Synthesis of 1-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]-5-benzyluracil and its amino analog new potent uridine phosphorylase inhibitors with high water solubility

Abstract

Acyclic nucleosides 1-[[2-hydroxy-1-(hydroxymethyl)ethoxy] methyl]-5-benzyluracil (DHPBU) (1) and 1-[[2-hydroxy-1-(aminomethyl)ethoxy]methyl]-5-benzyluracil (AHPBU) (2) have been synthesized by direct coupling of bis(trimethylsilyl)-5-benzyluracil with the corresponding chloromethyl ether, followed by removal of the blocking groups. Compounds 1 and 2 were found to be very potent inhibitors of uridine phosphorylase isolated from Sarcoma 180 cells, with a Ki value of 0.098 and 0.020 microM, respectively, and exhibited no apparent cytotoxicity against Sarcoma 180 host cells. Furthermore, 1 and 2 have shown excellent water solubility (270 and greater than 300 mg/mL at 25 degrees C, respectively), which is a factor critical for the formulation that often limits the usefulness of a particular compound as a chemotherapeutic agent.