Synthesis and pharmacological evaluation of new 1,2-dithiolane based antioxidants.
Molecules containing a dithiolane moiety are widely investigated due to their antioxidant properties. The archetypal representative of this class of compounds is lipoic acid and indeed the lipoic acid-dihydrolipoic acid couple is part of the antioxidant defence system of the cell. In the course of a program aiming to find improved antioxidants effective in vivo, we designed, synthesised and pharmacologically investigated new lipoic acid analogs. The salient feature of these structures is the connection, via a thioamide or a thiocarbamate, of a 1,2-dithiolane moiety bearing a carbon chain and a N-alkyl-substituted morpholine ring. It was expected that the antioxidant and chelating properties of these functional groups combined with the basicity of the morpholine ring will impact on the antioxidant as well as on the partition and solubility characteristics of the compounds. Indeed in vitro and in vivo pharmacological investigation showed that these new molecules and especially those containing a thiocarbamate linker possess superior antioxidant properties compared with alpha-lipoic acid and to the amide or carbamate linker analogs. In particular, some of these compounds efficiently cross the blood brain barrier (BBB) thus providing efficient protection from lethality in a situation of induced oxidative stress. Moreover the absence of the 1,2-dithiolane moiety does not completely abolish antioxidant effects thus demonstrating that these compounds are distinct new chemical entities and not merely lipoic acid prodrugs. The chemical and pharmacological features of these new antioxidants are presented and discussed in the following paper.
Guillonneau
Claude
C
Chemistry Research Division A, institut de recherches Servier, 11, rue des Moulineaux, 92150 Suresnes, France.
Charton
Yves
Y
Ginot
Yves-Michel
YM
Fouquier-d'Hérouël
Marie-Victoire
MV
Bertrand
Marc
M
Lockhart
Brian
B
Lestage
Pierre
P
Goldstein
Solo
S
D000496:Alloxan; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis* / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006943:Hyperglycemia / Q000139:chemically induced / Q000517:prevention & control; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009025:Morpholines; D018384:Oxidative Stress / Q000187:drug effects; D013854:Thioamides; D013859:Thiocarbamates; D008063:Thioctic Acid / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology*; D020122:tert-Butylhydroperoxide / Q000037:antagonists & inhibitors
C448825:1,2-dithiolane; D000975:Antioxidants; D009025:Morpholines; D013854:Thioamides; D013859:Thiocarbamates; D000496:Alloxan; D008063:Thioctic Acid; D020122:tert-Butylhydroperoxide