title: Discovery of Novel Cinchona-Alkaloid-Inspired Oxazatwistane Autophagy Inhibitors.
abstract: 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.
authors.affiliation: Max Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Str. 11, 44227, Dortmund, Germany.
authors.forename: Luca
authors.initials: L
authors.lastname: Laraia
authors.affiliation: Max Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Str. 11, 44227, Dortmund, Germany.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Ohsawa
authors.affiliation: Chemical Genomics Center of the Max Planck Society, Otto-Hahn-Str. 15, 44227, Dortmund, Germany.
authors.forename: Georgios
authors.initials: G
authors.lastname: Konstantinidis
authors.affiliation: Max Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Str. 11, 44227, Dortmund, Germany.
authors.forename: Lucas
authors.initials: L
authors.lastname: Robke
authors.affiliation: Chemical Genomics Center of the Max Planck Society, Otto-Hahn-Str. 15, 44227, Dortmund, Germany.
authors.forename: Yao-Wen
authors.initials: YW
authors.lastname: Wu
authors.affiliation: Max Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Str. 11, 44227, Dortmund, Germany.
authors.forename: Kamal
authors.initials: K
authors.lastname: Kumar
authors.affiliation: Max Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Str. 11, 44227, Dortmund, Germany.|Technische Universität Dortmund, Fakultät Chemie und Chemische Biologie, Otto-Hahn-Str. 6, 44227, Dortmund, Germany.
authors.forename: Herbert
authors.initials: H
authors.lastname: Waldmann
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002929:Cinchona / Q000737:chemistry; D002930:Cinchona Alkaloids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells
chemical_list: D001688:Biological Products; D002930:Cinchona Alkaloids
keywords: alkaloids; autophagy; inhibitors; medicinal chemistry; natural products