Design, Synthesis, and Phenotypic Profiling of Pyrano‐Furo‐Pyridone Pseudo Natural Products. Issue 41 (28th August 2019)

• Record Type: Journal Article
• Authors: Christoforow, Andreas; Wilke, Julian; Binici, Aylin; Pahl, Axel; Ostermann, Claude; Sievers, Sonja; Waldmann, Herbert
• Is Part Of: Angewandte Chemie international edition. Volume 58:Issue 41(2019)
• Page Start: 14715
• Page End: 14723
• Publication Date: 2019-08-28
• Subjects: cell painting assays -- cell-based screening -- high-throughput screening -- inhibitors -- pseudo natural products; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201907853
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: Natural products (NPs) inspire the design and synthesis of novel biologically relevant chemical matter, for instance through biology‐oriented synthesis (BIOS). However, BIOS is limited by the partial coverage of NP‐like chemical space by the guiding NPs. The design and synthesis of "pseudo NPs" overcomes these limitations by combining NP‐inspired strategies with fragment‐based compound design through de novo combination of NP‐derived fragments to unprecedented compound classes not accessible through biosynthesis. We describe the development and biological evaluation of pyrano‐furo‐pyridone (PFP) pseudo NPs, which combine pyridone‐ and dihydropyran NP fragments in three isomeric arrangements. Cheminformatic analysis indicates that the PFPs reside in an area of NP‐like chemical space not covered by existing NPs but rather by drugs and related compounds. Phenotypic profiling in a target‐agnostic "cell painting" assay revealed that PFPs induce formation of reactive oxygen species and are structurally novel inhibitors of mitochondrial complex I. Abstract : Not quite natural : Phenotypic profiling of pseudo natural products (NPs) obtained by de novo combination of pyridone‐ and dihydropyran fragments reveals a new class of inhibitors of mitochondrial complex I.