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An Acetate Prodrug of a Pyridinol-Based Vitamin E Analogue

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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.

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Abbreviations

AAPH:

2,2’-azobis-(2-amidinopropane) dihydrochloride

BSO:

L-buthionine-(S, R)-sulfoximine

C11 BODIPY581/591 :

4,4-difluoro-5-(4-phenyl-1,3-butadienyl)-4-bora-3a, 4a-diaza-s-indacene-3-propionic acid

Calcein AM:

calcein acetoxymethyl

DCF:

dichlorofluorescein

DCFH-DA:

dichlorodihydrofluorescein diacetate

DEM:

diethyl maleate

DLPC:

1, 2-dilinoleoylphosphatidylcholine

DMSO:

dimethylsulfoxide

EBS:

Eagle’s balanced salt

FBS:

fetal bovine serum

FCCP:

carbonyl cyanide p-trifluoromethoxyphenylhydrazone

FRDA:

Friedreich’s ataxia

GSH:

glutathione

HSSB:

Hanks’ balanced salt solution buffer

MEM:

Eagle’s minimal essential medium

ROS:

reactive oxygen species

SOPC:

1-stearoyl-2-oleoyl-phosphatidylcholine

TMRM:

tetramethylrhodamine methyl ester

α-TOH:

α-tocopherol

βFGF:

basic fibroblast growth factor

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ACKNOWLEDGMENTS & DISCLOSURES

This work was supported in part by a research grant from the Friedreich’s Ataxia Research Alliance.

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Authors and Affiliations

  1. Biodesign Institute & Department of Chemistry & Biochemistry, Arizona State University, 1001 South McAllister Avenue, Tempe, Arizona, 85287, USA

    Omar M. Khdour, Jun Lu & Sidney M. Hecht

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  1. Omar M. Khdour
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  2. Jun Lu
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Correspondence to Sidney M. Hecht.

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Khdour, O.M., Lu, J. & Hecht, S.M. An Acetate Prodrug of a Pyridinol-Based Vitamin E Analogue. Pharm Res 28, 2896–2909 (2011). https://doi.org/10.1007/s11095-011-0491-9

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