Discovery of Novel Cinchona-Alkaloid-Inspired Oxazatwistane Autophagy Inhibitors

Research output: Contribution to journalJournal article – Annual report year: 2017Researchpeer-review

Without internal affiliation

DOI

  • Author: Laraia, Luca

    Max Planck Institute

  • Author: Ohsawa, Kosuke

    Max Planck Institute

  • Author: Konstantinidis, Georgios

    Max Planck Institute

  • Author: Robke, Lucas

    Max Planck Institute

  • Author: Wu, Yao-Wen

    Max Planck Institute

  • Author: Kumar, Kamal

    Max Planck Institute

  • Author: Waldmann, Herbert

    Max Planck Institute

View graph of relations

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.
Original languageEnglish
JournalAngewandte Chemie
Volume129
Issue number8
Pages (from-to)2177–2182
ISSN0044-8249
DOIs
Publication statusPublished - 2017
Externally publishedYes
CitationsWeb of Science® Times Cited: No match on DOI

ID: 140022401