新型基于吡咯[4,3,2-de]喹啉类STAT3抑制剂的设计、合成与抗肿瘤活性研究

本课题以吡咯[4,3,2-de]喹啉类天然产物Ammosamide B/F骨架为核心，结合计算机辅助药物设计手段，进行结构优化，设计与合成全新结构的STAT3抑制剂。STAT3信号转导通路是近年抗癌药物研究的重要靶点，吡咯并喹啉类具有广谱的抗肿瘤活性，本课题首次利用金属催化的C-H官能团化反应及C-杂原子偶联反应以构建芳杂环稠和的吡咯[4,3,2-de]喹啉类骨架，引入多种报道的活性片段和亲水性基团，构建活性分子库；通过测试化合物对肿瘤细胞抗增殖活性、对STAT3磷酸化抑制活性、对STAT3-STAT3二聚化的影响，分析构效关系，以期发现苗头化合物。本研究将为后期探讨此类化合物的作用模式与作用机制，以及发现新型基于吡咯[4,3,2-de]喹啉类STAT3抑制剂的抗肿瘤药物的研究奠定基础。

The project was focused on the design and synthesis of novel STAT3 inhibitors of natural product Ammosamide B-F-like pyrrolo[4,3,2-de]quinoline analogs, based on the computer aided drug design technique and structural optimization method. Constitutive activation of signal transducer and activator of transcription 3 (STAT3) has been found in a wide variety of cancers, promoting it as a very attractive therapeutic target. for cancer therapy. Ammosamide analogues showed high selectivity against a diversity of cancer cell lines. In this study, The new approach for the synthesis of heteroaromatic ring fused pyrroloquinoline skeleton was developed for the first time ,by using aryl heteropyrimidine structures based on matal -catalyzed C-H functionalization reaction and C-heteroatomic coupling reaction.A structurally diverse library including two class bioactive compounds of target compounds (class I and class II), which have various bioactive groups on key skeleton would be constructed. The screen assay would be described on antitumor activity in vitro , on inhibitory activity of STAT3 phosphorylation，STAT3-STAT3 dimerization and STAT3-DNA binding, and then, structure-activity relationship and inhibotor action model would be discussed in order to find novel STAT3 inhibitors. The study would developed a new synthetic approach on Ammosamides-like pyrroloquinoline derivatives, provide an approach on design new small antitumor compounds on STAT3 inhibitors, and establish the foundation for finding new antitumor drugs based on STAT3 signaling pathway.