Tetrahydro-1,8-naphthyridinol analogues of alpha-tocopherol as antioxidants in lipid membranes and low-density lipoproteins.

Tetrahydro-1,8-naphthyridinol analogues of alpha-tocopherol as antioxidants in lipid membranes and low-density lipoproteins. Research Abstract Details 

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Tetrahydro-1,8-naphthyridinol analogues of alpha-tocopherol as antioxidants in lipid membranes and low-density lipoproteins. Abstract Text:

Tae-gyu Nam,Christopher L Rector,Hye-young Kim,Andreas F-P Sonnen,Roland Meyer,Werner M Nau,Jeffrey Atkinson,Julia Rintoul,Derek A Pratt,Ned A Porter,

Recently we demonstrated that the C(7)-unsubstituted tetrahydro-1,8-naphthyridin-3-ol has more than an order of magnitude better peroxyl radical trapping activity than alpha-tocopherol (alpha-TOH) in inhibited autoxidations in benzene. In order to prepare analogues more structurally related to alpha-TOH for further studies in vitro and in vivo, we developed synthetic approaches to C(7)-monoalkyl and C(7)-dialkyl analogues using a sequence involving (1) AgNO3-mediated hydroxymethyl radical addition to 1,8-naphthyridine, (2) regioselective alkyllithium addition by cyclic chelation in a nonpolar solvent, (3) iodination of the naphthyridine at C(3), and (4) CuI-medidated benzyloxylation of the aryl iodide followed by catalytic hydrogenolysis. An alpha-TOH isostere was prepared by a Wittig coupling of a C16 side chain identical to that of alpha-TOH to the naphthyridinols. The C(7)-mono- and dialkyl analogues exhibited more than an order of magnitude higher antioxidant activity (k(inh) = (5.3-6.1) x 10(7) M(-1) s(-1)) than alpha-TOH (k(inh) = 0.35 x 10(7) M(-) s(-1)) in benzene, as determined by a newly developed peroxyl radical clock. In addition to the strong antioxidant activity in benzene, the closest alpha-TOH analogue (naphthyridinol-based tocopherol, N-TOH) showed excellent inhibition of the oxidation of cholesteryl esters in human low-density lipoprotein and spared endogenous alpha-TOH in these experiments. Lateral diffusion of N-TOH in 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine liposomes was comparable to that of alpha-TOH, suggesting that it will have good antioxidant characteristics in both membranes and lipoproteins. Furthermore, a binding assay using a fluorescent tocopherol analogue showed that N-TOH binds to recombinant human tocopherol transfer protein better than alpha-TOH itself, suggesting that distribution of unnatural antioxidants such as N-TOH in vivo is possible.

Tetrahydro-1,8-naphthyridinol analogues of alpha-tocopherol as antioxidants in lipid membranes and low-density lipoproteins. Publishing Authors By Initials

TG Nam,CL Rector,HY Kim,AF Sonnen,R Meyer,WM Nau,J Atkinson,J Rintoul,DA Pratt,NA Porter,

For similar heterocyclic compounds: heterocyclic compounds, 2-ring: benzopyrans: vitamin e: tocopherols: alpha-tocopherol research abstracts see: heterocyclic compounds: heterocyclic compounds, 2-ring: benzopyrans: vitamin e: tocopherols: alpha-tocopherol research

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Tetrahydro-1,8-naphthyridinol analogues of alpha-tocopherol as antioxidants in lipid membranes and low-density lipoproteins. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Journal of the American Chemical Society

VOLUME: 129

Page Numbers: 10211-9

Journal Abbreviation: J. Am. Chem. Soc.

ISSN: 0002-7863

DAY: 27

MONTH: 07

YEAR: 2007

Tetrahydro-1,8-naphthyridinol analogues of alpha-tocopherol as antioxidants in lipid membranes and low-density lipoproteins. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 7503056

Tetrahydro-1,8-naphthyridinol analogues of alpha-tocopherol as antioxidants in lipid membranes and low-density lipoproteins. Keywords Mesh Terms:

KEYWORDS: alpha-Tocopherol

MESH TERMS: pharmacology

Chemical & Substance for Abstract: Tetrahydro-1,8-naphthyridinol analogues of alpha-tocopherol as antioxidants in lipid membranes and low-density lipoproteins. Information

Substance Name: 1-palmitoyl-2-oleoylphosphatidylcholine

Registry Number: 6753-55-5

Grant and Affiliation Information for Tetrahydro-1,8-naphthyridinol analogues of alpha-tocopherol as antioxidants in lipid membranes and low-density lipoproteins.

AFFILIATION: Center in Molecular Toxicology and Vanderbilt Institute of Chemical Biology, Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, USA.

Country: United States

AGENCY: United States PHS

GRANT: P01-013125

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MEDLINETA: J Am Chem Soc

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