title: The chemistry of nicotinamide adenine dinucleotide (NAD) analogues containing C-nucleosides related to nicotinamide riboside.
abstract: Oncolytic C-nucleosides, tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide) and benzamide riboside (3-beta-D-ribofuranosylbenzamide) are converted in cell into active metabolites thiazole-4-carboxamide- and benzamide adenine dinucleotide, TAD and BAD, respectively. TAD and BAD as NAD analogues were found to bind at the nicotinamide adenine dinucleotide (cofactor NAD) site of inosine monophosphate dehydrogenase (IMPDH), an important target in cancer treatment. The synthesis and evaluation of anticancer activity of a number of C-nucleosides related to tiazofurin and nicotinamide riboside then followed and are reviewed herein. Interestingly, pyridine C-nucleosides (such as C-nicotinamide riboside) are not metabolized into the corresponding NAD analogues in cell. Their conversion by chemical methods is described. As dinucleotides these compounds show inhibition of IMPDH in low micromolar level. Also, the synthesis of BAD in metabolically stable bis(phosphonate) form is discussed indicating the usefulness of such preformed inhibitors in drug development. Among tiazofurin analogues, Franchetti and Grifantini found, that the replacement of the sulfur by oxygen (as in oxazafurin) but not the removal of nitrogen (tiophenfurin) of the thiazole ring resulted in inactive compounds. The anti cancer activity of their synthetic dinucleotide analogues indicate that inactive compounds are not only poorly metabolized in cell but also are weak inhibitors of IMPDH as dinucleotides.
authors.affiliation: Pharmasset, Inc., 1860 Montreal Road, Tucker, Atlanta, GA 30084, USA. kpankiewicz@pharmasset.com
authors.forename: Krzysztof W
authors.initials: KW
authors.lastname: Pankiewicz
authors.forename: Kyoichi A
authors.initials: KA
authors.lastname: Watanabe
authors.forename: Krystyna
authors.initials: K
authors.lastname: Lesiak-Watanabe
authors.forename: Barry M
authors.initials: BM
authors.lastname: Goldstein
authors.forename: Hiremagalur N
authors.initials: HN
authors.lastname: Jayaram
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D009243:NAD / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D016566:Organoselenium Compounds; D011726:Pyridinium Compounds; D012254:Ribavirin / Q000031:analogs & derivatives / Q000494:pharmacology; D012263:Ribonucleosides; D012265:Ribonucleotides / Q000032:analysis; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D016566:Organoselenium Compounds; D011726:Pyridinium Compounds; D012263:Ribonucleosides; D012265:Ribonucleotides; C018613:nicotinamide-beta-riboside; D009243:NAD; D009536:Niacinamide; D012254:Ribavirin; D007168:IMP Dehydrogenase; C039064:selenazofurin; C033706:tiazofurin