结构及序列双模态识别的靶向血管内皮生长因子（VEGF）G-四链体新型配体结构设计及活性研究

血管内皮生长因子（VEGF）是肿瘤血管新生的重要调节因子之一。稳定VEGF启动子区域G-四链体结构的配体可有效抑制VEGF的表达，由此能够高效识别并稳定该G-四链体结构的配体有望成为新型的血管新生抑制剂。本项目以VEGF G-四链体为靶点，以新型异喹啉生物碱为核心骨架，以我们前期对G-四链体及其配体的系统研究为基础，结合DNA G-四链体结构匹配单元和寡聚核苷酸序列定位单元的优势，利用“结构”和“序列”的双模态识别策略，开展新型靶向配体的研究。通过评价系列化合物对VEGF的表达、对新生血管的抑制作用及抗肿瘤活性，总结构效关系，筛选得到高活性配体，为后续以VEGF G-四链体为靶点的药物研发提供研究基础。

Vascular endothelial growth factor (VEGF), is a key regulator of angiogenesis, plays an important role in tumor survival, growth and metastasis. The polypurine/polypyrimidine sequence located upstream of the promoter region in VEGF can form specific parallel G-quadruplex structures. And the small molecules, which can interact with the VEGF G-quadruplex, resulting in the down-regulated transcription and express this gene and potentially reducing VEGF-simulated angiogenesis. In this project, we focus on the VEGF G-quadruplex as the target, choose the isoquinoline alkaloid as the core skeleton, design and synthesize a series of ligands for the VEGF G-quadruplex by using structural recognition and sequence positioning dual-mode strategy. Moreover, the inhibitory effect of these derivatives on the expression of VEGF genes and protein, and the cytotoxic activity and the antitumor mechanism of these derivatives were studied and summarized. This project also aims to provide a solid theoretical foundation for the design of anti-tumor candidate drugs which targeted to VEGF G-quadruplex.