Potentiation of 2'-deoxyguanosine cytotoxicity by a novel inhibitor of purine nucleoside phosphorylase, 8-amino-9-benzylguanine.
We have synthesized and evaluated a series of 9-substituted analogues of 8-aminoguanine, a known inhibitor of human purine nucleoside phosphorylase (PNP) activity. The ability of these agents to inhibit PNP has been investigated. All compounds were found to act as competitive (with inosine) inhibitors of PNP, with Ki values ranging from 0.2 to 290 microM. The most potent of these analogues, 8-amino-9-benzylguanine; exhibited a Ki value that was 4-fold lower than that determined for the parent base, 8-aminoguanine. As a metabolically stable compound in human blood, 8-amino-9-benzylguanine was more effective than 8-aminoguanine at potentiating the toxicity of 2'-deoxyguanosine to MOLT-4 T-lymphoblasts in culture. 8-Amino-9-benzylguanine is the most potent base or nucleoside inhibitor of human PNP reported to date, and it is a promising lead compound in the development of more effective PNP inhibitors.
Shewach
D S
DS
Chern
J W
JW
Pillote
K E
KE
Townsend
L B
LB
Daddona
P E
PE
D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003849:Deoxyguanosine / Q000008:administration & dosage*; D004357:Drug Synergism; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D006801:Humans; D007700:Kinetics; D008214:Lymphocytes; D010430:Pentosyltransferases / Q000037:antagonists & inhibitors*; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000964:Antimetabolites, Antineoplastic; C047715:8-amino-9-benzylguanine; D006147:Guanine; D010430:Pentosyltransferases; D011683:Purine-Nucleoside Phosphorylase; D003849:Deoxyguanosine