Novel iminobenzoxathiolone compound inhibits nuclear factor-κB activation targeting inhibitory κB kinase β and down-regulating interleukin-1β expression in lipopolysaccharide-activated macrophages

Benzoxathiolone derivatives have been reported to show pharmacological potentials in the psoriasis and acne. However, molecular basis for these pharmacological properties is little known. We postulated that the derivatives could mediate some of their pharmacological actions by modulating nuclear factor (NF)-kappa B activation, which is closely linked to the inflammatory and immune disorders. In this study, a novel iminobenzoxathiolone LYR-71 of 6-methyl-2-propylimino-6,7-dihydro-5H-benzo[1,3]oxathiol-4-one has been demonstrated to inhibit in vitro catalytic activity of inhibitory kappa B (I kappa B) kinase beta (IKK beta), a key enzyme required for NF-kappa B activation, with an IC50 value of 7 mu M. LYR-71 inhibited IKK beta-mediated phosphorylation of cytoplasmic I kappa B alpha in lipopolysaccharide (LPS)-activated macrophages, and sequentially preventing I kappa B alpha degradation as well as transcriptional activation of NF-kappa B. Furthermore, LYR-71 down-regulated LPS-induced transcription of interleukin (IL)-1 beta or other cytokines in the cells, and inhibited expression vector IKK beta-elicited IL-1 beta promoter activity. Taken together, LYR-71 was an efficient inhibitor of IKK beta, preventing NF-kappa B activation in macrophages, and this mechanism of action could contribute its down-regulatory effect on LPS-induced expression of inflammatory cytokines at the transcription level. (C) 2008 Elsevier Inc. All rights reserved.