Identification of a Novel Pseudo‐Natural Product Type IV IDO1 Inhibitor Chemotype
Abstract: Natural product (NP)‐inspired design principles provide invaluable guidance for bioactive compound discovery. Pseudo‐natural products (PNPs) are de novo combinations of NP fragments to target biologically relevant chemical space not covered by NPs. We describe the design and synthesis of apoxidoles, a novel pseudo‐NP class, whereby indole‐ and tetrahydropyridine fragments are linked in monopodal connectivity not found in nature. Apoxidoles are efficiently accessible by an enantioselective [4+2] annulation reaction. Biological evaluation revealed that apoxidoles define a new potent type IV inhibitor chemotype of indoleamine 2,3‐dioxygenase 1 (IDO1), a heme‐containing enzyme considered a target for the treatment of neurodegeneration, autoimmunity and cancer. Apoxidoles target apo‐IDO1, prevent heme binding and induce unique amino acid positioning as revealed by crystal structure analysis. Novel type IV apo‐IDO1 inhibitors are in high demand, and apoxidoles may provide new opportunities for chemical biology and medicinal chemistry research.
- Location
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Deutsche Nationalbibliothek Frankfurt am Main
- Extent
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Online-Ressource
- Language
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Englisch
- Bibliographic citation
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Identification of a Novel Pseudo‐Natural Product Type IV IDO1 Inhibitor Chemotype ; day:29 ; month:08 ; year:2022 ; extent:1
Angewandte Chemie / International edition. International edition ; (29.08.2022) (gesamt 1)
- Creator
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Davies, Caitlin
Dötsch, Lara
Ciulla, Maria Gessica
Hennes, Elisabeth
Yoshida, Kei
Gasper, Raphael
Scheel, Rebecca
Sievers, Sonja
Strohmann, Carsten
Kumar, Kamal
Ziegler, Slava
Waldmann, Herbert
- DOI
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10.1002/anie.202209374
- URN
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urn:nbn:de:101:1-2022083015441155802953
- Rights
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Last update
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15.08.2025, 7:38 AM CEST
Data provider
Deutsche Nationalbibliothek. If you have any questions about the object, please contact the data provider.
Associated
- Davies, Caitlin
- Dötsch, Lara
- Ciulla, Maria Gessica
- Hennes, Elisabeth
- Yoshida, Kei
- Gasper, Raphael
- Scheel, Rebecca
- Sievers, Sonja
- Strohmann, Carsten
- Kumar, Kamal
- Ziegler, Slava
- Waldmann, Herbert
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