Abstract
The adenosine analogs 4-amino- and 4-methoxy-8-(D-ribofuranosylamino)-pyrimido[5, 4-d]pyrimidine provide ID50 values against the human lymphoblast line WI-L2 of 0.18 μM and 0.05 μM, respectively. Cultured WI-L2 and in vivo mouse L1210 tumor lines selected for resistance to these analogs are characterized by a deficiency in adenosine kinase activity. These compounds completely inhibit de novo purine and pyrimidine biosynthesis as measured by [14C]-bicarbonate incorporation and reduce by > 85% the rate of incorporation into nucleotides of either [14C]-hypoxanthine, -adenine, or -orotate and by > 60% [14C]-nicotinamide into NAD; a requirement for PRPP is common to each of these incorporation pathways. In contrast the rates of incorporation of [14C]-adenosine, -5-aminoimidazole-4-carboxamide riboside and -uridine, which do not require PRPP for incorporation, are relatively unaffected. Treatment of cells with the 4-amino analog causes a 50% reduction in the PRPP pool and, in studies of inosine-driven, adenine incorporation by HPRT deficient cells, > 95% reduction in PRPP availability. Studies with the human erythrocyte PRPP synthetase indicate that at physiological phosphate concentrations, 1-5 mU, the monophosphate form of these adenosine analogs maintains the enzyme in an inactive form. At high phosphate concentrations, > 32 mU, the monophosphates of the analogs have no effect on the activity of PRPP synthetase.
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Willis, R., Nord, L., Breen, T. et al. 174 POTENT AND SPECIFIC INHIBITORS OF HAMMALIAN PHOSPHO-RIBOSYLPYROPHOSPHATE (PRPP) SYNTHETASE. Pediatr Res 24, 140 (1988). https://doi.org/10.1203/00006450-198807000-00198
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DOI: https://doi.org/10.1203/00006450-198807000-00198