Design, synthesis, and antioxidant potency of novel alpha-tocopherol analogues in isolated membranes and intact cells.
In this study, we have designed novel chromanyl derivatives that share with alpha-tocopherol a chromanyl head but differ in the lateral chain in: (i) length and saturation (FEBL-45, 50, 70), (ii) position of double bonds in Z or E (FEBL-50 and 53 and their respective 6-chromanyl methyl derivatives FEBL-161 and 162), or (iii) presence of additional antioxidant molecules, such as the catechol compound hydroxytyrosol (FEBL-80) or dopamine (FEBL-82, 95). The efficiency of these compounds in preventing free-radical-induced oxidative stress was investigated in isolated membranes as well as intact cells. The results of this study clearly show that all compounds synthesized were active in: (i) inhibiting AAPH- or tert-BOOH-induced lipid peroxidation in microsomes and (ii) preventing H2O2-induced ROS production, cell damage, and heat-shock protein expression in immortalized RAT-1 fibroblasts. Such effects were dose- and time-dependent. Independent of the kind of pro-oxidant used, differences in the antioxidant potency of these compounds were found in relation to the chemical structure with respect to the natural alpha-tocopherol: (1) The concomitant presence of a chromanyl head and an additional aromatic ring markedly increased the antioxidant potency of the molecule. In particular, FEBL-82 and FEBL-95, resulting from the molecular combination of trolox and dopamine, were much more potent than alpha-tocopherol, alpha-tocotrienol, and the other synthetic compounds. Moreover, they were also more potent than trolox and dopamine, used alone or in combination, suggesting synergistic cooperative interactions in the molecule between chromanyl and catechol moieties. (2) The length of the side chain affected the antioxidant properties of the molecule: FEBL-70, which displays a bulky squalene side chain, was less effective than the natural alpha-tocotrienol and the synthetic FEBL-45 and FEBL-50. (3) The presence of polyunsaturated double bonds in the side chain in the Z configuration (FEBL-53, FEBL-162) increased the antioxidant potency of the molecule with respect to the E configuration (FEBL-50, FEBL-161).
Palozza
Paola
P
Institute of General Pathology, Catholic University, 00168 Rome, Italy. p.palozza@rm.unicatt.it
Simone
Rossella
R
Picci
Nevio
N
Buzzoni
Lisa
L
Ciliberti
Nunzia
N
Natangelo
Anna
A
Manfredini
Stefano
S
Vertuani
Silvia
S
D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000494:pharmacology*; D002396:Catechols / Q000737:chemistry; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002470:Cell Survival; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D005347:Fibroblasts / Q000378:metabolism; D005609:Free Radicals; D006360:Heat-Shock Proteins / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D018384:Oxidative Stress; D051381:Rats; D024502:alpha-Tocopherol / Q000031:analogs & derivatives* / Q000138:chemical synthesis
D000975:Antioxidants; D002396:Catechols; D005609:Free Radicals; D006360:Heat-Shock Proteins; D024502:alpha-Tocopherol; C034221:catechol