Anti-inflammatory arene--chromium complexes acting as specific inhibitors of NOD2 signalling

ChemMedChem. 2010 Dec 3;5(12):2065-71. doi: 10.1002/cmdc.201000320.

Abstract

Inflammation is a hallmark of microbial infection in mammals and is the result of a pathogen-induced release of inflammatory effectors. In humans a variety of germ-line encoded receptors, so-called pattern-recognition receptors, respond to conserved signatures on invading pathogens, which results in the transcriptional activation of pro-inflammatory responses. Inflammation is often detrimental to the host and leads to tissue damage and/or systemic dysfunctions. Thus, specific inhibitors of these pathways are desirable for medical interventions. Herein we report on the synthesis and use of some chromium-containing compounds (arene--Cr(CO)₃ complexes) with a core structure related to anti-inflammatory diterpenes produced by the sea whip Pseudopterogorgia elisabethae. By using cell-based reporter assays we identified complexes with a potent inhibitory activity on tumour necrosis factor (TNF), Toll-like receptor (TLR), and nucleotide binding domain, leucine-rich repeat-containing receptor (NLR) pathways. Moreover, we found one complex to be a specific inhibitor of inflammatory responses mediated by the NLR protein NOD2, a pivotal innate immune receptor involved in bacterial recognition. Synthesis and characterisation of a set of derivatives of this substance revealed structural requirements for NOD2 specificity. Taken together, our studies suggest this type of arene--Cr(CO)₃ complex as a potential lead for the development of antiphlogistica and pharmacologically relevant NOD2 inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / chemical synthesis
  • Anti-Inflammatory Agents / chemistry*
  • Anti-Inflammatory Agents / pharmacology
  • Chromium / chemistry*
  • Coordination Complexes / chemical synthesis
  • Coordination Complexes / chemistry*
  • Coordination Complexes / pharmacology
  • Diterpenes / chemistry
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism
  • Nod2 Signaling Adaptor Protein / antagonists & inhibitors*
  • Nod2 Signaling Adaptor Protein / metabolism
  • Signal Transduction
  • Structure-Activity Relationship

Substances

  • Anti-Inflammatory Agents
  • Coordination Complexes
  • Diterpenes
  • NF-kappa B
  • Nod2 Signaling Adaptor Protein
  • Chromium