Regioselective Synthesis of Imidazoquinazoline Quinone Nucleosides and Quinazoline Amino Nucleosides. Studies of Their Xanthine Oxidase and Purine Nucleoside Phosphorylase Substrate Activity

Article abstract of DOI:10.1021/jo00002a052

The regioselective synthesis of 3-ribofuranosylimidazo<4,5-g>quinazoline-4,8,9(3H,7H)-trione (1) (benzoquinone-stretched-out inosine) and 8-(ribofuranosylamino)quinazolin-4(3H)-one (2) was carried out in conjunction with the design of reductive alkylating nucleosides and new purine nucleoside mimics, respectively.The preparation of 1 was carried out by regioselective ribosylation of 4-nitroimidazo<4,5-g>quinazolin-8(3H,7H)-one (3) followed by nitro group reduction, Fremy oxidation, and deacetylation.Regiocontrol of ribosylation has steric origins: the 4-nitro group of 3 directs silylation to the N(1) position, which results in ribosylation exclusively at the N(3) position under Vorbrueggen reaction conditions.Regiocontrol during the preparation of 2 was possible by generating a stabilized ribofuranosyl carbocation, which selectively reacts with the amine group of the base.Nucleoside 1 is a purine-like quinone by virtue of its oxidation by xanthine oxidase.The potential inosine mimic 2 does not undergo phosphorolysis by purine nucleoside phosphorylase (PNPase), but the base form (8-aminoquinazolin-4(3H)-one) does bind to the PNPase active site as tightly as hypoxanthine.Factors which contribute to this binding behavior are discussed.