Tetrahydro-1,8-naphthyridinol analogues of alpha-tocopherol as antioxidants in lipid membranes and low-density lipoproteins
- Authors
- Nam, Tae-gyu; Rector, Christopher L.; Kim, Hye-young; Sonnen, Andreas F. -P.; Meyer, Roland; Nau, Werner M.; Atkinson, Jeffrey; Rintoul, Julia; Pratt, Derek A.; Porter, Ned A.
- Issue Date
- Aug-2007
- Publisher
- AMER CHEMICAL SOC
- Keywords
- CHAIN-BREAKING ANTIOXIDANTS; VITAMIN-E; BIOLOGICAL MOLECULES; FLUORESCENT-PROBE; AUTOXIDATION; PEROXIDATION; DIFFUSION; OXIDATION; PHENOLS; PROTEIN
- Citation
- JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, v.129, no.33, pp.10211 - 10219
- Indexed
- SCIE
SCOPUS
- Journal Title
- JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
- Volume
- 129
- Number
- 33
- Start Page
- 10211
- End Page
- 10219
- URI
- https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/43485
- DOI
- 10.1021/ja072371m
- ISSN
- 0002-7863
- Abstract
- 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 C-16 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-1 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.
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