基于氮杂环铱配合物的G4-DNA结构探针的合成及作用机理研究

项目名称： 基于氮杂环铱配合物的G4-DNA结构探针的合成及作用机理研究

项目编号： No.21461028

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 数理科学和化学

项目作者： 梁伟江

作者单位： 玉林师范学院

项目金额： 45万元

中文摘要： 为了寻找高效低毒的G4-DNA结构探针，本项目拟合成系列n-R-4a, 10, 11-苯并三氮唑（3,2a）芴-5,6-苯并吡嗪衍生物-(N-C)铱配合物(N-C =4,7-二苯基邻菲啰啉，联吡啶，邻菲啰啉)。采用UV熔点、FRET熔点、荧光滴定、荧光竞争滴定、CD滴定、NMR光谱、凝胶电泳、S1核酸酶分解和突变实验，研究铱配合物对G4-DNA稳定性的影响；借助铱配合物对十种不同结构G4-DNA的识别，探索选择性识别与构象、序列和四分体层数的关系，揭示propeller loop, lateral loop和diagonal loop在选择性识别中的差异，铱配合物与loop碱基的结合位点及与G4-DNA的作用模式; 通过体外MTT法和体内动物模型药效实验，评估铱配合物的活性；进行水中质量测定和交叉耐药性实验，检验它们的水溶性和交叉耐药性，为开发高效低毒的高活性抗癌药物先导化合物提供技术支持

中文关键词： 氮杂环铱配合物；G4-DNA结构探针；合成；作用机理

英文摘要： To find G4-DNA structural probe with high efficiency and low toxicity, a series of n-R-4a, 10, 11-triazabenzo[3,2a]fluorene -5,6-benzoparadiazine derivative-(N-C)iridium complexes (N-C=4,7-diphenyl-1,10-phenanthroline, 2,2- bipyridine, and 1,10-phenanthroline) will be synthesized. On the basis of the combination of UV and FRET melting assays, fluorometric titration, fluorescence competition titration, CD titration, NMR spectroscopy, gel electrophoresis, S1 nuclease decomposition and mutagenicity test, the effects of the position isomerism, electron effect and chiral isomerism on the stability of G4-DNA should be investigated. The chiral L and D could selectively recognize five different human telomeric G4-DNA structures, which might reveal the relationship between chiral selectivity and conformation, sequence, four-G-tetrad, the difference among propeller loop, lateral loop and diagonal loop in the chiral selectivity, the binding site in loop bases and binding mode. Antitumor activity is able to be estimated by means of MTT methods in vitro and experimental pharmacodynamics in vivo animal model. According to solubility quantitative determination in distilled water and cross-resistance study, aqueous solubility and cross resistance may be detected, which will be capable of providing a technical assistance for developing an highly active oxaliplatin analogues with good water solubility and mild cross resistance.

英文关键词： azaheterocyclic iridium complexes;G4-DNA structural probe;synthesis;action mechanism