Omar M Khdour1, Jun Lu, Sidney M Hecht. 1. Biodesign Institute & Department of Chemistry & Biochemistry, Arizona State University, 1001 South McAllister Avenue, Tempe, Arizona 85287, USA.
Abstract
PURPOSE: To investigate of an approach to stabilize a novel pyridinol based α-tocopherol analogue (1) as a prodrug by acetylation of its phenol moiety. METHODS: Biochemical indicators of oxidative stress in mitochondria were utilized to gain insight into the cytoprotective mechanism(s) of compound 1 acetate. Oxygen free radical scavenging activity was measured using DCF probe in a cultured cell model system that had been placed under oxidative stress. Lipid peroxidation was examined both in a cell-free system and in oxidatively stressed cultured cells. The bioenergetic parameters of mitochondria were evaluated by measuring mitochondrial membrane potential (Δψ(m)) and the MPT. RESULTS: The present results suggest strongly that the antioxidant efficacy of compound 1 can be improved by using it as a prodrug. The tested prodrug has shown to be activated as a function of time, presumably due to susceptibility to enzymatic hydrolysis, and exhibits an antioxidant effect in time-dependent manner, providing a compound that is more effective than α-tocopherol acetate with regard to all protective properties studied. CONCLUSIONS: An effective approach to stabilize compound 1 was realized by using its acetate as a prodrug.
PURPOSE: To investigate of an approach to stabilize a novel pyridinol based α-tocopherol analogue (1) as a prodrug by acetylation of its phenol moiety. METHODS: Biochemical indicators of oxidative stress in mitochondria were utilized to gain insight into the cytoprotective mechanism(s) of compound 1 acetate. Oxygen free radical scavenging activity was measured using DCF probe in a cultured cell model system that had been placed under oxidative stress. Lipid peroxidation was examined both in a cell-free system and in oxidatively stressed cultured cells. The bioenergetic parameters of mitochondria were evaluated by measuring mitochondrial membrane potential (Δψ(m)) and the MPT. RESULTS: The present results suggest strongly that the antioxidant efficacy of compound 1 can be improved by using it as a prodrug. The tested prodrug has shown to be activated as a function of time, presumably due to susceptibility to enzymatic hydrolysis, and exhibits an antioxidant effect in time-dependent manner, providing a compound that is more effective than α-tocopherol acetate with regard to all protective properties studied. CONCLUSIONS: An effective approach to stabilize compound 1 was realized by using its acetate as a prodrug.
Authors: Vittorio Calabrese; Raffaele Lodi; Caterina Tonon; Velia D'Agata; Maria Sapienza; Giovanni Scapagnini; Andrea Mangiameli; Giovanni Pennisi; A M Giuffrida Stella; D Allan Butterfield Journal: J Neurol Sci Date: 2005-06-15 Impact factor: 3.181
Authors: K Ouahchi; M Arita; H Kayden; F Hentati; M Ben Hamida; R Sokol; H Arai; K Inoue; J L Mandel; M Koenig Journal: Nat Genet Date: 1995-02 Impact factor: 38.330
Authors: Timothy P Dalton; Ying Chen; Scott N Schneider; Daniel W Nebert; Howard G Shertzer Journal: Free Radic Biol Med Date: 2004-11-15 Impact factor: 7.376
Authors: Manikandadas M Madathil; Omar M Khdour; Jennifer Jaruvangsanti; Sidney M Hecht Journal: ACS Med Chem Lett Date: 2013-07-25 Impact factor: 4.345