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-1beta from human peripheral blood monocytes stimulated with lipopolysaccharide (LPS), with IC50 v alues in the 0.2-5.0-muM range. Some members of the series have also s hown inhibition of septic shock induced in mice by injection of LPS, a lthough with low potency. Qualitative structure-activity relationships have shown that the enone is required for activity, which may be medi ated by conjugate addition of a biological nucleophile to the chalcone . Electron-poor aromatic rings beta to the ketone give enhanced potenc y. 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 selecti vity which would not be expected for simple, nonspecific alkylating ag ents.