1-AZARIBOFURANOSIDE ANALOGS AS DESIGNED INHIBITORS OF PURINE NUCLEOSIDE PHOSPHORYLASE - SYNTHESIS AND BIOLOGICAL EVALUATION

Pyrrolidine analogues of 2-deoxyribofuranose, having nitrogen in place of anomeric carbon, have been synthesised as potential transition sta te analogues of enzymatic nucleoside cleavage. Efficient synthetic met hods were developed that allowed the synthesis of a wide range of 4-su bstituted 3-hydroxypyrrolidines starting from pyrroline and using open ing of the pyrrolidine 3,4-epoxide with carbon nucleophiles. Among the compounds synthesised were the 4-cyano[(+/-)-16], 4-hydroxymethyl [(/-)-22] and 4-carboxymethyl derivatives [(+/-)-18]. From the hydroxyme thyl derivative [(+/-)-22] N-alkylation with chloromethyl uracil gave an inosine analogue [(+/-)-23]. The new compounds were tested for inhi bition of human erythrocyte purine nucleoside phosphorylase. Compound (+/-)-22 was found to show non-competitive inhibition of the enzyme wi th a K-i of 160 mu M. This suggested that (+/-)-22 binds to the ribofu ranose portion of the active site. Furthermore, a solid-phase synthesi s of 1'-azanucleoside analogues was developed.