Synthesis Of 9-(1-Deoxy-1-phosphono-β-D-psicofuranosyl)-1,9-dihydro-6H-purin-6-one as a Potential Transition State Analog Inhibitor of Purine Nucleoside Phosphorylase

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A fifteen-step synthesis of the proposed purine nucleoside phosphorylase (PNP) transition state analog inhibitor 9-(1-deoxy-1-phosphono-β-D-psicofuranosyl)-1,9-dihydro-6H-purine-6-one (2) is described starting with 1,2:4,5-disopropylidene-β-D-psicopyranose (12). Catalytic hydrogenation of 9-[3-O-benzyl-1-(dibenzyloxy-phosphinyl)-1-deoxy-β-D-psicofuranosyl]-6-benzyloxypurine (27b) under basic conditions gave the unstable 2 which was found to have a half-life of 39 min at pH 7 and 81 min at pH 8. The low PNP inhibitory activity found for 2 (IC50 = 25 μM at 50 mM phosphate concentration) may be due entirely to the presence of the decomposition product hypoxanthine which is itself an inhibitor (IC50 = 8.6 μM).