Design, synthesis and biological evaluation of exiguamine A analogues as IDO1 inhibitors

Eur J Med Chem. 2021 Nov 5:223:113631. doi: 10.1016/j.ejmech.2021.113631. Epub 2021 Jun 12.

Abstract

A series of exiguamine A analogues were designed and synthesized via 15 steps. Their inhibitory activities against IDO1 were tested and the structure-activity relationships were studied. Most compounds exhibited potent IDO1 inhibitory activities with IC50 values at the level of 10-7-10-8 M. Compound 21f was the most potent IDO1 inhibitor with an IC50 value of 65.3 nM, which was comparable with the positive control drug epacadostat (IC50 = 46 nM). Moreover, compound 21f showed higher selectivity for IDO1 over tryptophan 2,3-dioxygenase (TDO) and no cytotoxicity at its effective concentration, rending it justifiable for further optimization and evaluation.

Keywords: Cancer immunotherapy; Exiguamine A; Indoleamine 2,3-dioxygenase 1.

MeSH terms

  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / toxicity
  • Humans
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
  • Indoles / chemical synthesis
  • Indoles / metabolism
  • Indoles / pharmacology*
  • Indoles / toxicity
  • Molecular Docking Simulation
  • Molecular Structure
  • Protein Binding
  • Spiro Compounds / chemical synthesis
  • Spiro Compounds / metabolism
  • Spiro Compounds / pharmacology*
  • Spiro Compounds / toxicity
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • IDO1 protein, human
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Indoles
  • Spiro Compounds
  • exiguamine A