Santonin-related compound 2 inhibits the expression of ICAM-1 in response to IL-1 stimulation by blocking the signaling pathway upstream of I kappa B degradation.
Santonin-related compounds (SRCs) were synthesized from the starting material L-alpha-santonin and tested for the biological activity on the expression of intercellular adhesion molecule-1 (ICAM-1) in response to IL-1 stimulation on human adenocarcinoma cells. One of the bromoketone derivatives termed SRC2 [11S-2 alpha-bromo-3-oxoeudesmanno-13,6 alpha-lactone] strongly inhibited the ICAM-1 expression at an IC(50) value of 5.9 microM, whereas L-alpha-santonin itself was totally inactive up to 100 microM. The blockage of ICAM-1 expression by SRC2 was not due to the direct inhibition of de novo RNA and protein synthesis. The nuclear translocation of NF-kappaB subunit p65 was markedly prevented by SRC2. Moreover, I kappa B alpha degradation upon IL-1 stimulation was strongly inhibited by SRC2. These observations suggest that SRC2 blocks the IL-1 signaling pathway upstream of I kappa B degradation.
Department of Bioengineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, 226-8501, Yokohama, Japan.
S
S
Kawai
T
T
Kataoka
H
H
Sugimoto
A
A
Nakamura
T
T
Kobayashi
K
K
Arao
Y
Y
Higuchi
M
M
Ando
K
K
Nagai
D001692:Biological Transport / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D012313:RNA / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D012500:Santonin / Q000031:analogs & derivatives / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D051996:Transcription Factor RelA; D014407:Tumor Cells, Cultured
D020672:I-kappa B Proteins; D007375:Interleukin-1; D016328:NF-kappa B; D051996:Transcription Factor RelA; D018799:Intercellular Adhesion Molecule-1; D012500:Santonin; D012313:RNA