- Benzoxathiole derivative blocks lipopolysaccharide-induced nuclear factor-κB activation and nuclear factor-κB-regulated gene transcription through inactivating inhibitory κB kinase β
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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)-κB 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-κB activation with an IC 50 value of 1 μM by blocking inhibitory κB (IκB) kinase β (IKKβ), and suppresses NF-κB-regulated expression of inflammatory genes in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. BOT-64 inhibits IKKβ-mediated IκBα phosphorylation in LPS-activated macrophages, resulting in sequential prevention of downstream events, including proteolytic degradation of IκBα, DNA binding ability, and transcriptional activity of NF-κB. 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-κB-regulated expression of inflammatory genes such as inducible nitric-oxide synthase, cyclooxygenase-2, tumor necrosis factor-α, 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. Copyright
- Byung, Hak Kim,Roh, Eunmiri,Hwa, Young Lee,Lee, In-Jeong,Ahn, Byeongwoo,Jung, Sang-Hun,Lee, Heesoon,Han, Sang-Bae,Kim, Youngsoo
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- Study on anti-proliferative effect of benzoxathiole derivatives through inactivation of NF-κB in human cancer cells
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To investigate the anti-proliferative effect of a newly discovered NF-kB inhibitor, 6,6-dimethyl-2-(phenylimino)-6,7-dihydrobenzo[d][1,3]oxathiol-4(5H)- one (1a), a series of its analogs (1b-n) were prepared and evaluated for their NF-κB inhibition and anti-proliferative activity against various human cancer cell lines. Slight variation of hydrophobicity by replacement of dimethyl group of 1a at 6-position with bulky isopropyl group and introduction of para-fluoro substitution on 2-phenyl group showed good NF-κB inhibitory activity and anti-proliferative activity. However, excessive increase in hydrophobicity with 2,4,6-trichloro substituents on phenyl group resulted in the loss of both the activities. From the SAR results, 2-phenylimino-6,7- dihydrobenzo[d][1,3]oxathiol-4(5H)-one was identified as the lead scaffold for investigating new anticancer agent through inactivation of NF-κB.
- Venkateswararao, Eeda,Anh, Hoang Le Tuan,Sharma, Vinay K.,Lee, Ki-Cheul,Sharma, Niti,Kim, Youngsoo,Jung, Sang-Hun
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supporting information; experimental part
p. 4523 - 4527
(2012/08/07)
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- THE CHEMISTRY OF PHOTOLYTICALLY AND THERMALLY GENERATED α-KETOCARBENES FROM IODONIUM YLIDES OF β-DIKETONES
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The reactions of Phenyliodonium dimedonate, 1, with various double bonds were investigated.The products are always heterocyclic compounds(5-member ring) in good yield.
- Hadjiarapoglou, Lazaros P.
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p. 4449 - 4450
(2007/10/02)
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