Müller Jonas I, Gulder Tobias A M
Chair of Technical Biochemistry, Technical University of Dresden, Bergstraße 66, 01069, Dresden, Germany.
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Department of Natural Product Biotechnology, Helmholtz Centre for Infection Research (HZI) and Department of Pharmacy at Saarland University, 66123, Saarbrücken, Germany.
Commun Chem. 2024 Feb 24;7(1):39. doi: 10.1038/s42004-024-01126-1.
The sorbicillinoid family is a large class of natural products known for their structural variety and strong, diverse biological activities. A special member of this family, sorbicillactone A, the first nitrogen-containing sorbicillinoid, exhibits potent anti-leukemic and anti-HIV activities and possesses a unique structure formed from sorbicillinol, alanine, and fumaric acid building blocks. To facilitate in-depth biological and structure-activity relationship studies of this promising natural product, we developed a chemoenzymatic approach that provides access to sorbicillactone A and several analogs with excellent yields under precise stereochemical control. The key steps of the highly convergent, stereoselective, and short route are the enantioselective oxidative dearomatization of sorbillin to sorbicillinol catalyzed by the enzyme SorbC and the subsequent Michael addition of a fumarylazlactone building block. Additionally, our synthetic findings and bioinformatic analysis suggest that sorbicillactone A is biosynthetically formed analogously.
山梨素类化合物是一大类天然产物，以其结构多样性和强大、多样的生物活性而闻名。该家族的一个特殊成员山梨素内酯A是首个含氮的山梨素类化合物，具有强大的抗白血病和抗HIV活性，并且拥有由山梨醇、丙氨酸和富马酸构建单元形成的独特结构。为了促进对这种有前景的天然产物进行深入的生物学和构效关系研究，我们开发了一种化学酶法，该方法能够在精确的立体化学控制下，以优异的产率获得山梨素内酯A和几种类似物。这条高度汇聚、立体选择性且简短的路线的关键步骤是由SorbC酶催化将山梨素对映选择性氧化脱芳构化为山梨醇，以及随后富马酰氮杂内酯构建单元的迈克尔加成反应。此外，我们的合成研究结果和生物信息学分析表明，山梨素内酯A的生物合成过程与此类似。
