Synthesis and biological evaluation of 1,1-difluoro-2-(tetrahydro-3-furanyl)ethylphosphonic acids possessing a N9-purinylmethyl functional group at the ring. a new class of inhibitors for purine nucleoside phosphorylases

Bioorg Med Chem Lett. 1999 Oct 4;9(19):2833-6. doi: 10.1016/s0960-894x(99)00495-3.

Abstract

1,1-Difluoro-2-(tetrahydro-3-furanyl)ethylphosphonic acids cis-3 and trans-3 possessing a N9-purinylmethyl functionality at the ring were synthesized and tested as "multi-substrate analogue" inhibitors for purine nucleoside phosphorylases. Radical cyclization of allyic alpha,alpha-difluorophosphonate (E)-7 was applied to construct the alpha,alpha-difluorophosphonate-functionalized tetrahydrofuranyl moiety. The IC50 values of cis-3 and trans-3 for human erythrocyte PNP-catalyzed phosphorylation of inosine were determined to be 88 and 320 nM, respectively. The stereochemistry of the inhibitors was found to affect significantly the inhibitory potency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology
  • Erythrocytes / enzymology
  • Fluorine Compounds / chemical synthesis*
  • Fluorine Compounds / pharmacology
  • Furans / chemical synthesis*
  • Furans / pharmacology
  • Gram-Positive Asporogenous Rods / enzymology
  • Humans
  • Inosine / metabolism
  • Molecular Structure
  • Organophosphonates / chemical synthesis*
  • Organophosphonates / pharmacology
  • Phosphorylation
  • Purine-Nucleoside Phosphorylase / antagonists & inhibitors*
  • Purines / chemical synthesis*
  • Purines / pharmacology

Substances

  • 1,1-difluoro-2-(tetrahydro-3-furanyl)ethylphosphonic acid
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Fluorine Compounds
  • Furans
  • Organophosphonates
  • Purines
  • Inosine
  • Purine-Nucleoside Phosphorylase