DNA靶向　；参考：《大连理工大学》2016年硕士论文

【摘要】：根据分子杂交的设计思想,本文从不同的DNA嵌入剂母体出发,引入吲哚、异喹啉作为药效团,设计合成三个系列新型DNA靶向抗肿瘤药物分子,确认化合物的分子结构,通过光谱测试、体外抗肿瘤活性等探究化合物与DNA之间的相互作用。以9,10-菲醌为原料,基于其本身的生物活性和吲哚类衍生物的抗肿瘤作用,设计合成6个含吲哚取代基的菲并[9,10-d]咪唑类衍生物,MS、1HNMR、13CNMR和单晶衍射等验证分子结构正确,并证实该系列分子具有大的近平面共轭结构。紫外吸收光谱、荧光光谱、圆二色谱、粘度测试等表明该系列化合物可以与DNA结合,引起DNA双螺旋结构的改变。体外抗肿瘤活性测试表明,该系列化合物能够有效地于微摩尔浓度抑制MCF-7、BGC-823肿瘤细胞增殖。以4-溴1,8-萘酐为原料,引入异喹啉作为药效团,设计合成4个含有异喹啉取代基的萘酰亚胺类衍生物。经MS和1HNMR、13CNMR等验证分子结构正确。通过分子与DNA作用前后的紫外、荧光、圆二色、离子效应、粘度测试等表明该系列分子能够与DNA结合,引起DNA构象转变,DNA链解旋松弛。体外抗肿瘤活性测试表明,该系列化合物对于MCF-7、BGC-823肿瘤细胞具有显著的抑制增殖作用。以4-溴-1,8-萘酐为原料,基于在萘酰亚胺母体上并入可以增大分子共轭面积的芳香环可增强分子DNA嵌入能力的研究基础,设计合成了4个N-取代-咪唑并萘酰亚胺类衍生物。经由MS和1HNMR、13CNMR等验证分子结构正确。利用紫外、荧光、圆二色谱、离子效应、粘度测试等探究该系列化合物与DNA的作用模式。MTT比色法探究化合物体外抗肿瘤活性,表明该系列化合物可以在微摩尔浓度显著抑制肿瘤细胞增殖,其中化合物Z2对于所选细胞株的抑制活性最大,其对BGC-823的IC50值为8.23μM。
[Abstract]:According to the design idea of molecular hybridization, three series of novel DNA targeted antitumor drug molecules were designed and synthesized by introducing indole and isoquinoline as pharmacophore from different DNA intercalant parent, and the molecular structure of the compounds was confirmed. The interaction between the compounds and DNA was investigated by spectroscopic test and in vitro anti-tumor activity. Based on its biological activity and the anti-tumor effect of indole derivatives, six phenanthroline derivatives containing indole-substituted group were designed and synthesized. It is confirmed that this series of molecules have large near plane conjugate structures. UV absorption spectrum, fluorescence spectrum, circular dichroism chromatography and viscosity measurement show that the series of compounds can bind to DNA and cause the change of double helix structure of DNA. The antitumor activity test in vitro showed that this series of compounds could effectively inhibit the proliferation of MCF-7 BGC-823 tumor cells at the micromolar concentration. Four naphthalimide derivatives containing isoquinoline substituents were designed and synthesized by using 4-bromo-1-buta-8-naphthalic anhydride as raw material and isoquinoline as pharmacophore. The molecular structure was confirmed by MS and 1HN MR13 CNMR. The UV, fluorescence, circular dichroism, ion effect and viscosity test show that the series of molecules can bind to DNA and cause the conformational transition of DNA to despin relaxation of DNA strand by UV, fluorescence, circular dichroism, ion effect and viscosity test. The antitumor activity test in vitro showed that this series of compounds could significantly inhibit the proliferation of MCF-7 BGC-823 tumor cells. Four N-substituted imidazole-naphthalimide derivatives were designed and synthesized from 4-bromo-1-butadiene-8-naphthalic anhydride. Four N-substituted imidazole-naphthalimide derivatives were designed and synthesized on the basis of the addition of aromatic rings on the base of naphthalene imide matrix to enhance the intercalation ability of the molecular DNA. The molecular structure was verified by MS and 1HN MR13 CNMR. UV, fluorescence, circular dichroism, ion effect and viscosity test were used to explore the interaction mode of this series of compounds with DNA. MTT colorimetric method was used to explore the antitumor activity of the compounds in vitro. The results showed that the series of compounds could significantly inhibit the proliferation of tumor cells at the micromolar concentration. The inhibitory activity of compound Z2 on the selected cell line was the highest, and the IC50 value of compound Z2 to BGC-823 was 8.23 渭 M.
【学位授予单位】：大连理工大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：O626

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