2'-substituted chalcone derivatives as inhibitors of interleukin-1 biosynthesis.
A series of 2'-substituted chalcone derivatives has been found to show potent inhibition of the production of IL-1 beta from human peripheral blood monocytes stimulated with lipopolysaccharide (LPS), with IC50 values in the 0.2-5.0-microM range. Some members of the series have also shown inhibition of septic shock induced in mice by injection of LPS, although with low potency. Qualitative structure-activity relationships have shown that the enone is required for activity, which may be mediated by conjugate addition of a biological nucleophile to the chalcone. Electron-poor aromatic rings beta to the ketone give enhanced potency. Although electronic effects in the other ring (directly attached to the ketone) are minimal, this ring must possess an ortho substituent for good activity without cytotoxicity, suggesting a degree of selectivity which would not be expected for simple, nonspecific alkylating agents.
Inflammatory Diseases Research, Du Pont Merck Pharmaceutical Co., Wilmington, Delaware 19880-0353.
D G
DG
Batt
R
R
Goodman
D G
DG
Jones
J S
JS
Kerr
L R
LR
Mantegna
C
C
McAllister
R C
RC
Newton
S
S
Nurnberg
P K
PK
Welch
M B
MB
Covington
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002599:Chalcone / Q000031:analogs & derivatives*; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D012772:Shock, Septic / Q000209:etiology / Q000517:prevention & control; D013329:Structure-Activity Relationship
D007375:Interleukin-1; D008070:Lipopolysaccharides; D002599:Chalcone