Santonin-related compound 2 inhibits the expression of ICAM-1 in response to IL-1 stimulation by blocking the signaling pathway upstream of IκB degradation

Abstract

Santonin-related compounds (SRCs) were synthesized from the starting material l-α-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)-2α-bromo-3-oxoeudesmanno-13,6α-lactone] strongly inhibited the ICAM-1 expression at an IC50 value of 5.9 μM, whereas l-α-santonin itself was totally inactive up to 100 μM. 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-κB subunit p65 was markedly prevented by SRC2. Moreover, IκBα degradation upon IL-1 stimulation was strongly inhibited by SRC2. These observations suggest that SRC2 blocks the IL-1 signaling pathway upstream of IκB degradation.