8-Amino-9-substituted guanines: potent purine nucleoside phosphorylase (PNP) inhibitors |
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| Authors: | J C Sircar C R Kostlan G W Pinter M J Suto T P Bobovski T Capiris C F Schwender M K Dong M E Scott M K Bennett |
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| Affiliation: | Department of Chemistry, Warner-Lambert/Parke-Davis Pharmaceutical Research, Ann Arbor, Michigan 48105. |
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| 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. |
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