NAD-analogues as potential anticancer agents: Conformational restrictions as basis for selectivity Journal Article


Authors: Pankiewicz, K. W.; Zatorski, A.; Watanabe, K. A.
Article Title: NAD-analogues as potential anticancer agents: Conformational restrictions as basis for selectivity
Abstract: 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.
Keywords: review; animal; animals; antimetabolites, antineoplastic; enzyme inhibitor; drug design; chemistry; drug antagonism; enzyme inhibitors; drug derivative; chemical structure; molecular structure; conformation; antineoplastic antimetabolite; molecular conformation; nad; synthesis; stereoisomerism; nicotinamide adenine dinucleotide; anticancer agents; inosinate dehydrogenase; humans; human; imp dehydrogenase; inhibitors of imp-dehydrogenase; nad-analogues; tiazofurin
Journal Title: Acta Biochimica Polonica
Volume: 43
Issue: 1
ISSN: 0001-527X
Publisher: Polish Biochemical Society  
Date Published: 1996-01-01
Start Page: 183
End Page: 193
Language: English
PUBMED: 8790723
PROVIDER: scopus
DOI/URL:
Notes: Article -- Export Date: 22 November 2017 -- Source: Scopus
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