1. Identification of a Novel Pseudo-Natural Product Type IV IDO1 Inhibitor Chemotype.
- Author
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Davies C, Dötsch L, Ciulla MG, Hennes E, Yoshida K, Gasper R, Scheel R, Sievers S, Strohmann C, Kumar K, Ziegler S, and Waldmann H
- Subjects
- Amino Acids, Enzyme Inhibitors chemistry, Heme, Indoleamine-Pyrrole 2,3,-Dioxygenase, Indoles, Pyrrolidines, Structure-Activity Relationship, Biological Products chemistry, Biological Products pharmacology
- 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., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
- Published
- 2022
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