Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.1.1.1 (alcohol dehydrogenase)
 9,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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-(beta-D-ribofuranosyl)nicotinamide (7) and 6-(beta-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-bromopyrid ine (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-(beta-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 microM) and to be a good competitive inhibitor of inosine monophosphate dehydrogenase (IMPDH, ID50 = 20 microM) as well as bovine glutamate dehydrogenase (GDH, Ki = 15 microM). 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 microM) of ADH.
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PMID:Synthesis of isosteric analogues of nicotinamide adenine dinucleotide containing C-nucleotide of nicotinamide or picolinamide. 809 76

Cofactor type inhibitors (NAD-analogues) of IMP-dehydrogenase (IMPDH) were synthesized and their application as potential anticancer agents are discussed. C-nucleoside isosteres of NAD, C-NAD and C-PAD, showed an effective competitive inhibition of IMPDH, C-NAD but not C-PAD caused extremely potent inhibition of alcohol dehydrogenase. We also synthesized compounds in which nicotinamide riboside was replaced with tiazofurin (TAD-analogues) and the 2' and 3'-positions of adenosine part were fluorinated. The ribose ring of 2'-deoxy-2'-fluoroadenosine is in the C3'-endo conformation whereas 3'-deoxy-3'-fluoroadenosine favors the C2'-endo sugar pucker. These derivatives are good inhibitors of IMPDH type II, the isoenzyme dominant in neoplastic cells. In contrast, all these analogues showed rather week inhibitory activity against alcohol dehydrogenase. Nicotinamide riboside derivatives in which the base and the sugar are linked through an oxygen or a methylene bridge were synthesized. NAD-analogues containing such conformationally restricted nicotinamide nucleoside moiety (syn or anti) are expected to be selective inhibitors of B-specific (IMPDH) or A-specific dehydrogenases, respectively.
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PMID:NAD-analogues as potential anticancer agents: conformational restrictions as basis for selectivity. 879 Jul 23

Synthetic nicotinamide adenine dinucleotide (NAD) analogues containing 5-beta-D-ribofuranosylnicotinamide (C-NAD), 6-beta-D-ribofuranosylpicolinamide (C-PAD), 3-beta-D-ribofuranosylbenzamide (BAD), and 2-beta-D-ribofuranosylthiazole-4-carboxamide (TAD) in place of the nicotinamide riboside moiety are described and evaluated as potential inhibitors of inosine monophosphate dehydrogenase (IMPDH). TAD and BAD showed potent inhibitory activity against the enzyme in the form of pyrophosphates, as well as metabolically stable methylene- and difluoromethylenebis(phosphonate)s. Fluorination at the C2' (ribo and arabino configuration) and C3' (ribo) of the adenosine moiety of TAD afforded analogues highly potent against IMPDH, but weakly active against alcohol dehydrogenase. With the exception of the methylenebis(phosphonate) analogue of TAD compounds containing a methylene bridge were poor inhibitors of growth of K562 cells. On the other hand, NAD analogues containing difluoromethylene linkage were highly effective in inhibition of K562 cell growth, as well as potent inducers of K562 cell differentiation. Such compounds, therefore, may be of potential therapeutic interest.
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PMID:Novel nicotinamide adenine dinucleotide analogues as potential anticancer agents: quest for specific inhibition of inosine monophosphate dehydrogenase. 953 71