以c-myc G-四链体为靶标的新型配体2,4-二取代嘧啶衍生物的设计、合成及生物活性研究

项目名称： 以c-myc G-四链体为靶标的新型配体2,4-二取代嘧啶衍生物的设计、合成及生物活性研究

项目编号： No.21302188

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 数理科学和化学

项目作者： 王立霞

作者单位： 中国科学院化学研究所

项目金额： 25万元

中文摘要： G-四链体作为一种特殊的DNA二级结构，参与了体内许多重要的生理过程，作为肿瘤检测或治疗的靶点具有非常重要的研究价值。尽管已报道的小分子配体可以对某些G-四链体有好的选择性，要想在复杂体系中实现对痕量浓度存在的G-四链体有特异的选择性，还需要配体对G-四链体的选择性、结合力有更大程度的提高。杂芳环嘧啶具有可调控的反应活性位点，而且2,4-位修饰还可以提供"非对称"特性。本项目是以c-myc G-四链体为靶标，2,4-位活性位点的嘧啶作为配体分子的核心骨架，开展新型配体的设计、合成及生物活性的研究。具体内容包括：2,4-二取代嘧啶衍生物的1）设计和合成；2）对靶标的靶向作用；3）结构优化。本项目旨在揭示2,4-二取代嘧啶衍生物结构变化对靶标选择能力、结合能力的规律，开发一种新型的高特异性、高选择性、高结合能力的小分子配体，为进一步的肿瘤检测探针或抗癌先导化合物的设计提供理论基础。

中文关键词： G-四链体；-芳基取代-喹唑啉酮；3; 8a-二取代吲哚啉酮；特异性识别；抗肿瘤活性

英文摘要： G-quadruplex as a special DNA secondary structure are involved in a myriad of biological processes, and have been a very important target for tumor detection or treatment. Small molecule ligands have been reported for good selectivity to some G-quadruplex, but for high specific recogniton of the trace amount of some G-quadruplex in complex system, the selectivity and the binding capacity must have a greater degree of improvement.The pyrimidine ring has the reactive sites with well-regulation, and could provide the "asymmetric" feature with the modification of its 2,4-sites. We will focus on c-myc G-quadruplex as the target, choose 2,4-disubstituted pyrimidine as the core skeleton, and finish the design, synthesis and bioactivity analysis of the new kind of ligands. Three parts will be included: design and synthesis, the ability targeting to the target， and structural optimization of the 2,4-disubstituted pyrimidine derivatives. This project aims to reveal the relationships of the 2,4-disubstituted pyrimidine derivatives and c-myc G-quadruplex, to develop a new type of ligands with high speciality, selectivity, and high binding capacity, and provides a solid theoretical foundation for the design of tumor detection probe or anti-cancer lead compounds in the future.

英文关键词： G-quadruplex；2-aryl quinazolinone；3; 8a-disubstituted indolizinone；specifical recognition；anti-cancer activities