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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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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
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author 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
author_facet 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
author_sort Davies, Caitlin
collection PubMed
description 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.
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spelling pubmed-98047812023-01-06 Identification of a Novel Pseudo‐Natural Product Type IV IDO1 Inhibitor Chemotype 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 Angew Chem Int Ed Engl Research Articles 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. John Wiley and Sons Inc. 2022-08-29 2022-10-04 /pmc/articles/PMC9804781/ /pubmed/35959923 http://dx.doi.org/10.1002/anie.202209374 Text en © 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
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
Identification of a Novel Pseudo‐Natural Product Type IV IDO1 Inhibitor Chemotype
title Identification of a Novel Pseudo‐Natural Product Type IV IDO1 Inhibitor Chemotype
title_full Identification of a Novel Pseudo‐Natural Product Type IV IDO1 Inhibitor Chemotype
title_fullStr Identification of a Novel Pseudo‐Natural Product Type IV IDO1 Inhibitor Chemotype
title_full_unstemmed Identification of a Novel Pseudo‐Natural Product Type IV IDO1 Inhibitor Chemotype
title_short Identification of a Novel Pseudo‐Natural Product Type IV IDO1 Inhibitor Chemotype
title_sort identification of a novel pseudo‐natural product type iv ido1 inhibitor chemotype
topic Research Articles
url 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
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