title: Antioxidant properties in a non-polar environment of difluoromethyl bioisosteres of methyl hydroxycinnamates.
abstract: OBJECTIVE
  Many natural antioxidants have poor pharmacokinetic properties that impair their therapeutic use. For hydroxycinnamic acids (HCAs) and other phenolic antioxidants, their major drawback is their low lipophilicity and a rapid metabolism. The difluoromethyl group may be considered as a 'lipophilic hydroxyl' due to its hydrogen bond donor and acceptor properties; this prompted us to assess it as a bioisosteric replacement of a phenolic hydroxyl for increasing the lipophilicity of HCAs.
  
  
  METHODS
  Six difluoromethyl-substituted methyl cinnamates (4a-c, 5a-c) related to caffeic acid were synthesized and their antioxidant activity evaluated by chemical (FRAP, DPPH scavenging, inhibition of β-carotene bleaching, at 1-200 μm), electrochemical (differential pulse voltammetry, cyclic voltammetry) and cell-based (inhibition of lipid peroxidation in erythrocytes, at 1 and 50 μm) assays.
  
  
  RESULTS
  Analogues 4a-c and 5a-c were inactive in FRAP and DPPH assays and only those containing a free phenolic hydroxyl (4a and 5a) exhibited electrochemical activity although with high redox potentials. Compounds 4a,b and 5a,b were active in the inhibition of β-carotene bleaching assay and all analogues inhibited lipid peroxidation in the human erythrocytes assay.
  
  
  CONCLUSIONS
  Lipophilic difluoromethyl-substituted cinnamic esters retain radical scavenging capabilities that prove useful to confer antioxidant properties in a non-polar environment.
authors.affiliation: Departamento de Química Orgánica and UMYMFOR (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Mario D
authors.initials: MD
authors.lastname: Martínez
authors.affiliation: Instituto de Biotecnología, Facultad de Ingeniería, Universidad Nacional de San Juan, San Juan, Argentina.
authors.forename: Lorena
authors.initials: L
authors.lastname: Luna
authors.affiliation: INQUIMAE (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Alvaro Y
authors.initials: AY
authors.lastname: Tesio
authors.affiliation: Instituto de Biotecnología, Facultad de Ingeniería, Universidad Nacional de San Juan, San Juan, Argentina.
authors.forename: Gabriela E
authors.initials: GE
authors.lastname: Feresin
authors.affiliation: Departamento de Química Orgánica and UMYMFOR (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Durán
authors.affiliation: Departamento de Química Orgánica and UMYMFOR (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Gerardo
authors.identifier: http://orcid.org/0000-0002-8559-7306
authors.initials: G
authors.lastname: Burton
mesh_terms: D000975:Antioxidants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000737:chemistry; D002478:Cells, Cultured; D003373:Coumaric Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004563:Electrochemistry; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005292:Ferricyanides / Q000737:chemistry; D005609:Free Radicals / Q000737:chemistry; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010851:Picrates / Q000737:chemistry; D019207:beta Carotene / Q000737:chemistry
chemical_list: D000975:Antioxidants; D001713:Biphenyl Compounds; D003373:Coumaric Acids; D005292:Ferricyanides; D005609:Free Radicals; D006845:Hydrocarbons, Fluorinated; D010851:Picrates; D019207:beta Carotene; C007931:hexacyanoferrate III; C004931:1,1-diphenyl-2-picrylhydrazyl
keywords: antioxidant activity; bioisosteres; difluoromethyl group; hydroxycinnamic acids; lipid peroxidation