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.

Immunomodulatory effects of royal jelly on aorta CD3, CD68 and eNOS expression in hypercholesterolaemic rats

“…These cells preferentially infiltrate unstable plaque and contribute to increased endothelial cell lysis in patients with acute coronary syndromes (Nakajima et al, 2002). The imbalance occurred between reactive oxygen species (ROS) generation and antioxidants, leading to oxidative damage which spreads over most cell targets such as DNA, lipids and proteins (Ortial et al, 2006). Free radicals can induce oxidative damage to the body and this damage might induce dysfunction of cells, organs and the whole body.…”

Fluorinated organic azides – their preparation and synthetic application

“…The synthesis and characterization of azide 16 prepared from iodide 11 is presented in this paper. On the other hand preparation of 1H,1H,2H,2H-perfluorooctyl azide 9 from the corresponding iodide 12 with sodium azide and Aliquat® 336, [55][56][57] in DMF, 14,58 in DMSO 45 or methyl-tridecylammonium chloride 59 has already been described. Prepared or purchased iodides were submitted to nucleophilic substitution with sodium azide.…”

SAR study of tyrosine–chlorambucil hybrid regioisomers; synthesis and biological evaluation against breast cancer cell lines

“…These amino-acid drug conjugates were then used as prodrugs to treat cancer cells. Furthermore, the development of amino acid-antioxidant conjugates and amino acid-anti-angiogenic conjugates were also recently reported in the literature (Ortial et al 2006;Durand et al 2009;Contino-Pépin et al 2009). Hence, amino-acid derivatives are a promising avenue, which must be further exploited in the search for new drug candidates.…”