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

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.

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。

吡咯[4,3,2-de]喹啉类分子具有较好的抗肿瘤活性，但其作用机制尚不明确。而STAT3信号转导通路是近年抗癌药物研究的重要靶点，尚无上市药物。因此，设计与合成全新结构的STAT3抑制剂具有重要意义。本项目期望探索发现新型的天然产物类STAT3抑制剂。以吡咯[4,3,2-de]喹啉类天然产物Ammosamide B骨架为核心，发展了一条新的合成路线，完成了天然产物Ammosamide B的全合成；之后对吡咯[4,3,2‐de]喹啉类母核进行结构修饰，设计合成了具有吡咯[4,3,2‐de]喹啉母核的Ammosamides类似物30个；合成了噁唑[5,4-h]吡咯并[4,3,2-de]喹啉类衍生物18个；将合成的系列化合物进行体外抗肿瘤活性筛选，发现其中一个化合物对肺癌细胞A549表现出较好活性（IC50=9.5uM），一个化合物对STAT3敏感的胰腺癌细胞 Panc-1 和MIAPACA2表现出较好选择性抑制活性（IC50=9.381 IC50=3.487），之后选取活性较好的化合物进行了针对STAT3通路抑制活性的研究，结果表明1个化合物对 MIAPACA2细胞STAT3的磷酸化具有较好的抑制活性, 有望成为后期活性研究的靶标化合物。本项研究为发现新型基于吡咯[4,3,2‐de]喹啉类STAT3抑制剂的先导化合物奠定了基础。本项目目前发表学术论文4篇，其中SCI论文2篇，会议论文2篇，申请专利2项。培养博士生1名，硕士生2名。