Novel antioxidant agents deriving from molecular combinations of vitamins C and E analogues: 3,4-dihydroxy-5(R)-[2(R,S)-(6-hydroxy-2,5,7,8-tetramethyl-chroman-2(R,S)-yl-methyl)-[1,3]dioxolan-4(S)-yl]-5H-furan-2-one and 3-O-octadecyl derivatives

Molecular combinations of two antioxidants (i.e., ascorbic acid and the pha rmacophore of alpha -tocopherol), namely the 2,3-dihydroxy-2,3-enono- 1,4-l actone and the chromane residues, have been designed and tested for their r adical scavenging activities. When evaluated for their capability to inhibi t malondialdehyde (MDA) production in rat liver microsomal membranes, the 3 ,4-dihydroxy-SR-2(R,S)-(6-hydroxy-2, 5,7,8-tetramethylchroman-2(R,S)yl-meth yl 1,3]dioxolan-4S-yl]-5H-furan-2-one (11a-d), exhibited an interesting act ivity. In particular the 5R,2R,2R,4S and 5R,2R,2S,4S isomers (11c,d) displa yed a potent antioxidant effect compared to the respective synthetic alpha -tocopheral analogue (5) and natural alpha -tocopherol or ascorbic acid, us ed alone or in combination. Moreover, the mixture of stereoisomers 11a-d al so proved to be effective in preventing damage induced by reperfusion on is olated rabbit heart, in particular at the higher concentration of 300 muM. In view of these results our study represents a new approach to potential t herapeutic agents for applications in pathological events in which a free r adical damage is involved. Design, synthesis and preliminary biological act ivity are discussed. (C) 2000 Elsevier Science Ltd. All rights reserved.