基于DNA G-四链体识别的抗肿瘤分子筛选及结构设计研究进展

Progress on G-quadruplex as targets in anticancer drug structure screening and rational design

以生物靶分子为基础进行抗肿瘤药物先导化合物的筛选是抗肿瘤药物研究的热点之一.DNAG-四链体结构的发现和现代分子生物学技术对其与癌症关系的揭示,为目前抗肿瘤药物研发提供了一个新的契机.能够诱导DNA形成G-四链体结构或者与G-四链体特异性结合并使之稳定的化合物有望抑制肿瘤细胞的生长,从而达到抗癌的作用.以G-四链体为抗癌药物作用靶点对化合物进行筛选和结构设计是目前化学家和生物学家的关注点.本文旨在针对靶向G-四链体的抗肿瘤分子筛选、结构设计以及抗肿瘤药物开发三个方面的最新研究进展进行综述.首先,介绍两种基于G-四链体对其配体结构特异性识别而对化合物进行结构筛选的研究方法:基于核磁共振进行抗肿瘤化合物筛选方法以及计算机虚拟筛选.其次,从化合物与G-四链体之间静电相互作用方面来进行G-四链体配体的结构设计,主要包括以下4种类型:(1)原位胺的质子化;(2)通过杂环芳香族化合物上的N-甲基化;(3)中心金属离子的存在;(4)不带电荷的化合物.最后,对目前基于G-四链体为抗肿瘤作用靶点、已经走向临床实验的CX-3543,AS1411两个抗肿瘤药物的开发与作用机制进行介绍.

Based on the recognition of bio-target molecules, screening novel anti-cancer drugs has become one of the research focuses. The revealing of the relationship between the G-quadruplex and cancer by modern molecular biology techniques provides a new opportunity to the anti-cancer drugs research. A general consensus is that organic molecules that induce or stabilize G-quadruplex structures could pave the way for the discovery of novel anti-cancer agents. Therefore, it attracts the interest of chemists and biologists in the research on anticancer drug structure screening and rational design target in G-quadruplex. The present article aims to highlight recent advances in the screening and design of G-quadruplex ligands and development of the anticancer drugs. Firstly, two screening approaches based on the recognition of G-quadruplex are introduced, one is fast screening of G-quadruplex ligands from natural plant extracts based on NMR, the other is screening anticancer compounds by molecular docking techniques. Secondly, the numerous ligands can be classified into four different categories on the basis of their cationic nature, (1) in situ protonation of an amine appendage, (2) N-methylation of an aza-aromatic moiety, (3) the presence of a metal centre, and (4) noncationic ligands. Finally, two quadruplex-related drug candidates CX3543 and AS1411 have entered phase I clinical trial, and the mechanism of them has been explored.