以G-四链体DNA为靶标的新型笼状芳基钌(II)配合物的设计、合成及生物活性研究

设计合成特异选择性靶向核酸的功能配合物研究是探索抗癌药物的新途径之一。G-四链体DNA作为一种具有特殊二级结构的核酸，具有重要的生物学功能。靶向G-四链体小分子化合物的研究也成为当前抗肿瘤研究的热点。根据G-四链体DNA具有富电子芳香末端平面的结构特点，本项目拟设计多核笼状芳基钌(II)配合物，此笼状配合物特点一是主配体和桥联配体均为具有大平面尺寸的有机小分子，特点二是带有六个以上的正电荷，拟借此结构特点实现配合物和G-四链体之间的π-π堆积作用和静电作用，达到对G-四链体特异选择性结合的目的。致力于探讨配合物与G-四链体之间的构效关系及选择性，进一步探索设计合成的笼状配合物与AS1411（一例具有G-四链体结构的核酸，现处于临床二期研究阶段的抗肿瘤潜在药物）之间的相互作用，以及配合物作为AS1411载体的生物活性研究。

The rational design of new DNA-binding functional complex that selectively recognize specific sequences that provides an effective approach for development of novel anticancer drugs. Guanine-rich DNA sequences can adopt a noncanonical structure called the G-quadruplex, which has shown the biological significance as potential anticancer target. And the use of small molecules that promote the formation and/or stabilize G-quadruplex structures has become attractive approaches in anticancer drug discovery. Based on the G-quartets are electron-rich aromatic structures, we plan to design new arene ruthenium cages which are constructed from planar main ligand and bridging-ligands together with arene ruthenium as the joint point. The chief distinguishing features of the complex is positively charged with the ligands are large π-aromatic surfaces, which will be beneficial to the selectivity binding to the G-quadruplex. We are going to focusing on the study of structure-activity relationships between complexes and G-quadruplex. Further we will investigate the interaction between complexes and AS1411, which is an ant proliferative G-rich phosphodiester oligonucleotide that is currently being tested as an anticancer agent in Phase II clinical trials. And the biological activities of metalla-cages, AS1411 and metalla-cages/AS1411complexes also will be explored.