Preliminary report on 8-amino-9-(2-thienylmethyl)guanine (PD 119,229), a novel and potent purine nucleoside phosphorylase inhibitor.
PD 119,229 [8-amino-9-(2-thienylmethyl)guanine] is a novel and potent inhibitor of human erythrocyte purine nucleoside phosphorylase (PNP) with a Ki of 0.067 microM. In a cell line assay using human MOLT-4 (T cell) and MGL-8 (B cell) lymphoblasts, PD 119,229 alone had no effect on the growth of either cell line at the highest concentration tested (100 microM). However, in the presence of a nontoxic concentration of 2'-deoxyguanosine (10 microM), the IC50 values of PD 119,229 for MOLT-4 and MGI-8 40-fold either cell line at the highest concentration tested (100 microM). However, in the presence of a nontoxic concentration of 2'-deoxyguanosine (10 microM), the IC50 values of PD 119,229 for MOLT-4 and MGI-8 were 0.9 and greater than 100 microM, respectively. The inhibition of growth of MOLT-4 was accompanied by a 40-fold increase in dGTP and a two-fold reduction in GTP, while no alteration in nucleotide profile was noted in MGL-8. Both the inhibition of growth of MOLT-4 and the accumulation of dGTP were substantially prevented by coaddition of 2'-deoxycytidine.
D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003848:Deoxyguanine Nucleotides / Q000378:metabolism; D003849:Deoxyguanosine / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D010430:Pentosyltransferases / Q000037:antagonists & inhibitors*; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*
D003848:Deoxyguanine Nucleotides; C054342:8-amino-9-(2-thienylmethyl)guanine; D006147:Guanine; D006160:Guanosine Triphosphate; C029603:deoxyguanosine triphosphate; D010430:Pentosyltransferases; D011683:Purine-Nucleoside Phosphorylase; D003849:Deoxyguanosine