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Discovery of Novel Cinchona‐Alkaloid‐Inspired Oxazatwistane Autophagy Inhibitors
Author(s) -
Laraia Luca,
Ohsawa Kosuke,
Konstantinidis Georgios,
Robke Lucas,
Wu YaoWen,
Kumar Kamal,
Waldmann Herbert
Publication year - 2017
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201611670
Subject(s) - biogenesis , autophagy , chemistry , cinchona , polyketide , natural product , alkaloid , combinatorial chemistry , stereochemistry , biochemistry , enantioselective synthesis , catalysis , enzyme , biosynthesis , gene , apoptosis
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.