Max Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Str. 11, 44227, Dortmund, Germany.
Chemical Genomics Center of the Max Planck Society, Otto-Hahn-Str. 15, 44227, Dortmund, Germany.
Angew Chem Int Ed Engl. 2017 Feb 13;56(8):2145-2150. doi: 10.1002/anie.201611670. Epub 2017 Jan 18.
The cinchona alkaloids are a privileged class of natural products and are endowed with diverse bioactivities. However, for compounds with the closely-related oxazatricyclo[4.4.0.0]decane ("oxazatwistane") scaffold, which are accessible from cinchonidine and quinidine by means of ring distortion and modification, biological activity has not been identified. We report the synthesis of an oxazatwistane compound collection through employing state-of-the-art C-H functionalization, and metal-catalyzed cross-coupling reactions as key late diversity-generating steps. Exploration of oxazatwistane bioactivity in phenotypic assays monitoring different cellular processes revealed a novel class of autophagy inhibitors termed oxautins, which, in contrast to the guiding natural products, selectively inhibit autophagy by inhibiting both autophagosome biogenesis and autophagosome maturation.
金鸡纳生物碱是一类具有独特结构的天然产物，具有多种生物活性。然而，对于那些结构密切相关的具有氧氮杂三环[4.4.0.0]癸烷（“氧氮杂螺环丁烷”）骨架的化合物，它们可以通过金鸡纳碱和奎宁的环变形和修饰得到，但尚未确定其生物活性。我们通过采用最先进的 C-H 官能化和金属催化交叉偶联反应作为关键的后期多样性生成步骤，报道了一个氧氮杂螺环丁烷化合物库的合成。在监测不同细胞过程的表型测定中探索氧氮杂螺环丁烷的生物活性，发现了一类新型的自噬抑制剂，称为氧自噬素，与指导天然产物不同，它们通过抑制自噬体生物发生和自噬体成熟来选择性地抑制自噬。
