CARDIOSELECTIVE AMMONIUM, PHOSPHONIUM, AND SULFONIUM ANALOGS OF ALPHA-TOCOPHEROL AND ASCORBIC-ACID THAT INHIBIT IN-VITRO AND EX-VIVO LIPID-PEROXIDATION AND SCAVENGE SUPEROXIDE RADICALS

Analogues of alpha-tocopherol and ascorbic acid with permanently catio nic substituents, i.e., phosphonium (8, 9), sulfonium (11), acylhydraz inium (13, 14), and ammonium (1, 16, 21), were synthesized, and the 2R and 2S enantiomers of the alpha-tocopherol analogues 1, 8, 11, and 13 were separated. The compounds were found to scavenge lipoperoxyl and superoxide radicals in vitro and accumulate in heart tissue (cardiosel ectivity) as demonstrated by measurement of ex vivo inhibition of lipi d peroxidation in mouse heart homogenates and confirmed by HPLC determ ination of drug concentrations for 1 and 11. The 2R and 2S enantiomers of 1 inhibited ex vivo lipid peroxidation to an equal extent. Thus th e in vivo uptake into myocytes (cardioselectivity) is independent of t he geometry at the chiral center and common to permanently cationic co mpounds.