title: Rational discovery and development of a mitochondria-targeted antioxidant based on cinnamic acid scaffold.
abstract: A novel mitochondria-targeted antioxidant (TPP-OH) was synthesized by attaching the natural hydrophilic antioxidant caffeic acid to an aliphatic lipophilic carbon chain containing a triphenylphosphonium (TPP) cation. This compound has similar antioxidant activity to caffeic acid as demonstrated by measurement of DPPH/ABTS radical quenching and redox potentials, but is significantly more hydrophobic than its precursor as indicated by the relative partition coefficients. The antioxidant activity of both compounds was intrinsic related to the ortho-catechol system, as the methoxylation of the phenolic functions, namely in TPP-OCH(3) and dimethoxycinnamic acid, gave compounds with negligible antioxidant action. The incorporation of the lipophilic TPP cation to form TTP-OH and TPP-OCH(3) allowed the cinnamic derivatives to accumulate within mitochondria in a process driven by the membrane potential. However, only TPP-OH was an effective antioxidant: TPP-OH protected cells against H(2)O(2) and linoleic acid hydroperoxide-induced oxidative stress. As mitochondrial oxidative damage is associated with a number of clinical disorders, TPP-OH may be a useful lead that could be added to the family of mitochondria-targeted antioxidants that can decrease mitochondrial oxidative damage.
authors.affiliation: CIQ/Departamento de Química e Bioquímica, Universidade do Porto, Porto, Portugal.
authors.forename: José
authors.initials: J
authors.lastname: Teixeira
authors.forename: Pedro
authors.initials: P
authors.lastname: Soares
authors.forename: Sofia
authors.initials: S
authors.lastname: Benfeito
authors.forename: Alexandra
authors.initials: A
authors.lastname: Gaspar
authors.forename: Jorge
authors.initials: J
authors.lastname: Garrido
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.forename: Fernanda
authors.initials: F
authors.lastname: Borges
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D002109:Caffeic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D002934:Cinnamates / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000378:metabolism; D008041:Linoleic Acids / Q000378:metabolism; D015227:Lipid Peroxidation; D008054:Lipid Peroxides / Q000378:metabolism; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects
chemical_list: C574296:2-(3-(3,4-dihydroxyphenyl)prop-2-enamido)ethyltriphenylphosphonium; C574295:2-(3-(3,4-dimethoxyphenyl)prop-2-enamido)ethyltriphenylphosphonium; D000975:Antioxidants; D002109:Caffeic Acids; D002934:Cinnamates; D008041:Linoleic Acids; D008054:Lipid Peroxides; D009943:Organophosphorus Compounds; C029010:cinnamic acid; C008285:linoleic acid hydroperoxide; D006861:Hydrogen Peroxide; C040048:caffeic acid