Design, synthesis and structure-activity relationship study of novel naphthoindolizine and indolizinoquinoline-5,12-dione derivatives as IDO1 inhibitors

Bioorg Med Chem. 2018 Sep 15;26(17):4886-4897. doi: 10.1016/j.bmc.2018.08.028. Epub 2018 Aug 24.

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) is regarded as a promising target for cancer immunotherapy. Many naphthoquinone derivatives have been reported as IDO1 inhibitors so far. Herein, two series of naphthoquinone derivatives, naphthoindolizine and indolizinoquinoline-5,12-dione derivatives, were synthesized and evaluated for their IDO1 inhibitory activity. Most of the target compounds showed significant inhibition potency and high selectivity for IDO1 over tryptophan 2,3-dioxygenase (TDO). The structure-activity relationship was also summarized. The most potent compounds 5c (IC50 23 nM, IDO1 enzyme), and 5b' (IC50 372 nM, HeLa cell) were identified as promising lead compounds.

Keywords: Cancer immunotherapy; Indoleamine 2,3-dioxygenase 1; Indolizinoquinoline-5,12-dione derivatives; Naphthoindolizine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • HEK293 Cells
  • Humans
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*
  • Indolizines / chemistry*
  • Inhibitory Concentration 50
  • Molecular Docking Simulation
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • IDO1 protein, human
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Indolizines