Anti-inflammatory agents III: Structure-activity relationships of brusatol and related quassinoids.
A series of quassinoids were observed to be potent inhibitors of induced inflammation and arthritis in rodents. Brusatol afforded the most potent activity followed by brucein-D. A 3-hydroxy-delta 3-2-oxo moiety in brusatol or a 1-hydroxy-delta 3-2-oxo moiety in brucein-D, as well as a C-15 ester-bearing delta-lactone ring in brusatol and C-11 and C-12 free hydroxyl groups are required in both quassinoids for potent anti-inflammatory activity. Preliminary studies indicate that one of the modes of action of quassinoids as anti-inflammatory agents is to stabilize lysosomal membranes, reducing the release of hydrolytic enzymes that cause damage to surrounding tissues.
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy; D005900:Glaucarubin / Q000031:analogs & derivatives / Q000032:analysis / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology; D008247:Lysosomes / Q000201:enzymology; D008297:Male; D051379:Mice; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010616:Phenanthrenes / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D036702:Quassins; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D010616:Phenanthrenes; D036702:Quassins; C020237:brusatol; D011451:Prostaglandin-Endoperoxide Synthases; D005900:Glaucarubin