REGIOSELECTIVE SYNTHESIS OF IMIDAZO[4,5-G]QUINAZOLINE QUINONE NUCLEOSIDES AND QUINAZOLINE AMINO NUCLEOSIDES - STUDIES OF THEIR XANTHINE-OXIDASE AND PURINE NUCLEOSIDE PHOSPHORYLASE SUBSTRATE ACTIVITY

The regioselective synthesis of 3-ribofuranosylimidazo[4,5-g]quinazoline-4,8-9(3H,7H)-trione (1) (benzoquinone-stretched-out inosine) and 8-(ribofuranosylamino)quinaozlin-4(3G)-one (2) was carried out in conjunction with the design of reductive alkylating nuclosides 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 origions: the 4-nitro group of 3 directs silylation to the N(1) position, which results in ribosylation exclusively at the N(3) position under Vorbruggen 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-amino-quinazolin-4(3H)-one) does bind to the PNPase active site as tightly as hypoxanthine. Factors which contribute to this binding behavior are discussed.