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ABSTRACT: Fluorescent nitrobenzoxadiazole analogues of alpha-tocopherol (NBD-alpha-Tocs; lambda(ex) = 468 nm, lambda(em) = 527 nm) have been made previously to aid study of the intracellular location and transfer of vitamin E. However, these analogues are susceptible to photobleaching while under illumination for confocal microscopy as well as in in vitro FRET transfer assays. Here we report the synthesis of three fluorescent analogues of alpha-tocopherol incorporating the more robust dipyrrometheneboron difluoride (BODIPY) fluorophore. A BODIPY-linked chromanol should have no intervening polar functional groups that might interfere with binding to the hydrophobic binding site of the tocopherol transfer protein (alpha-TTP). A key step in bringing the two ring systems together was a metathesis reaction of vinyl chromanol and an alkenyl BODIPY. An o-tolyl containing second generation Grubbs catalyst was identified as the best catalyst for effecting the metathesis without detectable alkene isomerization, which when it occurred produced a mixture of chain lengths in the alkyl linker. C8-BODIPY-alpha-Toc 10c (lambda(ex) = 507 nm, lambda(em) = 511 nm, epsilon(507) = 83,000 M(-1) cm(-1)) having an eight-carbon chain between the chromanol and fluorophore, had the highest affinity for alpha-TTP (K(d) = 94 +/- 3 nM) and bound specifically as it could not be displaced with cholesterol.
The Journal of Organic Chemistry 04/2010; 75(9):2883-92. · 4.45 Impact Factor
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David Beattie,
Andrew Brearley,
Zarin Brown,
Steven J Charlton,
Brian Cox,
Robin A Fairhurst,
John R Fozard,
Peter Gedeck,
Paul Kirkham,
Koremu Meja,
Lana Nanson,
James Neef,
Helen Oakman,
Gillian Spooner,
Roger J Taylor,
Robert J Turner, Ryan West,
Hannah Woodward
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ABSTRACT: The synthesis of two series of 4'-aza-carbocyclic nucleosides are described in which the 4'-substituent is either a reversed amide, relative to the carboxamide of NECA, or an N-bonded heterocycle. Using established purine substitution patterns, potent and selective examples of agonists of the human adenosine A(2A) receptor have been identified from both series. The propionamides 14-18 and the 4-hydroxymethylpyrazole 32 were determined to be the most potent and selective examples from the 4'-reversed amide and 4'-N-bonded heterocyclic series, respectively.
Bioorganic & medicinal chemistry letters 02/2010; 20(3):1219-24. · 2.65 Impact Factor
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Journal of Labelled Compounds 10/2008; 51(13):413 - 418.
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ABSTRACT: The oxidative metabolism of tocopherols and tocotrienols by monooxygenases is a key factor in the plasma and tissue clearance of forms of vitamin E other than alpha-tocopherol. It is well known that a commonly ingested form of vitamin E, gamma-tocopherol, has greatly reduced plasma half-life (faster clearance) than alpha-tocopherol. The tocotrienols are metabolized even faster than gamma-tocopherol. Both gamma-tocopherol and alpha- and delta-tocotrienol possess intriguing biological activities that are different from alpha-tocopherol, making them potentially of interest for therapeutic use. Unfortunately, the fast clearance of non-alpha-tocopherols from animal tissues is a significant hurdle to maximizing their effect(s) as dietary supplements. We report here the design and synthesis of N-heterocycle-containing analogues of alpha-tocopherol that act as inhibitors of Cyp4F2, the key monooxygenase responsible for omega-hydroxylation of the side chain of tocols. In particular, an omega-imidazole containing compound, 1, [(R)-2-(9-(1H-imidazol-1-yl)nonyl)-2,5,7,8-tetramethylchroman-6-ol] had an ED(50) for inhibition of gamma-CEHC production from gamma-tocopherol of approximately 1 nM when tested in HepG2 cells in culture. Furthermore, feeding of 1 to mice along with rapidly metabolized delta-tocopherol, resulted in a doubling of the delta-tocopherol/alpha-tocopherol ratio in liver (P<0.05). Thus, 1 may be a useful adjuvant to the therapeutic use of non-alpha-tocopherols.
Bioorganic & medicinal chemistry 08/2008; 16(16):7631-8. · 2.82 Impact Factor
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ABSTRACT: Vitamin E is a family of chromanols that vary by the degree of methylation of the chroman ring as well as the nature of the hydrophobic side chain at C2 that serves to anchor these lipids in biological membranes. The tocopherols contain saturated side chains, whereas the tocotrienols contain three sites of unsaturation and are derived from geranylgeranyl diphosphate. A growing interest in the unique biological activities of the tocotrienols has led us to begin syntheses of isotopically substituted forms and other derivatives that will be useful for probing the metabolism and membrane behavior of the tocotrienols. In order to be certain of our ability to selectively modify sites on the parent molecules it was necessary to make as complete an assignment of the 1H and 13C NMR as possible. Herein we report multidimensional NMR data (HSQC, COSY, ADEQUATE(1,1), C--H HMBC, and NOESY) that have allowed us to assign the identity of almost all the resonances for alpha-, beta-, gamma-, and delta-tocotrienol.
Magnetic Resonance in Chemistry 04/2008; 46(3):287-94. · 1.44 Impact Factor
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Ryan. West
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ABSTRACT: Since its discovery nearly a century ago, a-tocopherol (vitamin E) research has been mainly focused on its ability to terminate the cycle of lipid peroxidation in membranes. Nitrobenzoxadiazole fluorescent analogues were made previously to study the intracellular transfer of vitamin E in cells. However, these molecules were reportedly susceptible to photobleaching while under illumination for transfer assays and microscopy. Here is reported the synthesis of a series of fluorescent analogues of vitamin E incorporating the more robust dipyrrometheneboron difluoride fluorophore (BDP-a-Tocs; Aex = 507 nm, Aem = 511 nm). C8-BDP-a-Toc 42c, having an eight-carbon chain between the chromanol and fluorophore, wa<; shown to bind specifically to a-tocopherol transfer protein with a dissociation constant of approximately 100 nM. Another fluorescent analogue of vitamin E with a thienyl derivative of BODIPY that is excited and fluoresces at longer wavelengths (Aex = 561 nm, Aem = 570 nm) is in development.
