Novel antioxidant agents deriving from molecular combinations of vitamins C and E analogues: 3,4-dihydroxy-5(R).
Molecular combinations of two antioxidants (i.e., ascorbic acid and the pharmacophore of alpha-tocopherol), namely the 2,3-dihydroxy-2,3-enono-1,4-lactone and the chromane residues, have been designed and tested for their radical scavenging activities. When evaluated for their capability to inhibit malondialdehyde (MDA) production in rat liver microsomal membranes, the 3,4-dihydroxy-5R-2(R,S)-(6-hydroxy-2,5,7,8-tetramethylchroman-2(R,S)yl-methyl)-1,3]dioxolan-4S-yl]-5H-furan-2-one (11a-d), exhibited an interesting activity. In particular the 5R,2R,2R,4S and 5R,2R,2S,4S isomers (11c,d) displayed a potent antioxidant effect compared to the respective synthetic alpha-tocopherol analogue (5) and natural alpha-tocopherol or ascorbic acid, used alone or in combination. Moreover, the mixture of stereoisomers 11a-d also proved to be effective in preventing damage induced by reperfusion on isolated rabbit heart, in particular at the higher concentration of 300 microM. In view of these results our study represents a new approach to potential therapeutic agents for applications in pathological events in which a free radical damage is involved. Design, synthesis and preliminary biological activity are discussed.
Manfredini
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S
Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Italy. mv9@unife.it
Vertuani
S
S
Manfredi
B
B
Rossoni
G
G
Calviello
G
G
Palozza
P
P
D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D001205:Ascorbic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D003402:Creatine Kinase / Q000378:metabolism; D004355:Drug Stability; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects; D008315:Malondialdehyde / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000517:prevention & control; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D000975:Antioxidants; D014810:Vitamin E; D008315:Malondialdehyde; D003402:Creatine Kinase; D001205:Ascorbic Acid