5-benzylacyclouridine and 5-benzyloxybenzylacyclouridine, potent inhibitors of uridine phosphorylase.
Various pyrimidine acyclonucleosides (1-(2'-hydroxyethoxymethyl)uracils) are specific inhibitors of uridine phosphorylase[Niedzwicki et al., Biochem. Pharmac. 30, 2097 (1981) )). 5-Benzyluracils have also been shown to inhibit this enzyme[Baker and Kelley, J. med. Chem. 13, 461 (1970); Woodman et al., Biochem. Pharmac. 29, 1059 (1980) )). We have synthesized the acyclonucleoside analogs of 5-benzyluracil (BU) and 5-benzyloxybenzyluracil (BBU). These compounds, 5-benzyl-1-(2'-hydroxyethoxymethyl)uracil (BAU) and 5-(m-benzyloxybenzyl)-1-(2'-hydroxyethoxymethyl)uracil (BBAU), are potent inhibitors of uridine phosphorylase. K1 values of 98 and 32 nM were estimated for BAU and BBAU respectively. These compounds are better inhibitors of uridine phosphorylase than BU (K1= 1575 nM), BBU (K1=270 nM), and all other compounds previously tested, and they have no effect on thymidine phosphorylase, uridine-cytidine kinase, or thymidine kinase. Potential chemotherapeutic applications of BAU and BBAU are discussed.
D000818:Animals; D000970:Antineoplastic Agents; D001665:Binding Sites; D003600:Cytosol / Q000201:enzymology; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy; D010430:Pentosyltransferases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D014543:Uridine Phosphorylase / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; C034753:5-benzylacyclouridine; D014498:Uracil; C034754:5-benzyloxybenzylacyclouridine; D010430:Pentosyltransferases; D014543:Uridine Phosphorylase