Medium sized lactones with hypolipidaemic and antioxidant activity: Synthesis and biological evaluation of promising dual-action anti-atherosclerosisdrugs

Macrocyclic lactones 1a-b have been synthesized and their potential therape utic value evaluated. The key structural feature of these active 'chimera' compounds is the 12-membered lactone ring that brings together the well-kno wn polysubstituted hydroquinone moiety of antioxidants and the alpha,alpha- dimethyl substituted acyl residue of gemfibrozil. Lactones 1a-b showed bett er 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 biosyn thesis in Hep-G(2) cells, was comparable to that of gemfibrozil. These feat ures, added to the lack of cytotoxicity, make this new class of medium size d lactones promising dual-action drugs useful as anti-atherosclerosis agent s. (C) 1999 Elsevier Science Ltd. All rights reserved.