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Phenotyping Reveals Targets of a Pseudo-Natural-Product Autophagy Inhibitor.


ABSTRACT: Pseudo-natural-product (NP) design combines natural product fragments to provide unprecedented NP-inspired compounds not accessible by biosynthesis, but endowed with biological relevance. Since the bioactivity of pseudo-NPs may be unprecedented or unexpected, they are best evaluated in target agnostic cell-based assays monitoring entire cellular programs or complex phenotypes. Here, the Cinchona alkaloid scaffold was merged with the indole ring system to synthesize indocinchona alkaloids by Pd-catalyzed annulation. Exploration of indocinchona alkaloid bioactivities in phenotypic assays revealed a novel class of azaindole-containing autophagy inhibitors, the azaquindoles. Subsequent characterization of the most potent compound, azaquindole-1, in the morphological cell painting assay, guided target identification efforts. In contrast to the parent Cinchona alkaloids, azaquindoles selectively inhibit starvation- and rapamycin-induced autophagy by targeting the lipid kinase VPS34.

SUBMITTER: Foley DJ 

PROVIDER: S-EPMC7383971 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Phenotyping Reveals Targets of a Pseudo-Natural-Product Autophagy Inhibitor.

Foley Daniel J DJ   Zinken Sarah S   Corkery Dale D   Laraia Luca L   Pahl Axel A   Wu Yao-Wen YW   Waldmann Herbert H  

Angewandte Chemie (International ed. in English) 20200421 30


Pseudo-natural-product (NP) design combines natural product fragments to provide unprecedented NP-inspired compounds not accessible by biosynthesis, but endowed with biological relevance. Since the bioactivity of pseudo-NPs may be unprecedented or unexpected, they are best evaluated in target agnostic cell-based assays monitoring entire cellular programs or complex phenotypes. Here, the Cinchona alkaloid scaffold was merged with the indole ring system to synthesize indocinchona alkaloids by Pd-c  ...[more]

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