title: 8-Amino-9-substituted guanines: potent purine nucleoside phosphorylase (PNP) inhibitors.
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 microM). They were also selectively cytotoxic to MOLT-4 lymphoblasts in the presence of a nontoxic amount (10 microM) 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-thienylmethyl)guanine; PD 119,229) has an IC50 of 0.17 microM (Ki = 0.067 microM), significantly more potent than the known standard, 8-aminoguanosine (IC50 = 1.40 microM). Thus it represents the most potent PNP inhibitor known to date when tested without limiting the concentration of inorganic phosphate.
mesh_terms: D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004912:Erythrocytes / Q000201:enzymology; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents; D066298:In Vitro Techniques; D010430:Pentosyltransferases / Q000037:antagonists & inhibitors*; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D007166:Immunosuppressive Agents; C033495:8-aminoguanine; D006147:Guanine; D010430:Pentosyltransferases; D011683:Purine-Nucleoside Phosphorylase