caa a22 4500 445314222 CHVBK 20180317142640.0 cr unu---uuuuu 170323e20111101xx s 000 0 eng 10.1007/s11095-011-0491-9 doi (NATIONALLICENCE)springer-10.1007/s11095-011-0491-9 An Acetate Prodrug of a Pyridinol-Based Vitamin E Analogue [Elektronische Daten] [Omar Khdour, Jun Lu, Sidney Hecht] 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 (Δψm) 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. Springer Science+Business Media, LLC, 2011 analogue nationallicence antioxidant nationallicence prodrug nationallicence pyridinol nationallicence reactive oxygen species (ROS) nationallicence stability nationallicence α-tocopherol acetate nationallicence AAPH : 2,2'-azobis-(2-amidinopropane) dihydrochloride nationallicence BSO : L-buthionine-(S, R)-sulfoximine nationallicence C11 BODIPY581/591 : 4,4-difluoro-5-(4-phenyl-1,3-butadienyl)-4-bora-3a, 4a-diaza-s-indacene-3-propionic acid nationallicence Calcein AM : calcein acetoxymethyl nationallicence DCF : dichlorofluorescein nationallicence DCFH-DA : dichlorodihydrofluorescein diacetate nationallicence DEM : diethyl maleate nationallicence DLPC : 1, 2-dilinoleoylphosphatidylcholine nationallicence DMSO : dimethylsulfoxide nationallicence EBS : Eagle's balanced salt nationallicence FBS : fetal bovine serum nationallicence FCCP : carbonyl cyanide p-trifluoromethoxyphenylhydrazone nationallicence FRDA : Friedreich's ataxia nationallicence GSH : glutathione nationallicence HSSB : Hanks' balanced salt solution buffer nationallicence MEM : Eagle's minimal essential medium nationallicence ROS : reactive oxygen species nationallicence SOPC : 1-stearoyl-2-oleoyl-phosphatidylcholine nationallicence TMRM : tetramethylrhodamine methyl ester nationallicence α-TOH : α-tocopherol nationallicence βFGF : basic fibroblast growth factor nationallicence Khdour Omar Biodesign Institute & Department of Chemistry & Biochemistry, Arizona State University, 1001 South McAllister Avenue, 85287, Tempe, Arizona, USA aut Lu Jun Biodesign Institute & Department of Chemistry & Biochemistry, Arizona State University, 1001 South McAllister Avenue, 85287, Tempe, Arizona, USA aut Hecht Sidney Biodesign Institute & Department of Chemistry & Biochemistry, Arizona State University, 1001 South McAllister Avenue, 85287, Tempe, Arizona, USA aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/11(2011-11-01), 2896-2909 0724-8741 28:11<2896 2011 28 11095 https://doi.org/10.1007/s11095-011-0491-9 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-011-0491-9 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Khdour Omar Biodesign Institute & Department of Chemistry & Biochemistry, Arizona State University, 1001 South McAllister Avenue, 85287, Tempe, Arizona, USA aut NATIONALLICENCE 700 1- Lu Jun Biodesign Institute & Department of Chemistry & Biochemistry, Arizona State University, 1001 South McAllister Avenue, 85287, Tempe, Arizona, USA aut NATIONALLICENCE 700 1- Hecht Sidney Biodesign Institute & Department of Chemistry & Biochemistry, Arizona State University, 1001 South McAllister Avenue, 85287, Tempe, Arizona, USA aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/11(2011-11-01), 2896-2909 0724-8741 28:11<2896 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer