靶向识别端粒G-四链体DNA的小分子配体喹唑啉类衍生物库的构建与作用机制研究

In recent decade, research for anti-cancer drugs targeting telomere/telomerase has become a hot topic. A series of 2,4-disubstituted quinazoline derivatives found to be a new type of highly selective ligand to bind with telomeric G-quadruplex DNA, which led to inhibition of telomere maintenance mechanism and induce the cancer cellular senescence phenotype. Compared with many G-quadruplex ligands with rigid or ?exible structures, the compounds synthesized in the present study are novel "imitative" tetracyclic aromatic system formed through intramolecular hydrogen bond, which enable adoption of moderate twisted and coplanar conformations of the aryl groups, and allow the ligands to well bind to the G-quadruplex with multiple-binding modes. To this end, we propose the ligand and G-quadruplex binding mode is one of the key factors that influence its biological activity, as a theoretical basis for designing efficient new highly selective ligand is a new way of thinking. On the basis of previous work, we will design and construct new quinazoline derivatives library to further investigate the structure-activity relationship of derivatives and clarify the mechanism of action of the multiple-binding modes through the study of the stabilization, selectivity, binding property and their biological effects in vivo or in vitro of the synthetic ligands to telomeric G-quadruplex. Then, to provide new ideas for the design of high selectivity and high activity of anti-cancer drug lead compounds targeting telomeric G-quadruplex.

以端粒/端粒酶为靶点发展新的抗癌药物，是近10年来抗癌药物研究的重要领域之一。我们设计合成的2, 4-二取代喹唑啉类衍生物已经证明能够靶向性的识别结合/稳定端粒G-四链体DNA，从而有效抑制癌细胞的端粒维持机制，促进癌细胞衰老、凋亡。与已报道的G-四链体配体不同，这类新型配体在分子内氢键的作用下具有"刚柔并济"的结构特点，并通过多重的结合模式与端粒G-四链体DNA结合。因此该喹唑啉类配体与端粒G-四链体的结合模式是影响其生物活性的关键因素之一，以此为理论基础设计高效、高选择性的新型配体是一个新的思路。本项目将在已有工作基础上设计合成新的喹唑啉类衍生物库，通过研究配体对端粒G-四链体DNA的结合和稳定能力、选择性、结合模式以及由此产生的细胞内外的生物学效应等总结衍生物的构效关系，阐明衍生物多重结合模式的作用机制，为设计高选择能力和高活性的靶向端粒G-四链体的抗癌药物先导化合物提供新的思路。

以G-四链体DNA发展新的抗癌药物，是近10年来抗癌药物研究的重要领域之一。我们设计合成的2, 4-二取代喹唑啉类衍生物已经证明能够靶向性的识别结合/稳定端粒G-四链体DNA，从而有效抑制癌细胞的端粒维持机制，促进癌细胞衰老、凋亡。本研究在此基础上开展了以下研究工作并取得了重要成果：（1）设计、合成了九个系列新型的喹唑啉及其类似物，并以此为基础构建了具有多样性结构的喹唑啉类化合物库。（2）综合运用各种生物物理和化学的研究方法对比分析了库中各个系列化合物与G-四链体的相互作用，阐明了结构与结合作用的关系。（3）对化合物库中分子进行了细胞内和细胞外的生物活性测试，包括化合物结合/稳定各类G-四链体DNA的能力及选择性、化合物体内外抗肿瘤活作用研究，阐明了结构与活性相关构效关系的信息，为基于G-四链体DNA发展高效低毒的新型抗肿瘤药物提供重要理论和实验依据。总体来说，本项目基本按照计划开展研究，完成了制定的研究目标并取得了相应的成果。目前已发表标注本基金资助的SCI论文4篇，中文核心期刊论文1篇，申请相关专利2个。