Synthesis of 1-[[2-hydroxy-1-(hydroxymethyl)ethoxy] methyl]-5-benzyluracil and its amino analogue, new potent uridine phosphorylase inhibitors with high water solubility.
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.
D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D051379:Mice; D010430:Pentosyltransferases / Q000037:antagonists & inhibitors*; D012510:Sarcoma 180 / Q000188:drug therapy / Q000201:enzymology; D012995:Solubility; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D014543:Uridine Phosphorylase / Q000037:antagonists & inhibitors*; D014867:Water
D014867:Water; D014498:Uracil; C044783:1-((2-hydroxy-1-(hydroxymethyl)ethoxy)methyl)-5-benzyluracil; C044784:1-((2-hydroxy-1-(aminomethyl)ethoxy)methyl)-5-benzyluracil; D010430:Pentosyltransferases; D014543:Uridine Phosphorylase