IDO1 and TDO inhibitory evaluation of analogues of the marine pyrroloiminoquinone alkaloids: Wakayin and Tsitsikammamines

Bioorg Med Chem Lett. 2021 May 15:40:127910. doi: 10.1016/j.bmcl.2021.127910. Epub 2021 Mar 10.

Abstract

Indoleamine 2,3-dioxygenase (IDO1) and tryptophane 2,3-dioxygenase (TDO) are two heme-containing enzymes which catalyze the conversion of tryptophan to N-formylkynurenine. Both enzymes are well establish therapeutic targets as important factors in the tumor immune evasion mechanism. A number of analogues of the marine pyrroloquinoline alkaloids tsitsikammamines or wakayin have been synthesized, two of them were synthesized using an original method to build the bispyrroloquinone framework. All the derivatives were evaluated in a cellular assay for their capacity to inhibit the enzymes. Six compounds have shown a significant potency on HEK 293-EBNA cell lines expressing hIDO1 or hTDO.

Keywords: Bispyrroloquinone; IDO1 and TDO; Marine alkaloids; Pyrroloiminoquinone; Tsitsikammamine; Wakayin.

MeSH terms

  • Alkaloids / chemical synthesis*
  • Alkaloids / metabolism
  • Aquatic Organisms / chemistry
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / metabolism
  • HEK293 Cells
  • Humans
  • Indole Alkaloids / chemistry
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*
  • Molecular Docking Simulation
  • Protein Binding
  • Protein Conformation
  • Pyrroles / chemistry
  • Pyrroloiminoquinones / chemical synthesis*
  • Pyrroloiminoquinones / metabolism
  • Quinolines / chemistry
  • Small Molecule Libraries / chemical synthesis*
  • Small Molecule Libraries / metabolism
  • Structure-Activity Relationship
  • Tryptophan Oxygenase / antagonists & inhibitors*

Substances

  • Alkaloids
  • Enzyme Inhibitors
  • Indole Alkaloids
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Pyrroles
  • Pyrroloiminoquinones
  • Quinolines
  • Small Molecule Libraries
  • pyrroloquinoline
  • wakayin
  • Tryptophan Oxygenase