Inhibition of uridine phosphorylase: synthesis and structure-activity relationships of aryl-substituted 5-benzyluracils and 1-[(2-hydroxyethoxy)methyl]-5-benzyluracils.

Abstract

A series of 1-[(2-hydroxyethoxy)methyl]-5-benzyluracils were synthesized and tested for inhibition of murine liver uridine phosphorylase (UrdPase). Inhibitors of UrdPase are reported to enhance the chemotherapeutic utility of 5-fluoro-2'-deoxyuridine and 5-fluorouracil and to ameliorate zidovudine-induced anemia in animal models. We prepared a series of 5-aryl-substituted analogues of 5-benzylacyclouridine (BAU), a good inhibitor of UrdPase (IC50 of 0.46 microM), to develop a compound with enhanced potency and improved pharmacokinetics. The first phase of structure-activity relationship studies on a series of 32 aryl-substituted 5-benzyluracils found several 5-(3-alkoxybenzyl) analogues of 5-benzyluracil with enhanced potency. The acyclovir side chain, the (2-hydroxyethoxy)methyl group, was substituted on the more potent aryl-substituted 5-benzyluracils. The two most potent compounds, 10y (3-propoxy) and 10dd (3-sec-butoxy), were inhibitors of UrdPase with IC50s of 0.047 and 0.027 microM, respectively. Six compounds were tested in vivo for effects on steady-state concentrations of circulating uridine in rats. Plasma uridine levels were elevated 3-9-fold by compound levels that ranged from 8 to 50 microM.

Bioisosterism: A Rational Approach in Drug Design

“…Halogens have been replaced by electron-withdrawing groups such as a cyano or trifluoromethyl group. Replacements of this type were observed in a series of 1-[(2-hydroxyethoxy)methyl]-5-benzyluracils ( 104 , Figure ) that were tested for inhibition of liver uridine phosphorylase (UrdPase) . Uridine phosphorylase is an enzyme that catalyzes the reversible phosphorolysis of pyrimidine nucleosides.…”

Design and synthesis of 4-piperazinyl quinoline derived urea/thioureas for anti-breast cancer activity by a hybrid pharmacophore approach

“…It is also clear that the replacement of the 7-chloro group with their bioisoteric functional group of the 7-trifluoromethyl substitution leads to the decrease in the antiproliferative activity on breast cancer cells 7 . The bioisoteric replacement of the chloro atom with stronger electron-withdrawing group of trifluoromethyl resulted in less potent analogs for the anticancer activity 7 , 27–29 .…”

Flexible Nucleobase Analogues: Novel Tools for Exploring Nucleic Acids

“…10) of 5-benzylacyclouridine (BAU). These compounds were screened against uridine phosphorylase (UrdPase), since inhibition of this enzyme is thought to enhance the therapeutic effect of nucleoside drugs such as 5-fluorouracil (Orr et al 1995). Later analogues exhibited increased inhibition of UrdPase, with enhanced pharmacodynamic effects compared to those noted for BAU (Orr et al 1997).…”