Anti‐inflammatory AreneChromium Complexes Acting as Specific Inhibitors of NOD2 Signalling

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.