SYNTHESIS OF (R)-1-[[2-HYDROXY-1-(AMINOMETHYL)ETHOXY]METHYL]-5-BENZYLURACIL AND (S)-1-[[2-HYDROXY-1-(AMINOMETHYL)ETHOXY]METHYL]-5-BENZYLURACIL, POTENT INHIBITORS OF URIDINE PHOSPHORYLASE

Optically pure (R)- and (S)-1-[[2-hydroxy-1-(aminomethyl) ethoxy]methyl]-5-benzyluracil [(R)-AHPBU and (S)-AHPBU, respectively], two potent uridine phosphorylase inhibitors, have been synthesized via multi-step syntheses starting from independent chiral compounds. The activity of (R)-AHPBU, (S)-AHPBU, and (R,S)-AHPBU which have been previously synthesized, on the inhibition of uridine phosphorylase from Sarcoma-180 cells has been studied and compared. The K values for (R,S) (R)- and (S)-AHPBU were determined to be 15+1.3,17+3.7 and 16+2.0 nM, respectively. This indicates that (R) and (S) optical enantiomers have the same affinity for binding to uridine phosphotylase. These acyclic pyrimidine amino nucleoside analogues represent a new class of potent uridine phosphorylase inhibitors, which has a bulky hydrophobic substituent at the 5-position in the uracil base, yet has remarkably high water solubility. © 1990, Taylor & Francis Group, LLC. All rights reserved.