Synthesis of (R - and (S)-1-[[2-Hydroxy-1-(aminomethyl)ethoxy]methyl]-5- benzyluracil,Potent Inhibitors of Uridine Phosphorylase |
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Authors: | Tai-Shun Lin Shi-Ping Xu Mao-Chin Liu William R. Mancini |
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Affiliation: | 1. Department of Pharmacology and Comprehensive Cancer Center , Yale University School of Medicine , New Haven, Connecticut , 06510;2. Department of Pharmacology , The University of Michigan Medical School , Ann Arbor, Michigan , 48109 |
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Abstract: | Abstract 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 15·2.3, 17·2.7 and 16·2.0 nM, respectively. This indicates that (R) and (S) optical enantiomers have the same affinity for binding to uridine phosphorylase. 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. |
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