title: Novel mitochondria-targeted antioxidants: plastoquinone conjugated with cationic plant alkaloids berberine and palmatine.
abstract: OBJECTIVE
  To develop effective mitochondria-targeted antioxidants composed entirely of natural constituents.
  
  
  METHODS
  Novel mitochondria-targeted antioxidants were synthesized containing plant electron carrier and antioxidant plastoquinone conjugated by nonyloxycarbonylmethyl residue with berberine or palmatine, penetrating cations of plant origin. These compounds, SkQBerb and SkQPalm, were tested in model planar phospholipid membranes and micelles, liposomes, isolated mitochondria and living cells.
  
  
  RESULTS
  SkQBerb and SkQPalm penetrated across planar bilayer phospholipid membrane in their cationic forms and accumulated in mitochondria isolated or in living human cells in culture. Reduced forms of SkQBerb and SkQPalm as well as C10Berb and C10Palm (SkQBerb and SkQPalm analogs lacking plastoquinol moiety) revealed radical scavenging activity in lipid micelles and liposomes, while oxidized forms were inactive. In isolated mitochondria and in living cells, berberine and palmatine moieties were not reduced, so antioxidant activity of C10Berb and C10Palm was not detected. SkQBerb and SkQPalm inhibited lipid peroxidation in isolated mitochondria at nanomolar concentrations; their prooxidant effect was observed at 1,000 times higher concentrations. In human cell cuture, nanomolar SkQBerb and SkQPalm prevented fragmentation of mitochondria and apoptosis induced by exogenous hydrogen peroxide.
  
  
  CONCLUSIONS
  This is the first successful attempt to construct mitochondria-targeted antioxidants composed entirely of natural components, namely plastoquinone, nonyl, acetyl and berberine or palmatine residues.
authors.affiliation: Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Vorobyevy Gory 1/40, Moscow 119899, Russia.
authors.forename: Konstantin G
authors.initials: KG
authors.lastname: Lyamzaev
authors.forename: Antonina V
authors.initials: AV
authors.lastname: Pustovidko
authors.forename: Ruben A
authors.initials: RA
authors.lastname: Simonyan
authors.forename: Tatyana I
authors.initials: TI
authors.lastname: Rokitskaya
authors.forename: Lidia V
authors.initials: LV
authors.lastname: Domnina
authors.forename: Olga Yu
authors.initials: OY
authors.lastname: Ivanova
authors.forename: Inna I
authors.initials: II
authors.lastname: Severina
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Sumbatyan
authors.forename: Galina A
authors.initials: GA
authors.lastname: Korshunova
authors.forename: Vadim N
authors.initials: VN
authors.lastname: Tashlitsky
authors.forename: Vitaly A
authors.initials: VA
authors.lastname: Roginsky
authors.forename: Yuriy N
authors.initials: YN
authors.lastname: Antonenko
authors.forename: Maxim V
authors.initials: MV
authors.lastname: Skulachev
authors.forename: Boris V
authors.initials: BV
authors.lastname: Chernyak
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Skulachev
mesh_terms: D000975:Antioxidants / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001599:Berberine / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001600:Berberine Alkaloids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004339:Drug Compounding; D016503:Drug Delivery Systems; D005347:Fibroblasts; D006367:HeLa Cells; D006801:Humans; D008051:Lipid Bilayers / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008956:Models, Chemical; D058990:Molecular Targeted Therapy; D008517:Phytotherapy; D028321:Plant Preparations / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010971:Plastoquinone / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D001600:Berberine Alkaloids; D008051:Lipid Bilayers; D028321:Plant Preparations; D001599:Berberine; C005413:palmatine; D010971:Plastoquinone