title: Inhibition of nucleoside transport by nitrobenzylthioformycin analogs.
abstract: The formycin analogs of nitrobenzylthioinosine and nitrobenzylthioguanosine were synthesized and evaluated as nucleoside transport inhibitors. These analogs have a potential therapeutic advantage over their parent compounds in that their C-nucleosidic linkages prevent them from being degraded to the immunosuppressive agents, 6-mercaptopurine and 6-thioguanine. 7-[(4-Nitrobenzyl)-thio]-3-(beta-D-ribofuranosyl)pyrazolo[4,3- d]pyrimidine (NBTF) and 5-amino-7-[(4-nitrobenzyl)thio]-3-(beta-D- ribofuranosyl)pyrazolo[4,3-d]pyrimidine (NBTGF) were inhibitors of nucleoside transport in human erythrocytes and HL-60 leukemia cells. The IC50 value for nitrobenzylthioinosine, NBTF and NBTGF with 10% erythrocyte suspensions were 18, 18 and 40 nM respectively. Specific binding studies with [3H]NBTF yielded a Kd of 3.4 nM with erythrocytes, approximately 10-fold higher than values reported for nitrobenzylthioinosine. NBTF and nitrobenzylthioinosine bound to HL-60 cells with Kd values of 8.1 and 0.81 nM respectively. The octanol/water partition coefficients of nitrobenzylthioinosine, NBTF and NBTGF were 3.5, 3.2, and 2.8 respectively. NBTF could be expected to be equipotent with nitrobenzylthioinosine in whole blood where inhibitor concentrations of 10(-7) to 10(-6) M are required in order to saturate erythrocytic binding sites; hence, it may exhibit the advantages inherent in a C-nucleoside.
authors.affiliation: Division of Biology and Medicine, Brown University, Providence, RI 02912.
authors.forename: J D
authors.initials: JD
authors.lastname: Stoeckler
authors.forename: C G
authors.initials: CG
authors.lastname: Rosenfield
authors.forename: S H
authors.initials: SH
authors.lastname: Chu
authors.forename: S Y
authors.initials: SY
authors.lastname: Li
authors.forename: E M
authors.initials: EM
authors.lastname: Acton
authors.forename: K J
authors.initials: KJ
authors.lastname: Ryan
authors.forename: R E
authors.initials: RE
authors.lastname: Parks
mesh_terms: D000241:Adenosine / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D004912:Erythrocytes / Q000378:metabolism; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism; D009705:Nucleosides / Q000097:blood / Q000378:metabolism*; D013868:Thioinosine / Q000031:analogs & derivatives / Q000494:pharmacology; D013872:Thionucleosides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D009705:Nucleosides; D013872:Thionucleosides; C065225:nitrobenzylthioguanine formycin; D013868:Thioinosine; C065224:nitrobenzylthioformycin; C001789:4-nitrobenzylthioinosine; D000241:Adenosine