1-Azaribofuranoside analogues as designed inhibitors of purine nucleoside phosphorylase. Synthesis and biological evaluation.

Abstract

Pyrrolidine analogues of 2-deoxyribofuranose, having nitrogen in place of anomeric carbon, have been synthesised as potential transition state analogues of enzymatic nucleoside cleavage. Efficient synthetic methods were developed that allowed the synthesis of a wide range of 4-substituted 3-hydroxypyrrolidines starting from pyrroline and using opening of the pyrrolidine 3,4-epoxide, with carbon nucleophiles. Among the compounds synthesised were the 4-cyano- [(+/-)-16], 4-hydroxymethyl [(+/-)-22] and 4-carboxymethyl derivates [(+/-)-18]. From the hydroxymethyl derivative [(+/-)-22] N-alkylation with chloromethyluracil gave an inosine analogue [(+/-)-23]. The new compounds were tested for inhibition of human erythrocyte purine nucleoside phosphorylase. Compound (+/-)-22 was found to show non-competitive inhibition of the enzyme with a Ki of 160 microM. This suggested that (+/-)-22 binds to the ribofuranose portion of the active site. Furthermore, a solid-phase synthesis of 1'-azanucleoside analogues was developed.