Chemical synthesis of benzamide adenine dinucleotide: Inhibition of inosine monophosphate dehydrogenase (types I and II)

Andrzej Zatorski, Kyoichi A. Watanabe, Stephen F. Carr, Barry M. Goldstein, Krzysztof W. Pankiewicz

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Treatment of 3-(2,3-O-isopropylidene-β-D-ribofuranosyl)benzamide (6) with POCl3 in (EtO)3-PO afforded only little phosphorylation product (8, 5%), but the major product was 5'-chlorobenzamide riboside (7, 85%). Reaction of 6 with 2-cyanoethyl N,N-diisopropylchlorophosphoramidite followed by 2- cyanoethanol/tetrazole treatment and oxidation with tert-butyl peroxide gave a 1:1 mixture of the desired 5'-O-bis(2-cyanoethyl) phosphate 9 and the chloro derivative 7. This mixture was treated with methanolic ammonia and partitioned between CHCl3 and water. The 2',3'-O-isopropylidenebenzamide mononucleotide (8) was obtained in 21.2% overall yield from the aqueous layer. Compound 8 was then converted into the corresponding imidazolide 11b which, upon coupling with 2',3'-O-acetonide of AMP, afforded the acetonide of benzamide adenine dinucleotide (15) in 94% yield together with small amounts of symmetrical pyrophosphates P1,P2-bis(2',3'-O-isopropylideneadenosin-5'- yl)pyrophosphate (13, 3%) and P1,P2-bis(2',3',O-isopropylidene-3- (carbamoylphenyl)-5'-ribosyl)pyrophosphate (14, 2%). Deprotection of 15 with Dowex 50/H+ in water afforded the desired benzamide adenine dinucleotide (BAD) in 93% yield. BAD inhibits inosine monophosphate dehydrogenase type I (IC50 = 0.78 μM) and type II (IC50 = 0.88 μM) with same degree of potency.

Original languageEnglish (US)
Pages (from-to)2422-2426
Number of pages5
JournalJournal of medicinal chemistry
Volume39
Issue number12
DOIs
StatePublished - Jun 7 1996

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