Synthesis of nonhydrolyzable analogues of thiazole-4-carboxamide and benzamide adenine dinucleotide containing fluorine atom at the C2' of adenine nucleoside: Induction of K562 differentiation and inosine monophosphate dehydrogenase inhibitory activity

Krystyna Lesiak, Kyoichi A. Watanabe, Alokes Majumdar, Michael Seidman, Kristen Vanderveen, Barry M. Goldstein, Krzysztof W Pankiewicz

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Abstract

Thiazole-4-carboxamide adenine dinucleotide (TAD) analogue 7 containing a fluorine atom at the C2' arabino configuration of the adenine nucleoside moiety was found to be a potent reducer of differentiation of K562 erythroid leukemia cells. This finding prompted us to synthesize its hydrolysis- resistant methylenebis(phosphonate) and difluoromethylenebis(phosphonate) analogues 8 and 9, respectively. Since both TAD and benzamide adenine dinucleotide (BAD) are potent inhibitors of inosine monophosphate dehydrogenase (IMPDH), the corresponding fluorine-substituted methylenebis(phosphonate) analogue 12 of BAD was also synthesized. Thus, 9- (2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine (13) was converted in five steps into the corresponding methylenebis(phosphonate) analogue 18. Dehydration of 18 with DCC led to the formation of the bicyclic trisanhydride intermediate 19a, which upon reaction with 2',3'-O-isopropylidenetiazofurin (20) or -benzamide riboside (21) followed by hydrolysis and deprotection afforded the desired methylene-bridged dinucleotides 8 and 12, respectively. The similar displacement of the 5'-mesyl function of 2',3-O-isopropylidene- 5'-O-mesyltiazefurin (24) with the difluoromethylenebis(phosphonic acid) derivative gave the phosphonate 25 which was coupled with 13 to afford 26. The desired difiuoromethylenebis(phosphonate) analogue 9 was obtained by deprotection with Dowex 50/H+. This compound as well as β-CF2-TAD (4) showed improved differentiation-inducing activity over β-CH2-TAD (3) whereas analogues containing the -CH2- linkage (8 and 12) were inactive.

Original languageEnglish (US)
Pages (from-to)2533-2538
Number of pages6
JournalJournal of Medicinal Chemistry
Volume40
Issue number16
DOIs
StatePublished - Aug 1 1997

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