Diverse Nrf2 Activators Coordinated to Cobalt Carbonyls Induce Heme Oxygenase-1 and Release Carbon Monoxide in Vitro and in Vivo

J Med Chem. 2016 Jan 28;59(2):756-62. doi: 10.1021/acs.jmedchem.5b01509. Epub 2016 Jan 15.

Abstract

The Nrf2/heme oxygenase-1 (HO-1) axis affords significant protection against oxidative stress and cellular damage. We synthesized a series of cobalt-based hybrid molecules (HYCOs) that combine an Nrf2 inducer with a releaser of carbon monoxide (CO), an anti-inflammatory product of HO-1. Two HYCOs markedly increased Nrf2/HO-1 expression, liberated CO and exerted anti-inflammatory activity in vitro. HYCOs also up-regulated tissue HO-1 and delivered CO in blood after administration in vivo, supporting their potential use against inflammatory conditions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Carbon Monoxide / blood
  • Carbon Monoxide / chemistry
  • Carbon Monoxide / metabolism*
  • Carboxyhemoglobin / metabolism
  • Cell Line
  • Cell Survival
  • Cobalt / chemistry*
  • Enzyme Activation / drug effects
  • Enzyme Induction / drug effects
  • Glutathione / biosynthesis
  • Heme Oxygenase-1 / biosynthesis
  • Heme Oxygenase-1 / drug effects*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NF-E2-Related Factor 2 / drug effects*
  • Neuroglia / drug effects
  • Neuroglia / metabolism
  • Up-Regulation / drug effects

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Cobalt
  • Carbon Monoxide
  • Carboxyhemoglobin
  • Heme Oxygenase-1
  • Glutathione