caa a22 4500 445314265 CHVBK 20180317142640.0 cr unu---uuuuu 170323e20111101xx s 000 0 eng 10.1007/s11095-011-0504-8 doi (NATIONALLICENCE)springer-10.1007/s11095-011-0504-8 Novel Mitochondria-Targeted Antioxidants: Plastoquinone Conjugated with Cationic Plant Alkaloids Berberine and Palmatine [Elektronische Daten] [Konstantin Lyamzaev, Antonina Pustovidko, Ruben Simonyan, Tatyana Rokitskaya, Lidia Domnina, Olga Ivanova, Inna Severina, Natalia Sumbatyan, Galina Korshunova, Vadim Tashlitsky, Vitaly Roginsky, Yuriy Antonenko, Maxim Skulachev, Boris Chernyak, Vladimir Skulachev] ABSTRACT: Purpose: 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. Conclusion: 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. Springer Science+Business Media, LLC, 2011 antioxidant nationallicence berberine nationallicence mitochondria nationallicence palmatine nationallicence plastoquinone nationallicence SkQ nationallicence ∆ψ : transmembrane electric potential difference nationallicence AAPH : 2,2′-azobis(2-amidinopropane) dihydrochloride nationallicence AMVN : 2,2′-azodi(2,4′-dimethylvaleronitrile) nationallicence BLM : bilayer planar phospholipid membrane nationallicence BSA : bovine serum albumin nationallicence C10Berb : 13-(decyloxycarbonylmethyl)berberine nationallicence C10Palm : 13-(decyloxycarbonylmethyl)palmatine nationallicence C12TPP : dodecyltriphenylphosphonium nationallicence CM-DCF-DA : 5-(−6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate nationallicence FCCP : trifluoromethoxycarbonylcyanide phenylhydrazone nationallicence MDA : malondialdehyde nationallicence MitoQ : 10-(6-ubiquinonyl) decyltriphenylphosphonium nationallicence ROS : reactive oxygen species nationallicence SkQ : cationic derivative of plastoquinone or methyl plastoquinone nationallicence SkQ1 : 10-(6-plastoquinonyl) decyltriphenylphosphonium nationallicence SkQBerb : 13-[9- (6-plastoquinonyl) nonyloxycarbonylmethyl] berberine nationallicence SkQPalm : 13-[9-(6-plastoquinonyl) nonyloxycarbonylmethyl] palmatine nationallicence SkQR1 : 10-(6-plastoquinonyl) decylrhodamine 19 nationallicence TBARS : thiobarbituric acid-reactive substances nationallicence Lyamzaev Konstantin Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Vorobyevy Gory 1/40, 119899, Moscow, Russia aut Pustovidko Antonina Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Vorobyevy Gory 1/40, 119899, Moscow, Russia aut Simonyan Ruben Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Vorobyevy Gory 1/40, 119899, Moscow, Russia aut Rokitskaya Tatyana Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Vorobyevy Gory 1/40, 119899, Moscow, Russia aut Domnina Lidia Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Vorobyevy Gory 1/40, 119899, Moscow, Russia aut Ivanova Olga Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Vorobyevy Gory 1/40, 119899, Moscow, Russia aut Severina Inna Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Vorobyevy Gory 1/40, 119899, Moscow, Russia aut Sumbatyan Natalia Chemical Faculty, Lomonosov Moscow State University, Vorobyevy Gory 1, 119991, Moscow, Russia aut Korshunova Galina Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Vorobyevy Gory 1/40, 119899, Moscow, Russia aut Tashlitsky Vadim Chemical Faculty, Lomonosov Moscow State University, Vorobyevy Gory 1, 119991, Moscow, Russia aut Roginsky Vitaly Institute of Chemical Physics, ul. Kosygina 4, 119977, Moscow, Russia aut Antonenko Yuriy Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Vorobyevy Gory 1/40, 119899, Moscow, Russia aut Skulachev Maxim Institute of Mitoengineering, Lomonosov Moscow State University, Vorobyevy Gory 1, 119992, Moscow, Russia aut Chernyak Boris Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Vorobyevy Gory 1/40, 119899, Moscow, Russia aut Skulachev Vladimir Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Vorobyevy Gory 1/40, 119899, Moscow, Russia aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/11(2011-11-01), 2883-2895 0724-8741 28:11<2883 2011 28 11095 https://doi.org/10.1007/s11095-011-0504-8 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-011-0504-8 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Lyamzaev Konstantin Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Vorobyevy Gory 1/40, 119899, Moscow, Russia aut NATIONALLICENCE 700 1- Pustovidko Antonina Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Vorobyevy Gory 1/40, 119899, Moscow, Russia aut NATIONALLICENCE 700 1- Simonyan Ruben Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Vorobyevy Gory 1/40, 119899, Moscow, Russia aut NATIONALLICENCE 700 1- Rokitskaya Tatyana Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Vorobyevy Gory 1/40, 119899, Moscow, Russia aut NATIONALLICENCE 700 1- Domnina Lidia Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Vorobyevy Gory 1/40, 119899, Moscow, Russia aut NATIONALLICENCE 700 1- Ivanova Olga Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Vorobyevy Gory 1/40, 119899, Moscow, Russia aut NATIONALLICENCE 700 1- Severina Inna Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Vorobyevy Gory 1/40, 119899, Moscow, Russia aut NATIONALLICENCE 700 1- Sumbatyan Natalia Chemical Faculty, Lomonosov Moscow State University, Vorobyevy Gory 1, 119991, Moscow, Russia aut NATIONALLICENCE 700 1- Korshunova Galina Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Vorobyevy Gory 1/40, 119899, Moscow, Russia aut NATIONALLICENCE 700 1- Tashlitsky Vadim Chemical Faculty, Lomonosov Moscow State University, Vorobyevy Gory 1, 119991, Moscow, Russia aut NATIONALLICENCE 700 1- Roginsky Vitaly Institute of Chemical Physics, ul. Kosygina 4, 119977, Moscow, Russia aut NATIONALLICENCE 700 1- Antonenko Yuriy Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Vorobyevy Gory 1/40, 119899, Moscow, Russia aut NATIONALLICENCE 700 1- Skulachev Maxim Institute of Mitoengineering, Lomonosov Moscow State University, Vorobyevy Gory 1, 119992, Moscow, Russia aut NATIONALLICENCE 700 1- Chernyak Boris Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Vorobyevy Gory 1/40, 119899, Moscow, Russia aut NATIONALLICENCE 700 1- Skulachev Vladimir Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Vorobyevy Gory 1/40, 119899, Moscow, Russia aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/11(2011-11-01), 2883-2895 0724-8741 28:11<2883 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer