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Identification of a Novel Pseudo‐Natural Product Type IV IDO1 Inhibitor Chemotype

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,...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9804781/
https://www.ncbi.nlm.nih.gov/pubmed/35959923
http://dx.doi.org/10.1002/anie.202209374
Descripción
Sumario: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.