Article

Synthesis of alpha-tocohexaenol (alpha-T6) a fluorescent, oxidatively sensitive polyene analogue of alpha-tocopherol

Toronto Research Chemicals, Inc., 2 Brisbane Rd., North York, ON, Canada M3J 2J8.
Bioorganic & medicinal chemistry (Impact Factor: 2.95). 11/2009; 18(2):777-86. DOI: 10.1016/j.bmc.2009.11.051
Source: PubMed

ABSTRACT A polyunsaturated analogue of alpha-tocopherol was synthesized that is both fluorescent and sensitive to peroxidative chemistry that occurs in phospholipid membranes. alpha-Tocohexaenol 1, [(S)-2,5,7,8-tetramethyl-2-((1E/Z,3E,5E,7E,9E)-4,8,12-trimethyltrideca-1,3,5,7,9,11-hexaenyl)chroman-6-ol, alpha-T6] was prepared by condensing a known triene fragment triphenyl-(2,6-dimethyl-octa-2,4,6-trienoic acid methyl ester)-phosphonium bromide with a protected chromanol aldehyde, (2S)-6-{[tert-butyl(dimethyl)silyl]oxy}-2,5,7,8-tetra-methyl-3,4-dihydro-2H-chromene-2-carbaldehyde. The full side chain was then completed with isopentyl(tri-n-butyl)phosphonium bromide to give 1. The geometry of the C1'-C2' alkene appears to be Z (cis) although the coupling constants of the olefinic protons are intermediate between values normally assigned to E and Z-isomers. In ethanol, alpha-T6 has a maximum absorption at 368nm with an absorption coefficient of 45,000M(-1) cm(-1), and displays a maximum fluorescence emission at 523nm. The susceptibility of alpha-T6 to peroxidative chemistry was dependent on the concentration of azo-initiators of lipid oxidation in acetonitrile solution as well as in phospholipid vesicles. A loss of fluorescence at 520nm was observed when alpha-T6 (vesicles or alpha-T6-lipid mixtures) was exposed to peroxidative conditions, and this loss mirrored the production of conjugated dienes and trienes during the peroxidation of bulk phospholipids. Addition of natural alpha-tocopherol during the AMVN induced oxidation of 4microM alpha-T6 and 0.5mg/ml soybean PC induced a characteristic lag phase, after which the fluorescence of alpha-T6 began to lessen. Thus, alpha-T6 may be a useful reporter not only of tocopherol location in cells, but also of the extent of peroxidative events.

1 Follower
 · 
172 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Vitamin E (α-tocopherol) has long been recognized as the major antioxidant in biological membranes, and yet many structurally related questions persist of how the vitamin functions. For example, the very low levels of α-tocopherol reported for whole cell extracts question how this molecule can successfully protect the comparatively enormous quantities of PUFA-containing phospholipids found in membranes that are highly susceptible to oxidative attack. The contemporary realization that membranes laterally segregate into regions of distinct lipid composition (domains), we propose, provides the answer. We hypothesize α-tocopherol partitions into domains that are enriched in polyunsaturated phospholipids, amplifying the concentration of the vitamin in the place where it is most needed. These highly disordered domains depleted in cholesterol are analogous, but organizationally antithetical, to the well-studied lipid rafts. We review here the ideas that led to our hypothesis. Experimental evidence in support of the formation of PUFA-rich domains in model membranes is presented, focusing upon docosahexaenoic acid that is the most unsaturated fatty acid commonly found. Physical methodologies are then described to elucidate the nature of the interaction of α-tocopherol with PUFA and to establish that the vitamin and PUFA-containing phospholipids co-localize in non-raft domains.
    Molecular Nutrition & Food Research 05/2010; 54(5):641 - 651. DOI:10.1002/mnfr.200900439 · 4.91 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: γ-Tocopherol, a component of the essential nutrient mixture commonly designated as vitamin E, was chemically combined with differently substituted monofluoro- and difluorophenyl moieties to produce potential antagonists for the human aryl hydrocarbon receptor (AhR). 5-Iodo-γ-tocopherol was a very reliable starting material for the Pd-catalyzed reaction with (fluorophenyl)boronic acids (Suzuki coupling). The ortho- and meta-fluoro-substituted derivatives showed conformational isomerism due to restricted rotation around the interaromatic bond. This effect was investigated by NMR spectroscopy. Three of the derivatives showed very high potency in assays and are promising candidates for further testing.
    European Journal of Organic Chemistry 05/2011; 2011(13):2450 - 2457. DOI:10.1002/ejoc.201100178 · 3.15 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The total synthesis of amphidinolide C and a second-generation synthesis of amphidinolide F have been accomplished through the use of a common intermediate to access both the C1-C8 and the C18-C25 sections. The development of a Ag-catalyzed cyclization of a propargyl benzoate diol is described to access both trans-tetrahydrofuran rings. The evolution of a Felkin-controlled, 2-lithio-1,3-dienyl addition strategy to incorporate C9-C11 diene as well as C8 stereocenter is detailed. Key controlling aspects in the sulfone alkylation/oxidative desulfurization to join the major subunits, including the exploration of the optimum masking group for the C18 carbonyl motif, are discussed. A Trost asymmetric alkynylation and a stereoselective cuprate addition to an alkynoate have been developed for the rapid construction of the C26-C34 subunit. A Tamura/Vedejs olefination to introduce the C26 side arm of amphidnolides C and F is employed. The late-stage incorporation of the C15, C18 diketone motif proved critical to the successful competition of the total syntheses.
    Journal of the American Chemical Society 07/2013; 135(29). DOI:10.1021/ja404796n · 11.44 Impact Factor

Preview

Download
32 Downloads
Available from

Similar Publications