Design and evaluation of 5'-modified nucleoside analogs as prodrugs for an E. coli purine nucleoside phosphorylase mutant.

Academic Article

Abstract

  • Our studies have led to the identification of an E. coli PNP mutant (M64V) that is able to cleave numerous 5'-modified nucleoside analogs with much greater efficiency than the wild-type enzyme. The biological activity of the three best substrates of this mutant (9-[6-deoxy-alpha-L-talofuranosyl]-6-methylpurine (methyl(talo)-MeP-R), 9-[6-deoxy-alpha-L-talofuranosyl]-2-F-adenine, and 9-[alpha-L-lyxofuranosyl]-2-F-adenine) were evaluated so that we can optimally utilize these compounds. Our results indicated that the mechanism of toxicity of methyl(talo)-MeP-R to mice was due to its cleavage to MeP by a bacterial enzyme, and that the toxicity of the two F-Ade analogs was due to their cleavage to F-Ade by mammalian methylthioadenosine phosphorylase.
  • Published In

    Keywords

  • Animals, Cell Line, Cell Line, Tumor, Chemistry, Pharmaceutical, Drug Design, Escherichia coli, Humans, Inhibitory Concentration 50, Mice, Models, Chemical, Mutation, Nucleosides, Prodrugs, Purine-Nucleoside Phosphorylase, Substrate Specificity, Thionucleosides
  • Author List

  • Parker WB; Allan PW; Ealick SE; Sorscher EJ; Hassan AEA; Silamkoti AV; Fowler AT; Waud WR; Secrist JA
  • Start Page

  • 387
  • End Page

  • 392
  • Volume

  • 24
  • Issue

  • 5-7