Synthesis of analogues of 5-aminoimidazole ribonucleotides and their effects as inhibitors and substrates of the enzymes, phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthetase involved in the biosynthesis of purine nucleotides de novo

Abstract

α- and β-D-Arabinofuranosyl, α- and β-D-xylofuranosyl nucleotide analogues and the 2-bromo derivatives of 5-amino-1-β-D-ribofuranosylimidazole 4-carboxylic acid 5′-phosphate (CAIR), a central intermediate in the de novo biosynthetic pathway to purine nucleotides, and its α-anomer have been synthesised by sequences of reactions from 2,3,5-tri-O-benzoyl-D-arabinofuranosyl azide, 3,5-O-isopropylidene-D-xylofuranosylamine or ethyl 5-amino-1-α- and β-D-ribofuranosyl-imidazole 4-carboxylates, respectively; the β- but not the α- forms are shown to have inhibitory activity on the enzyme duet AIR-carboxylase and SAICAR-kinosynthetase whilst the arabinose and xylose analogues of CAIR were also converted by a mixture of pathway enzymes through at least two steps into the arabinose and xylose analogues of 5-amino-1-β-D-ribofuranosylimidazole 4-carboxamide 5′-phosphate (AICAR), respectively.