N-PhosphonocarbonylpyrrolidineDerivatives of Guanine: A New Class of Bi-Substrate Inhibitors ofHuman Purine Nucleoside Phosphorylase.

A complete series of pyrrolidine nucleotides, (3R)- and (3S)-3-(guanin-9-yl)pyrrolidin-1-N-ylcarbonylphosphonic acids and (3S,4R)-, (3R,4S)-, (3S,4S)-, and (3R,4R)-4-(guanin-9-yl)-3-hydroxypyrrolidin-1-N-ylcarbonylphosphonic acids, were synthesized and evaluated as potentialinhibitors of purine nucleoside phosphorylase (PNP) isolated fromperipheral blood mononuclear cells (PBMCs) and cell lines of myeloidand lymphoid origin. Two compounds, (S)-3-(guanin-9-yl)pyrrolidin-1-N-ylcarbonylphosphonic acid (2a) and (3S,4R)-4-(guanin-9-yl)-3-hydroxypyrrolidin-1-N-ylcarbonylphosphonic acid (6a), were recognizedas nanomolar competitive inhibitors of PNP isolated from cell lineswith Kivalues within the ranges of 16–100and 10–24 nM, respectively. The low MESGKiand PiKivalues of both compounds for PNP isolated from PBMCs suggest thatthese compounds could be bisubstrate inhibitors that occupy both thephosphate and nucleoside binding sites of the enzyme. [ABSTRACT FROM AUTHOR]