Abstract
A series of 8-amino-9-substituted guanines was synthesized and their activity evaluated against human purine nucleoside phosphorylase (PNP). All compounds were found to be potent inhibitors of human PNP (IC50s: 0.17–126 μM). They were also selectively cytotoxic to MOLT-4 lymphoblasts in the presence of a nontoxic amount (10 μM) of the PNP substrate, 2′-deoxyguanosine (GdR). The most potent of these analogs, 2,8-diamino-1,9-dihydro-9-(2-thienylmethyl)-6H-purin-6-one (8-amino-9-(2-thienyl-methyl)guanine; PD 119,229) has an IC50 of 0.17 μM (Ki=0.067 μM), significantly more potent than the known standard, 8-aminoguanosine (IC50=1.40 μM). Thus it represents the most potent PNP inhibitor known to date when tested without limiting the concentration of inorganic phosphate.
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Sircar, J.C., Kostlan, C.R., Pinter, G.W. et al. 8-amino-9-substituted guanines: Potent purine nucleoside phosphorylase (PNP) inhibitors. Agents and Actions 21, 253–256 (1987). https://doi.org/10.1007/BF01966482
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DOI: https://doi.org/10.1007/BF01966482