Anti-inflammatory arene--chromium complexes acting as specific inhibitors of NOD2 signalling.
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.
Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Germany.
Harald
H
Bielig
Janna
J
Velder
Aroonchai
A
Saiai
Maureen
M
Menning
Sonja
S
Meemboor
Wiltrud
W
Kalka-Moll
Martin
M
Krönke
Hans-Günther
HG
Schmalz
Thomas A
TA
Kufer
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002857:Chromium / Q000737:chemistry*; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004224:Diterpenes / Q000737:chemistry; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D056831:Coordination Complexes; D004224:Diterpenes; D016328:NF-kappa B; D053473:Nod2 Signaling Adaptor Protein; D002857:Chromium