No abstract

The synthesis and stereochemical characteristics of pyrrolidino‐, isoquinolino‐ and indolo‐enaminones 2–11 are reported. The inhibition of cyclooxygenase was determined in a bovine thrombocyte intact cell assay and that of 5‐lipoxygenase using intact bovine polymorphonuclear leucocytes. Except compound 2c′ which is a well‐balanced dual inhibitor of both enzymes, all other enaminone derivatives are weak inhibitors of both cyclooxygenase and 5‐lipoxygenase. Structure‐activity relationships of the enaminones in relation to known anti‐inflammatory drugs are discussed.

Treatment of an equimolar mixture of stilbene 7 and cinnamyl alcohol 8 with silver carbonate in acetone-benzene afforded a ca. 2:1:2:1 mixture of the stilbenolignan (+/-)-aiphanol (1) and congeners 2-4 each of which show significant anti-angiogenic and COX-2 inhibitory properties.

Alkoxyflavonols were synthesized by the Algar‐Flynn‐Oyamada (AFO) cyclization of chalcones. Hydroxyflavonols were prepared by dealkylation of methoxyflavonols by refluxing in hydroiodic acid. The alkoxyflavonols 3‐hydroxy‐2‐(2,3,4‐trimethoxy‐phenyl)‐ 4H‐chromen‐4‐one (6), 2‐(4‐ethoxyphenyl)‐3‐hydroxy‐4H‐ chromen‐4‐one (7), 2‐(4‐butoxyphenyl)‐3‐hydroxy‐4H‐ chromen‐4‐one (10), and 2‐(3‐n‐butoxyphenyl)‐3‐hydroxy‐4H‐ chromen‐4‐one (11) as well as the trihydroxy derivative 3‐hydroxy‐ 2‐(3,4,5‐trihydroxyphenyl)‐4H‐chromen‐4‐one (18) displayed high anti‐inflammatory activity in carrageenin‐induced rat paw edema. Additionally, the inhibition of enzymes of the arachidonic acid cascade by the derivatives was investigated in vitro. In contrast to the natural compound quercetin, the com‐pounds were more potent inhibiting cyclooxygenase‐1 than 5‐lipoxygenase except for 3‐hydroxy‐7‐methoxy‐2‐(4‐methoxyphenyl)‐ 4H‐chromen‐4‐one (5). No correlation between the antiinflammatory activity in the rat paw edema test and the inhibition of 5‐lipoxygenase or cyclooxygenase‐1 could be observed. In conclusion, the present results suggest that other effects than inhibition of these enzymes of the arachidonic acid cascade are important for the anti‐inflammatory activity of the investigated alkoxyflavonols.

The pyrrolidino enaminones, with the carboxylic acid chain fixed at the nitrogen, inhibit cyclooxygenase more potently or selectively than 5-lipoxygenase. According to the structure-activity relationships discussed the potency depends significantly on the chain length of the carboxylic acid, the substitution pattern of the heterocyclic moiety and of the phenyl group. Compound 4c is the most efficient inhibitor of cyclooxygenase. For the binding profile the unfolded conformation of arachidonic acid and the energy-minimized conformations of flurbiprofen, diclofenac, ML 3000, and lead compound 4a were compared. In addition to known structural features, similar distances of the carboxylic acid function and the phenyl residue were found as hypothesized to explain the interaction with the active sites of the enzyme. The inhibition of cyclooxygenase was determined in a bovine thrombocyte intact cell assay and that of 5-lipoxygenase using intact bovine PMNLs.