Liu Jie, Zhang Ruirui, Mallick Shubhadip, Patil Sohan, Wientjens Chantal, Flegel Jana, Krupp Anna, Strohmann Carsten, Grassin Corentin, Merten Christian, Pahl Axel, Grigalunas Michael, Waldmann Herbert
Department of Chemical Biology, Max Planck Institute of Molecular Physiology Otto-Hahn-Street 11 44227 Dortmund Germany
Faculty of Chemistry, Chemical Biology, Technical University Dortmund Otto-Hahn-Street 6 44221 Dortmund Germany.
Chem Sci. 2023 Jun 21;14(29):7936-7943. doi: 10.1039/d3sc01240a. eCollection 2023 Jul 26.
combination of natural product (NP) fragments by means of efficient, complexity- and stereogenic character-generating transformations to yield pseudo-natural products (PNPs) may explore novel biologically relevant chemical space. Pyrrolidine- and tetrahydroquinoline fragments rarely occur in combination in nature, such that PNPs that embody both fragments might represent novel NP-inspired chemical matter endowed with bioactivity. We describe the synthesis of pyrrolo[3,2-]quinolines by means of a highly enantioselective intramolecular -1,3-dipolar cycloaddition catalysed by the AgOAc/()-DMBiphep complex. The cycloadditions proceeded in excellent yields (up to 98%) and with very high enantioselectivity (up to 99% ee). Investigation of the resulting PNP collection in cell-based assays monitoring different biological programmes led to the discovery of a structurally novel and potent inhibitor of the Hedgehog signalling pathway that targets the Smoothened protein.
通过高效、能产生复杂性和立体化学特征的转化反应将天然产物（NP）片段组合起来以生成拟天然产物（PNP），这可能会探索出新型的具有生物学相关性的化学空间。吡咯烷片段和四氢喹啉片段在自然界中很少同时出现，因此包含这两种片段的PNP可能代表了具有生物活性的、受新型NP启发的化学物质。我们描述了通过由醋酸银/（-）-DMBiphep络合物催化的高度对映选择性分子内-1,3-偶极环加成反应来合成吡咯并[3,2-]喹啉。环加成反应的产率极高（高达98%），对映选择性也非常高（高达99% ee）。在基于细胞的检测中对所得的PNP集合进行研究，监测不同的生物学程序，从而发现了一种结构新颖且有效的刺猬信号通路抑制剂，该抑制剂靶向Smoothened蛋白。
