基于多吡啶钌（II）双核配合物的不对称合成构建端粒酶抑制剂

In recent years, the study on highly effective telomerase inhibitors has been a hot topic in the field of antitumor drug development. Chiral polypyridyl ruthenium(II) dinuclear complexes as telomerase inhibitors has shown great academic value and application potential, owing to their common advantages such as extensive optical and electrical properties, high feasibility for modification and others. However, the reported methods for preparing chiral polypyridyl ruthenium (II) dinuclear complexes are relatively few, moreover, they are all either costly and time consuming, or of poor universality, which has greatly limited the further research on them. This project is the first time to explore the asymmetric synthetic method for chiral polypyridyl ruthenium (II) dinuclear complexes. We plan to adopt the "chiral-auxiliary-mediated asymmetric synthesis" strategy to develop a simple and efficient method for the asymmetric syntheses of polypyridyl ruthenium (II) dinuclear complexes. The skeletal structure of these dinuclear(II) ruthenium complexes is used as the lead scaffold, and the telomere G-quadruplex DNA is used as the target. We intend to build a molecule library for chiral polypyridyl ruthenium(II) dinuclear complex derivatives, with the general principles for novel drug design, such as skeleton transition, isosteric electron and drug stitching etc. We will finally study the drug activities for the whole molecule library, and preliminarily establish the relative structure-activity relationship models, which could provide a significant reference for the further development for polypyridyl ruthenium (II) dinuclear complex antitumor drugs.

近年来，高效端粒酶抑制剂是抗癌药物研发领域的热点。手性多吡啶钌(II)双核配合物作为端粒酶抑制剂拥有巨大的抗癌药物应用潜力，但缺乏高效可靠的制备方法而使之应用受限。本项目拟运用“手性辅基介导”的策略，探索发展一种简单高效的手性多吡啶钌(II)双核配合物的不对称合成方法；以该类配合物的手性双核骨架为先导结构，端粒G-四链体DNA为靶标，运用骨架跃迁、电子等排、药物拼接等原理创制一系列结构新颖、作用机制独特的手性多吡啶钌(II)双核配合物衍生物的分子库；用谱学方法和细胞实验对该分子库进行生物活性研究，建立多吡啶钌(II)双核配合物的构效关系模型，阐明端粒酶抑制活性与抗癌作用的相关性。本研究不仅为手性多吡啶钌(II)双核配合物的不对称合成提供一种新的方法，而且还将揭示多吡啶钌(II)双核配合物的抗癌作用机制和对映体构效关系的普遍规律，从而为新型金属抗癌药物的研发提供积极的借鉴。

本项目运用了“手性辅基介导”的策略，探索了一种简单的手性多吡啶钌(II)双核配合物的不对称合成方法，得到了对映选择性良好的双核配合物；基于这个方法，我们拓展了八面体钌(II)配合物的种类和数量，丰富了无机配位合成化学。其次，基于钌(II)配合物分子库，我们研究了十个具有典型代表结构的钌(II)配合物的抗肿瘤活性。通过整合生物信息学分析方法和生化实验技术手段，我们筛选得到具有良好荧光性质和高选择性抗脑胶质瘤的钌配合物，发现其能够靶向线粒体DNA，为脑胶质瘤的基因突变诊断和治疗一体化提供了新的研究思路。同时，我们也筛选得到了一个具有良好抗隐球菌致脑膜炎的多吡啶八面体钌(II)配合物，其最小抑菌浓度（MIC）和最小杀真菌浓度（MFC）值显着低于作为对照的氟康唑。与隐球菌致脑膜炎模型小鼠相比，负载有钌(II)配合物的脂质体显着延长了携带脑炎的小鼠的存活天数。本研究为金属药物的靶向治疗开发提供了一定的借鉴。