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.

Identification of a Novel Pseudo-Natural Product Type IV IDO1 Inhibitor Chemotype / Davies, C.; Dotsch, L.; Ciulla, M. G.; Hennes, E.; Yoshida, K.; Gasper, R.; Scheel, R.; Sievers, S.; Strohmann, C.; Kumar, K.; Ziegler, S.; Waldmann, H.. - In: ANGEWANDTE CHEMIE. INTERNATIONAL EDITION. - ISSN 1433-7851. - 61:40(2022), pp. e202209374-e202209374. [10.1002/anie.202209374]

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

Ciulla M. G.;
2022

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
61
40
e202209374
e202209374
Identification of a Novel Pseudo-Natural Product Type IV IDO1 Inhibitor Chemotype / Davies, C.; Dotsch, L.; Ciulla, M. G.; Hennes, E.; Yoshida, K.; Gasper, R.; Scheel, R.; Sievers, S.; Strohmann, C.; Kumar, K.; Ziegler, S.; Waldmann, H.. - In: ANGEWANDTE CHEMIE. INTERNATIONAL EDITION. - ISSN 1433-7851. - 61:40(2022), pp. e202209374-e202209374. [10.1002/anie.202209374]
Davies, C.; Dotsch, L.; Ciulla, M. G.; Hennes, E.; Yoshida, K.; Gasper, R.; Scheel, R.; Sievers, S.; Strohmann, C.; Kumar, K.; Ziegler, S.; Waldmann, H.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1326449
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