Inhibition of kynurenine production by N,O-substituted hydroxylamine derivatives.

Abstract

The inhibition of kynurenine production is considered a promising target for cancer immunotherapy. In this study, an amino acid derivative, compound 1 was discovered using a cell-based assay with our screening library. Compound 1 suppressed kynurenine production without inhibiting indoleamine 2,3-dioxygenase 1 (IDO1) activity. The activity of 1 was derived from the inhibition of IDO1 by a metabolite of 1, O-benzylhydroxylamine (OBHA, 2a). A series of N-substituted 2a derivatives that exhibit potent activity in cell-based assays may represent effective prodrugs. Therefore, we synthesized and evaluated novel N,O-substituted hydroxylamine derivatives. The structure-activity relationships revealed that N,O-substituted hydroxylamine 2c inhibits kynurenine production in a cell-based assay. We conducted an in vivo experiment with 2c, although the effectiveness of O-substituted hydroxylamine derivatives in vivo has not been previously reported. The results indicate that N,O-substituted hydroxylamine derivatives are promising IDO1 inhibitors.

• Authors: Masatomi Iijima, Yasunari Otsuka, Shun-Ichi Ohba, Isao Momose
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 106 Pg. 129731 (Jul 01 2024) ISSN: 1464-3405 [Electronic] England
• PMID: 38621594 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2024 Elsevier Ltd. All rights reserved.

Chemical References

• Kynurenine
• Indoleamine-Pyrrole 2,3,-Dioxygenase
• Hydroxylamine
• Hydroxylamines
• IDO1 protein, human
• Enzyme Inhibitors

Topics

• Kynurenine (metabolism)
• Indoleamine-Pyrrole 2,3,-Dioxygenase (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship
• Humans
• Hydroxylamine (chemistry, pharmacology)
• Hydroxylamines (chemistry, pharmacology)
• Molecular Structure
• Animals
• Enzyme Inhibitors (pharmacology, chemical synthesis, chemistry)
• Mice
• Dose-Response Relationship, Drug