Identification of a Novel Pseudo-Natural Product Type IV IDO1 Inhibitor Chemotype
Davies C, Dötsch L, Ciulla MG, Hennes E, Yoshida K, Gasper R, Scheel R, Sievers S, Strohmann C, Kumar K, Ziegler S, Waldmann H (2022). Angew Chem Int Ed Engl.
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. The gropup of Herbert Waldmann describes 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.