Synthesis, chemical, and biological properties of vinylogous hydroxamic acids: dual inhibitors of 5-lipoxygenase and IL-1 biosynthesis.
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.
Wright
S W
SW
Du Pont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0353.
Harris
R R
RR
Kerr
J S
JS
Green
A M
AM
Pinto
D J
DJ
Bruin
E M
EM
Collins
R J
RJ
Dorow
R L
RL
Mantegna
L R
LR
Sherk
S R
SR
D000818:Animals; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013025:Glycine max; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014753:Vinyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D006877:Hydroxamic Acids; D007375:Interleukin-1; D016859:Lipoxygenase Inhibitors; D014753:Vinyl Compounds