Nuclear Factor-κB Mediated Inhibition of Cytokine Production by Imidazoline Scaffolds

Abstract

The mammalian nuclear transcription factor NF-kappaB is responsible for the transcription of multiple cytokines, including the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6). Elevated levels of pro-inflammatory cytokines play an important role in the pathogenesis of inflammatory disorders such as rheumatoid arthritis (RA). Inhibition of the pro-inflammatory transcription factor NF-kappaB has therefore been identified as a possible therapeutic treatment for RA. We describe herein the synthesis and biological activity of a series of imidazoline-based scaffolds as potent inhibitors of NF-kappaB mediated gene transcription in cell culture as well as inhibitors of TNF-alpha and IL-6 production in interleukin 1 beta (IL-1beta) stimulated human blood.

Structural–activity relationship study of highly-functionalized imidazolines as potent inhibitors of nuclear transcription factor-κB mediated IL-6 production

“…In order to validate the results from this integrated cell line and demonstrate the reliability of this high-throughput screen, HeLa cells were transiently transfected with 6x jB driver reporter gene pNF-jB-Luc and the internal control plasmid pRL-TK, which provides low levels of Renilla luciferase production (see Supplementary data). 46 Similar results were observed using both luciferasebased reporter assays, indicating the data obtained from the stable HeLa/NF-jB-luc cell line was representative of NF-jB mediated gene transcription.…”

“…Previously, we reported that this moiety is critical for stability of the imidazoline scaffold and the ester functionality was found to be optimal at the R 2 position. 46 We extended this series to include n-propyl and isopropyl esters (7 and 8). Again, the inhibition of IL-6 production in stimulated human blood corresponded well with the inhibition of luciferase production in the HeLa cells ( Table 2).…”

“…44,45 A small series of this class of imidazolines was investigated for its potential anti-inflammatory activity and found to inhibit both TNF-a and IL-6 production in human blood stimulated by IL-1b. 46 In our efforts to improve the potency and develop a better understanding of the structural requirements for biological activity, we herein describe the synthesis and anti-inflammatory properties of several imidazoline derivatives functionalized at the R 1 -R 4 positions (Scheme 1). Biological evaluation of this library of imidazolines led to the discovery of several analogues with the ability to substantially inhibit NF-jB mediated transcription in cell culture and cytokine production in stimulated human blood.…”

Analysing the effect of I1 imidazoline receptor ligands on DSS-induced acute colitis in mice

“…Furthermore, various novel imidazoline scaffolds were shown to inhibit human proteasome (Lansdell et al 2013), which in turn prevented NF-κB mediated gene transcription in cell cultures (Sharma et al 2004;Kahlon et al 2009) and the production of proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in human blood (Kahlon et al 2009). Although in the majority of these studies other molecular targets than IRs were found to mediate the anti-inflammatory action of imidazoline drugs, the intriguing hypothesis of Molderings et al (2007a, b) that I1-IRs may belong to the family of S1P receptors and represent mixtures of homo and/or heterodimers of S1P1-3 receptors suggests that also pharmacological modulation of I1-IRs may result in reduced inflammation.…”

Panel docking of small-molecule libraries — Prospects to improve efficiency of lead compound discovery

“…To this end, a non-classical motif based on an Nheteroaryl substituted 2-imidazoline, which we hypothesised may be particularly suited for binding to the protein kinase Hinge segments, was investigated. The 2-imidazoline moiety holds some promise as a novel scaffold for protein kinases as it possesses high solubility in aqueous environment (Remko et al, 2006) and, based on the reported broad range of biological activities against unrelated targets (Favaloro et al, 2003;Ferretti et al, 2002;Guo et al, 2008;Hong et al, 2005;Kahlon et al, 2009;Li & Zhang, 2011), can also be considered a privileged structure (Evans et al, 1988). Exploiting privileged structures with drug-like properties has been a popular approach to drug discovery, particularly within the pharmaceutical industry.…”