Medium sized lactones with hypolipidaemic and antioxidant activity: synthesis and biological evaluation of promising dual-action anti-atherosclerosis drugs.
Macrocyclic lactones 1a-b have been synthesized and their potential therapeutic value evaluated. The key structural feature of these active 'chimera' compounds is the 12-membered lactone ring that brings together the well-known polysubstituted hydroquinone moiety of antioxidants and the alpha,alpha-dimethyl substituted acyl residue of gemfibrozil. Lactones 1a-b showed better activity than probucol, a classical phenolic antioxidant, in preventing the Cu++-induced oxidative modification of human LDL. The hypolipidaemic activity of the new lactones, evaluated as the inhibition of lipids biosynthesis in Hep-G2 cells, was comparable to that of gemfibrozil. These features, added to the lack of cytotoxicity, make this new class of medium sized lactones promising dual-action drugs useful as anti-atherosclerosis agents.
Baldazzi
C
C
Dipartimento di Chimica Organica, A. Mangini, Università di Bologna, Italy.
Calderoni
F
F
Marotta
E
E
Piani
S
S
Righi
P
P
Rosini
G
G
Saguatti
S
S
Tiozzo
R
R
Calandra
S
S
Venturelli
F
F
D000975:Antioxidants / Q000494:pharmacology*; D001161:Arteriosclerosis / Q000188:drug therapy*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002460:Cell Line; D003601:Cytotoxicity Tests, Immunologic; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D017392:Thiobarbituric Acid Reactive Substances; D013997:Time Factors
D000975:Antioxidants; D000960:Hypolipidemic Agents; D007783:Lactones; D017392:Thiobarbituric Acid Reactive Substances