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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.

The carrageenan pleurisy model, which is characterized by cellular influx and oedema, has been used to examine the effects of anti-inflammatory compounds such as naproxen. Interleukin-1alpha and beta (IL-1) are known to be pro-inflammatory mediators, and their roles in this model are unknown. Intrapleural injection of 1% viscarin carrageenan or saline was administered to male Lewis rats. Four to 24 h later, cell counts, fluid volumes and IL-1beta levels (measured by ELISA) were determined in the pleural cavity. Serum corticosterone levels were measured only at 4 h. Significant increases in IL-1beta levels precede cell influx suggesting IL-1beta plays a role in the maintenance of cell accumulation in the pleural cavity. None of the drugs tested, including the IL-1 receptor antagonist, maintained pleural cell influx and IL-1beta levels at control levels. When human IL-1alpha or beta or rat IL-1beta were injected individually into the pleural cavity, none of these cytokines were pro-inflammatory, as measured by increased cell influx and fluid extravasation. These results suggest that although IL-1beta levels increase in the pleural cavity in response to carrageenan, IL-1 per se is not the initiator of the pro-inflammatory events of cell influx and oedema in this model.

Vinylogous hydroxamic acids (3-(N-hydroxy-N-alkylamino)-2-propen-1-ones, VHA) were prepared as antiinflammatory agents. The synthesis, chemical properties, and in vitro biological activities of these relatively unexplored compounds are described. The VHAs were prepared by condensation of the appropriate N-substituted hydroxylamine with any of the three reagents: a 1,3-dicarbonyl compound (method A); a vinylogous amide (method B); or an alkynone (method C). The VHAs exist as one or more tautomers in solution with the relative proportions of each being dependent upon the structure of the VHA, solvent, and pH. VHAs undergo some of the typical reactions of hydroxamic acids as well as those of vinylogous amides. VHAs are active as inhibitors of 5-lipoxygenase and of IL-1 biosynthesis in vitro, which do not inhibit other enzymes of the arachidonic acid cascade. They have been shown by ESR studies to bring about inhibition of soybean type 1 15-lipoxygenase by reduction of the active site iron.

We have investigated the role of recombinant human interleukin-1 beta (rIL-1 beta) and recombinant human tumor necrosis factor alpha (rTNF-alpha) on PLA2 activity, protein synthesis and eicosanoid production in bovine pulmonary artery endothelial cells. Cellular PLA2 activity increased 4-fold and production of PGE2 increased 3-fold at 1-2 hrs in the presence of 10 units/ml rIL-1 beta. PLA2 activity increased 3-fold at 30 min and PGE2 production increased 2-fold with 5 x 10(-9) M rTNF-alpha. The data show that endothelial cells respond more rapidly to rIL-1 beta (2-6 hr) and rTNF-alpha (30 min) than do chondrocytes and synovial cells (6-16 hrs), suggesting endothelial cells may play a primary role in initiating the inflammatory response.