NUCLEOSIDES .5. SYNTHESIS OF GUANINE AND FORMYCIN-B DERIVATIVES AS POTENTIAL INHIBITORS OF PURINE NUCLEOSIDE PHOSPHORYLASE

In an effort to develop potent human purine nucleoside phosphorylase ( PNP) inhibitors as immunosuppressive and chemotherapeutic agents. seve ral 8-aminoguanine derivatives were synthesized and evaluated as poten tial PNP inhibitors. These studies were designed to investigate the hy drophobic effect of a substituent on the N-9 of the purine heterocycle and/or the C-5' positions. Compounds such as 8-aminoguanosine, guanos ine, formycin B, and 8-aminoacyclovir containing a p-(fluorosulfonyl)b enzoyl moiety were synthesized. The affinity of these compounds to ery throcytic PNP was determined and none of these compounds showed a bett er affinity than those of the parent compounds. However, we found that the effect of hydrophobicity at the N-9 and the C-5' positions might play an important role in binding to the active site of PNP. Thus, 8-a mino-5'-deoxy-5'-(phenylthio)guanosine (19) was found to be the best i nhibitor in this series of compounds with a K(i) = 0.45 muM.