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Benzoxathiole Derivative Blocks Lipopolysaccharide-Induced Nuclear Factor-B Activation and Nuclear Factor-B-Regulated Gene Transcription through Inactivating Inhibitory B Kinase β

College of Pharmacy (B.H.K., E.R., H.L., S.-B.H., Y.K.), College of Veterinary Medicine (B.A.), and Research Center for Bioresource and Health (H.Y.L., I.-J.L.), Chungbuk National University, Cheongju, Korea; and College of Pharmacy, Chungnam National University, Daejeon, Korea (S.-H.J.)

Benzoxathiole derivatives have been used in the treatment of acne and have shown cytostatic, antipsoriatic, and antibacterial properties. However, little is known about the molecular basis for these pharmacological properties, although nuclear factor (NF)-B activation is closely linked to inflammation and cell proliferation. Here, we demonstrate that the novel small-molecule benzoxathiole 6,6-dimethyl-2-(phenylimino)-6,7-dihydro-5H-benzo-[1,3]oxathiol-4-one (BOT-64) inhibits NF-B activation with an IC₅₀ value of 1 µM by blocking inhibitory B(IB) kinase β (IKKβ), and suppresses NF-B-regulated expression of inflammatory genes in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. BOT-64 inhibits IKKβ-mediated IB phosphorylation in LPS-activated macrophages, resulting in sequential prevention of downstream events, including proteolytic degradation of IB, DNA binding ability, and transcriptional activity of NF-B. BOT-64 inhibits LPS-inducible IKKβ activity in the cells and catalytic activity of highly purified IKKβ. Moreover, the effect of BOT-64 on cell-free IKKβ was abolished by substitution of Ser-177 and Ser-181 residues in the activation loop of IKKβ to glutamic acid residues, indicating a direct interaction site of benzoxathiole. BOT-64 attenuates NF-B-regulated expression of inflammatory genes such as inducible nitric-oxide synthase, cyclooxygenase-2, tumor necrosis factor-, interleukin (IL)-1β, and IL-6 in LPS-activated or expression vector IKKβ-transfected macrophages. Furthermore, BOT-64 dose-dependently increases the survival rates of endotoxin LPS-shocked mice.

Address correspondence to: Dr. Youngsoo Kim, College of Pharmacy, Chungbuk National University, Cheongju 361-763, Korea. E-mail: youngsoo{at}chungbuk.ac.kr