5-Benzylbarbituric acid derivatives, potent and specific inhibitors of uridine phosphorylase

Abstract

5-Benzylbarbituric acid derivatives were synthesized as a series of new, specific, and potent inhibitors of uridine phosphorylase. Among these, 5-( m-benzyloxy)benzyl-1-[(2-hydroxyethoxy)methyl] barbituric acid (5-benzyloxybenzylbarbituric acid acyclonucleoside, BBBA) was found to be the most potent with K i values of 1.1 ± 0.2 and 2.6 ± 0.3 nM with uridine phosphorylase from human and mouse livers, respectively. BBBA exhibited competitive inhibition with uridine phosphorylase from both human and mouse livers. The 5-benzylbarbituric acid derivatives are specific inhibitors of uridine phosphorylase, as they had no effect on thymidine phosphorylase (EC 2.4.2.4), thymidine kinase (EC 2.7.1.21), uridine-cytidine kinase (EC2.7.1.48), orotate phosphoribosyltransferase (EC2.4.2.10), orotidine 5'-monophosphate decarboxylase (EC 4.1.2.23), and dihydrouracil dehydrogenase (EC 1.3.1.2). These compounds are more potent, easier to synthesize, and have better water solubility than their uracil counterparts as inhibitors of uridine phosphorylase. Furthermore, the 5-benzylbarbituric acids were found to be better inhibitors of human uridine phosphorylase than the murine enzyme, whereas the reverse holds true for the 5-benzyluracil derivatives. The 5-benzylbarbituric acid derivatives have potential usefulness in the therapy of cancer and AIDS, as well as other pathological and physiological disorders.