Novel iminobenzoxathiolone compound inhibits nuclear factor-kappaB activation targeting inhibitory kappaB kinase beta and down-regulating interleukin-1beta 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)-kappaB 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 kappaB (IkappaB) kinase beta (IKKbeta), a key enzyme required for NF-kappaB activation, with an IC(50) value of 7 microM. LYR-71 inhibited IKKbeta-mediated phosphorylation of cytoplasmic IkappaBalpha in lipopolysaccharide (LPS)-activated macrophages, and sequentially preventing IkappaBalpha degradation as well as transcriptional activation of NF-kappaB. Furthermore, LYR-71 down-regulated LPS-induced transcription of interleukin (IL)-1beta or other cytokines in the cells, and inhibited expression vector IKKbeta-elicited IL-1beta promoter activity. Taken together, LYR-71 was an efficient inhibitor of IKKbeta, preventing NF-kappaB 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.
College of Pharmacy & Research Center for Bioresource and Health, Chungbuk National University, Cheongju 361-763, Republic of Korea.
Min Hee
MH
Kim
Hwa Young
HY
Lee
Eunmiri
E
Roh
Byung Hak
BH
Kim
Eun Yong
EY
Chung
Yong Rok
YR
Lee
In Jeong
IJ
Lee
Heesoon
H
Lee
Chong-Kil
CK
Lee
Sang-Bae
SB
Han
Youngsoo
Y
Kim
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D015536:Down-Regulation; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D007097:Imines / Q000737:chemistry / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000633:toxicity*; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D051379:Mice; D015394:Molecular Structure; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007097:Imines; D053583:Interleukin-1beta; C530478:LYR 71; D008070:Lipopolysaccharides; D016328:NF-kappa B; C482199:lipopolysaccharide, E coli O55-B5; D051550:I-kappa B Kinase