Development of Novel Nrf2/ARE Inducers Bearing Pyrazino[2,1-a]isoquinolin Scaffold with Potent In Vitro Efficacy and Enhanced Physicochemical Properties

Molecules. 2017 Sep 13;22(9):1541. doi: 10.3390/molecules22091541.

Abstract

Pyrazino[2,1-a]isoquinolin analogues were reported as potent activators of Nrf2/ARE signaling both in vitro and in vivo by our group. In this study, we simplified the ring system to investigate the functions of various parts of the pyrazino[2,1-a]isoquinolin scaffold. We proved that the tetrahydroisoquinoline was not essential for activity and the pyrido[1,2-a]pyrazin analogues 3b and 3g retained the cellular Nrf2/ARE activation activity. Besides, this simplification significantly enhanced water solubility and membrane permeability, indicating that these compounds are more favourable for the further development of therapeutic agents around Nrf2 activation.

Keywords: Nrf2 activator; oxidative stress; physicochemical properties; pyrido[1,2-a]pyrazin analogues.

MeSH terms

  • Antioxidant Response Elements*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Discovery*
  • Gene Expression
  • Genes, Reporter
  • Humans
  • Inhibitory Concentration 50
  • Isoquinolines / chemical synthesis
  • Isoquinolines / chemistry*
  • Isoquinolines / pharmacology*
  • Molecular Structure
  • NF-E2-Related Factor 2 / agonists*
  • NF-E2-Related Factor 2 / genetics*
  • Oxidative Stress / drug effects
  • Pyrazines / chemistry*

Substances

  • Isoquinolines
  • NF-E2-Related Factor 2
  • Pyrazines