Novel multisubstrate inhibitors of mammalian purine nucleoside phosphorylase

In an effort to develop potent multisubstrate-analog inhibitors of purine nucleoside phosphorylase (PNP), three nucleoside phosphonates were designed utilizing structural information from the previously reported structures of complexes of bovine PNP with substrates and products. The nucleoside phosphonates contain an acetal linkage at the O2' and O3' positions and a two-C-atom spacer between the ribose and phosphate moieties. The linkage enables the compounds to simultaneously occupy the purine-, ribose- and phosphate-binding sites. The chemical syntheses, inhibition profiles and structural characterization of these novel multisubstrate analog inhibitors with bovine PNP are described.