靶向bcl-2 mRNA G-四链体的新型氨基糖核酸嵌入剂的合成与作用机制研究

G-四链体是新型抗肿瘤药物的有效作用靶点之一。本项目针对现有G-四链体配体存在的结合亲和力不强、作用选择性不高等问题，选择bcl-2 mRNA G-四链体为靶分子，通过对天然氨基寡糖进行结构剖析，结合计算机辅助设计预测结果，设计带有氨基糖片段的新型G-四链体配体分子，选择合适的保护基策略，构建新颖的结构多样性化合物库，采用NMR和CD检测方法，确认具有高选择性识别mRNA G-四链体的作用，继而进行体外抗肿瘤活性评价，总结较为系统的构效关系。此外，通过考察Bcl-2蛋白调节作用和质粒构建相关技术，探索相应的靶向作用机制，深入讨论氨基糖片段的生物学功能。本项目为建立与mRNA G-四链体产生特异结合、充分结合和有效结合的核酸嵌入剂的发现策略提供一条科学有效的新思路。

G-quadruplex has been proved to be one of the effective targets for developing novel antitumor drugs. The proposal aims to achieve novel aminosugar-intercalator conjugate with high affinity, selectivity and specificity, and subsequently use them as G-quadruplex ligands to act on bcl-2 mRNA G-quadruplex. A series of novel aminosugar-intercalator conjugates were designed on the basis of the latest released G-quadruplex-binding functions of some natural aminoglycoside, and will be synthesized via appropriate protective function group strategy. The research approach will be guided by computer-aided design to better fit the aminosugar-intercalator complexes into the targeting sequence-dependent grooves and loops, and their effective binding will be determined by the NMR and CD spectroscopy. Finally, the in vitro antitumor activity evaluation, the protein expression modulation and the plasmid construction will be helpful to conclude the SARs and explore the corresponding mechanism. Projects from this proposed research ultimately afford new and significant approach to mRNA-based G-quadruplex ligands, and seek to go beyond the evident limits of current DNA G-quadruplex ligands. This will be beneficial to provide new scientific idea for finding G-quadruplex ligand leads.