Synthesis of isosteric analogues of nicotinamide adenine dinucleotide containing C-nucleotide of nicotinamide or picolinamide Journal Article

  


Authors: Pankiewicz, K. W.; Zeidler, J.; Ciszewski, L. A.; Bell, J. E.; Goldstein, B. M.; Jayaram, H. N.; Watanabe, K. A.
Article Title: Synthesis of isosteric analogues of nicotinamide adenine dinucleotide containing C-nucleotide of nicotinamide or picolinamide
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. © 1993, American Chemical Society. All rights reserved.
Keywords: unclassified drug; nonhuman; animal cell; mouse; animal; mice; enzyme inhibition; antimetabolites, antineoplastic; antineoplastic activity; drug potency; enzyme inhibitor; drug synthesis; liver; protein processing; cattle; nad; stereochemistry; nicotinamide adenine dinucleotide; horses; competitive inhibition; glutamate dehydrogenase; alcohol dehydrogenase; horse; inosinate dehydrogenase; ribonucleosides; niacinamide; adenine derivative; leukemia l1210; priority journal; article; support, u.s. gov't, p.h.s.; imp dehydrogenase; tiazofurin; nicotinamide derivative; picolinic acids; 5 (beta d ribofuranosyl)nicotinamide (5',5 adenosine pyrophosphate; 6 (beta d ribofuranosyl)picolinamide; 6 (beta d ribofuranosyl)picolinamide (5',5 adenosine pyrophosphate; c nucleoside; picolinamide
Journal Title: Journal of Medicinal Chemistry
Volume: 36
Issue: 13
ISSN: 0022-2623
Publisher: American Chemical Society  
Date Published: 1993-06-25
Start Page: 1855
End Page: 1859
Language: English
DOI: 10.1021/jm00065a008
PUBMED: 8099976
PROVIDER: scopus
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-0027279134&doi=10.1021%2fjm00065a008&partnerID=40&md5=225c754a97a91f3cc3cc0a3656e25eb5
Notes: Article -- Export Date: 1 March 2019 -- Source: Scopus
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MSK Authors
  1. Kyoichi A Watanabe
    125 Watanabe
  2. Krzystof W. Pankiewicz
    43 Pankiewicz
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