Synthesis of Isosteric Analogues of Nicotinamide Adenine Dinucleotide Containing C-Nucleotide of Nicotinamide or Picolinamide

Krzysztof W. Pankiewicz, Joanna Zeidler, Lech A. Ciszewski, J. Ellis Bell, Barry M. Goldstein, Hiremagalur N. Jayaram, Kyoichi A. Watanabe

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23 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1855-1859
Number of pages5
JournalJournal of medicinal chemistry
Volume36
Issue number13
DOIs
StatePublished - 1993

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