title: Does hydrophobicity always enhance antioxidant drugs? A cut-off effect of the chain length of functionalized chlorogenate esters on ROS-overexpressing fibroblasts.
abstract: OBJECTIVE
  Phenolic antioxidants are currently attracting a growing interest as potential therapeutic agents to counteract diseases associated with oxidative stress. However, their high hydrophilicity results in a poor bioavailability hindering the development of efficient antioxidant strategies. A promising way to overcome this is to increase their hydrophobicity by lipophilic moiety grafting to form the newly coined 'phenolipids'. Although hydrophobicity is generally considered as advantageous regarding antioxidant properties, it is nevertheless worth investigating whether increasing hydrophobicity necessarily leads to a more efficient antioxidant drug.
  
  
  METHODS
  To answer this question, the antioxidant capacity of a homologous series of phenolics (chlorogenic acid and its methyl, butyl, octyl, dodecyl and hexadecyl esters) toward mitochondrial reactive oxygen species (ROS) generated in a ROS-overexpressing fibroblast cell line was investigated using 2',7'-dichlorodihydrofluorescein.
  
  
  RESULTS
  Overall, the long chain esters (dodecyl and hexadecyl esters) were more active than the short ones (methyl, butyl, and octyl esters), with an optimal activity for dodecyl chlorogenate. Moreover, dodecyl chlorogenate exerted a strong antioxidant capacity, for concentration and incubation time below the cytotoxicity threshold, making it a promising candidate for further in-vivo studies. More importantly, we found that the elongation of the chain length from 12 to 16 carbons led unexpectedly to a 45% decrease of antioxidant capacity.
  
  
  CONCLUSIONS
  The understanding of this sudden collapse of the antioxidant capacity through the cut-off theory will be discussed in this article, and may contribute towards development of a rational approach to design novel amphiphilic antioxidant drugs, especially phenolipids with medium fatty chain.
authors.affiliation: aCIRAD, UMR Ingénierie des Agropolymères et Technologies Émergentes, and bINRA, UMR Différenciation Cellulaire et Croissance, Montpellier, France.
authors.forename: Mickaël
authors.initials: M
authors.lastname: Laguerre
authors.forename: Chantal
authors.initials: C
authors.lastname: Wrutniak-Cabello
authors.forename: Béatrice
authors.initials: B
authors.lastname: Chabi
authors.forename: Luis J
authors.initials: LJ
authors.lastname: López Giraldo
authors.forename: Jérôme
authors.initials: J
authors.lastname: Lecomte
authors.forename: Pierre
authors.initials: P
authors.lastname: Villeneuve
authors.forename: Gérard
authors.initials: G
authors.lastname: Cabello
mesh_terms: D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002461:Cell Line, Transformed; D002726:Chlorogenic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D005347:Fibroblasts / Q000378:metabolism*; D005452:Fluoresceins / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D004952:Esters; D005452:Fluoresceins; D017382:Reactive Oxygen Species; C065013:2',7'-dichlorodihydrofluorescein; D002726:Chlorogenic Acid; D004247:DNA