title: Fluorinated amphiphilic amino acid derivatives as antioxidant carriers: a new class of protective agents.
abstract: The use of classical antioxidants is limited by their low bioavailabilities, and therefore, high doses are usually required to display significant protective activity. In a recent article (J. Med. Chem. 2003, 46, 5230) we showed that the ability of the alpha-phenyl-N-tert-butylnitrone (PBN) to restore the viability of ATPase-deficient human skin fibroblasts was greatly enhanced by grafting it on a fluorinated amphiphilic carrier. With the aim of extending this concept to other antioxidants, we present here the design, the synthesis, and the physicochemical measurements of a new series of fluorinated amphiphilic antioxidant derivatives. The hydroxyl radical scavenging activity and the radical reducing potency of these newly designed compounds were respectively demonstrated in an ABTS competition and an ABTS(*+) reduction assay. We also showed that the protective effects of amphiphilic antioxidants derived from PBN, Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) or lipoic acid (5-[1,2]-dithiolan-3-ylpentanoic acid) in primary cortical mixed cell cultures exposed to oxidotoxins are greatly improved compared to their parent compounds in the following rank-order: (1) PBN, (2) Trolox, and (3) lipoic acid. In contrast, the protective activity of indole-3-propionic acid was slightly decreased by grafting it on the amphiphilic carrier. Similar observations were made in in vivo experiments using aquatic invertebrate microorganisms, called rotifers, which were exposed to lethal concentrations of nonselective (H(2)O(2)) and mitochondria-selective (doxorubicin) oxidotoxins. The conclusion of these studies is that fluorinated amphiphilic PBN, Trolox, and lipoic acid derivatives exhibit very potent protective activities in in vitro and in vivo experiments. The findings demonstrated herein therefore strongly suggest that the amphiphilic character enhances the bioavailability of the antioxidants and allows for a selective targeting of mitochondria.
authors.affiliation: Laboratoire de Chimie BioOrganique et des Systèmes Moléculaires Vectoriels, Faculté des Sciences, Université d'Avignon et des Pays de Vaucluse, 84000 Avignon, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Ortial
authors.forename: Grégory
authors.initials: G
authors.lastname: Durand
authors.forename: Burkhard
authors.initials: B
authors.lastname: Poeggeler
authors.forename: Ange
authors.initials: A
authors.lastname: Polidori
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Pappolla
authors.forename: Jutta
authors.initials: J
authors.lastname: Böker
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Hardeland
authors.forename: Bernard
authors.initials: B
authors.lastname: Pucci
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000737:chemistry*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004317:Doxorubicin / Q000633:toxicity; D005461:Fluorine / Q000737:chemistry*; D006861:Hydrogen Peroxide / Q000494:pharmacology / Q000633:toxicity; D015394:Molecular Structure; D010084:Oxidation-Reduction; D020011:Protective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D013501:Surface-Active Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology
chemical_list: D000596:Amino Acids; D000975:Antioxidants; D020011:Protective Agents; D013501:Surface-Active Agents; D005461:Fluorine; D004317:Doxorubicin; D006861:Hydrogen Peroxide