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

Research output: Contribution to journalArticle

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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)picolmamide (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
Pages (from-to)1855-1859
Number of pages5
JournalJournal of Medicinal Chemistry
Volume36
Issue number13
StatePublished - 1993

Fingerprint

Niacinamide
NAD
Nucleotides
Nucleosides
Inosine Monophosphate
Glutamate Dehydrogenase
Alcohol Dehydrogenase
Cyclization
Adenosine Monophosphate
Hydroxyl Radical
Liver
Adenosine
Inhibitory Concentration 50
Horses
Oxidoreductases
Cell Proliferation
picolinamide
Derivatives

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Pankiewicz, K. W., Zeidler, J., Ciszewski, L. A., Ellis Bell, J., Goldstein, B. M., Jayaram, H. N., & Watanabe, K. A. (1993). Synthesis of isosteric analogues of nicotinamide adenine dinucleotide containing C-nucleotide of nicotinamide or picolinamide. Journal of Medicinal Chemistry, 36(13), 1855-1859.

Synthesis of isosteric analogues of nicotinamide adenine dinucleotide containing C-nucleotide of nicotinamide or picolinamide. / Pankiewicz, Krzysztof W.; Zeidler, Joanna; Ciszewski, Lech A.; Ellis Bell, J.; Goldstein, Barry M.; Jayaram, Hiremagalur N.; Watanabe, Kyoichi A.

In: Journal of Medicinal Chemistry, Vol. 36, No. 13, 1993, p. 1855-1859.

Research output: Contribution to journalArticle

Pankiewicz, KW, Zeidler, J, Ciszewski, LA, Ellis Bell, J, Goldstein, BM, Jayaram, HN & Watanabe, KA 1993, 'Synthesis of isosteric analogues of nicotinamide adenine dinucleotide containing C-nucleotide of nicotinamide or picolinamide', Journal of Medicinal Chemistry, vol. 36, no. 13, pp. 1855-1859.
Pankiewicz KW, Zeidler J, Ciszewski LA, Ellis Bell J, Goldstein BM, Jayaram HN et al. Synthesis of isosteric analogues of nicotinamide adenine dinucleotide containing C-nucleotide of nicotinamide or picolinamide. Journal of Medicinal Chemistry. 1993;36(13):1855-1859.
Pankiewicz, Krzysztof W. ; Zeidler, Joanna ; Ciszewski, Lech A. ; Ellis Bell, J. ; Goldstein, Barry M. ; Jayaram, Hiremagalur N. ; Watanabe, Kyoichi A. / Synthesis of isosteric analogues of nicotinamide adenine dinucleotide containing C-nucleotide of nicotinamide or picolinamide. In: Journal of Medicinal Chemistry. 1993 ; Vol. 36, No. 13. pp. 1855-1859.
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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)picolmamide (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.",
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AU - Pankiewicz, Krzysztof W.

AU - Zeidler, Joanna

AU - Ciszewski, Lech A.

AU - Ellis Bell, J.

AU - Goldstein, Barry M.

AU - Jayaram, Hiremagalur N.

AU - Watanabe, Kyoichi A.

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