title: Tetrahydro-1,8-naphthyridinol analogues of alpha-tocopherol as antioxidants in lipid membranes and low-density lipoproteins.
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 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.
authors.affiliation: Center in Molecular Toxicology and Vanderbilt Institute of Chemical Biology, Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, USA.
authors.forename: Tae-gyu
authors.initials: TG
authors.lastname: Nam
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Rector
authors.forename: Hye-young
authors.initials: HY
authors.lastname: Kim
authors.forename: Andreas F-P
authors.initials: AF
authors.lastname: Sonnen
authors.forename: Roland
authors.initials: R
authors.lastname: Meyer
authors.forename: Werner M
authors.initials: WM
authors.lastname: Nau
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Atkinson
authors.forename: Julia
authors.initials: J
authors.lastname: Rintoul
authors.forename: Derek A
authors.initials: DA
authors.lastname: Pratt
authors.forename: Ned A
authors.initials: NA
authors.lastname: Porter
mesh_terms: D000975:Antioxidants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002352:Carrier Proteins / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D015227:Lipid Peroxidation / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000737:chemistry* / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry; D008958:Models, Molecular; D009287:Naphthyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010713:Phosphatidylcholines / Q000737:chemistry*; D024502:alpha-Tocopherol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D002352:Carrier Proteins; D008077:Lipoproteins, LDL; D008081:Liposomes; D009287:Naphthyridines; D010713:Phosphatidylcholines; C017763:alpha-tocopherol transfer protein; D024502:alpha-Tocopherol; C028694:1-palmitoyl-2-oleoylphosphatidylcholine