合成方法的创新驱动新型药物先导化合物的发现及结构优化进程。我们前期工作：1）建立了创新的多样性碳氢官能化反应体系用于抗肿瘤活性分子的高效合成，2）发现多个新型结构的异喹啉酮、哌啶酮、苯并异噁唑类苗头化合物并初步评估了其体外抗A549/HepG2活性，3）揭示了化合物VST-O23靶向并下调FGFR1激酶等特征。目前构效关系不够清晰、作用机制及靶标尚不明确等因素限制了上述化合物的后续优化。据此，本项目拟通过发展双导向基团协同介导、选择性β-F消除、P-中心手性Bronsted酸协同催化等调控策略建立化学/区域/立体三重精准选择性的碳氢官能化反应用于苗头化合物的功能性结构优化；结合体外药效学评价阐明其构效关系及手性分子的构型-活性关系；通过靶点识别/验证、小分子/靶标蛋白复合物晶体结构解析等手段明确其作用靶标及潜在抗肿瘤作用机制。项目研究成果将有望获得结构新颖、活性更优、机制明确的先导化合物。

The innovation of synthetic methodology promotes the discovery and structural modification of novel drug lead compounds. Our previous work: 1) developed diverse C-H functionalization reactions for the efficient synthesis of antitumor active molecules, 2) disclosed several novel complexes based on isoquinolone, piperidine or benzoisoxazole skeletons as the hit compounds and preliminarily evaluated the corresponding in vitro anti-A549/HepG2 activity, 3) clarified the fact that VST-O23 targeted to and down-regulated FGFR1 kinase. Presently, the structure-activity relationship is not clear, as well as the antitumor mechanism and the target, which affect the further modification of these compounds. Accordingly, this project plans to establish chemo-, regio- and stereoselective triple specific C-H functionalization via synergetic dual directing groups enabled, selective β-F elimination and P-stereogenic chiral Bronsted acid catalyzed strategies, thus leading to the functionalized structural modification of the obtained hit compounds; reveal the structure-activity relationship and the configuration-activity relationship of chiral molecules via evaluating of the in vitro pharmacodynamic research; clarify the potential antitumor mechanism through the identification and validation of drug targets and the crystal analysis of small molecule-target protein complexes. The implementation of the project will help to discover lead compounds with novel structures, higher activity and clear mechanism.