- Synthesis of Isosteric Analogues of Nicotinamide Adenine Dinucleotide Containing C-Nucleotide of Nicotinamide or Picolinamide
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Two isosteric analogues of nicotinamide adenine dinucleotide, C-NAD (11) and C-PAD (12), in which the nicotinamide riboside portion is replaced by a C-nucleoside, were synthesized from 5-(β-D-ribofuranosyl)nicotinamide (7) and 6-(β-D-ribofuranosyl)picolinamide (8), respectively.Nucleoside 7 was prepared from the 2,3-O-isopropylidene-5-O-(tetrahydropyranyl)-D-ribonolactone (13) and 3-cyano-5-lithiopyridine as reported earlier.Nucleoside 8 was obtained by conversion of the bromo function of the 6-(2,3:4,5-di-O-isopropylidene-D-altro-pentitol-1-yl)-2-bromopyridine (14)into a carboxamido group followed by mesylation of the anomeric hydroxyl group to give derivative 18.Treatment of 18 with CF3COOH/CHCl3 caused deisopropylidenation with simultaneous cyclization into the desired 6-(β-D-ribofuranosyl)picolinamide (8).NAD analogues, C-NAD (11) and C-PAD (12), were synthesized by imidazole-catalyzed coupling of the corresponding 5'-monophosphates of 7 and 8 with the adenosine-5'-monophosphate.Dinucleotide 11 was found to inhibit the proliferation of L1210 cells (IC50 = 7 μM) and to be a good competitive inhibitor of inosine monophosphate dehydrogenase (IMPDH, ID50 = 20 μM) as well as bovine glutamate dehydrogenase (GDH, Ki = 15 μM).Interestingly, C-NAD (11) caused extremely potent noncompetitive inhibition of horse liver alcohol dehydrogenase (ADH, Ki = 1.1 nM), whereas C-PAD (12) was found to be a much less potent competitive inhibitor (Ki = 20 μM) of ADH.
- Pankiewicz, Krzysztof W.,Zeidler, Joanna,Ciszewski, Lech A.,Bell, J. Ellis,Goldstein, Barry M.,et al.
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- A general and efficient synthesis of pyridin-2-yl C-ribonucleosides bearing diverse alkyl, aryl, amino, and carbamoyl groups in position 6
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(Chemical Equation Presented) An efficient and practical methodology of preparation of 6-substituted pyridin-2-yl C-ribonucleosides was developed. A one-pot two-step addition of 2-lithio-6-bromopyridine to TBS-protected ribonolactone followed by acetylation gave 1β-(6-bromopyridin-2-yl)-1-O- acetyl-2,3,5-tri-O-(tertbutyldimethylsilyl)-D-ribofuranose in high yield. Its reduction with Et3SiH and BF3·Et2O afforded the desired TBS-protected 6-bromopyridine C-ribonucleoside as pure β-anomer in good overall yield of 63%. This intermediate was then subjected to a series of palladium catalyzed cross-coupling reactions, aminations and aminocarbonylations to give a series of protected 1β-(6-alkyl-, 6-aryl-, 6- amino-, and 6-carbamoylpyridin-2-yl)-C-ribonucleosides. Deprotection of silylated nucleosides by Et3N·3HF gave a series of title free C-ribonucleosides (12 examples).
- Stefko, Martin,Slavetinska, Lenka,Klepetarova, Blanka,Hocek, Michal
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supporting information; experimental part
p. 442 - 449
(2010/03/30)
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