Synthesis and biological evaluation of 9-deazaguanine derivatives connected by a linker to difluoromethylene phosphonic acid as multi-substrate analogue inhibitors of PNP

Bioorg Med Chem Lett. 2007 Aug 1;17(15):4173-7. doi: 10.1016/j.bmcl.2007.05.054. Epub 2007 May 21.


9-(5',5'-difluoro-5'-phosphonopentyl)-9-deazaguanine (DFPP-DG) was designed as a multi-substrate analogue inhibitor against purine nucleoside phosphorylase (PNP) on the basis of X-ray crystallographic data obtained for a binary complex of 9-(5',5'-difluoro-5'-phosphonopentyl)guanine (DFPP-G) with calf spleen PNP. DFPP-DG and its analogous compounds were adjusted by length of the linker achieved by the Sonogashira-coupling reaction between a 9-deaza-9-iodoguanine derivative and omega-alkynyldifluoromethylene phosphonates as a key reaction. DFPP-DG is a very potent PNP inhibitor with apparent inhibition constants (in the presence of 1 mM phosphate) of 4.4 and 8.1 nM versus calf spleen and human erythrocyte PNPs, respectively. One of its analogues, homo-DFPP-DG, with longer chain linking phosphonate and 9-deazaguanine is even more potent versus human enzyme, with an apparent inhibition constant of 5.3 nM (in the presence of 1mM phosphate).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cattle
  • Clodronic Acid / analogs & derivatives*
  • Clodronic Acid / chemistry
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Erythrocytes / drug effects
  • Erythrocytes / enzymology
  • Guanine / analogs & derivatives*
  • Guanine / chemical synthesis
  • Guanine / chemistry
  • Guanine / pharmacology
  • Humans
  • Models, Molecular
  • Purine-Nucleoside Phosphorylase / antagonists & inhibitors*
  • Purine-Nucleoside Phosphorylase / blood
  • Purine-Nucleoside Phosphorylase / metabolism
  • Spleen / drug effects
  • Spleen / enzymology
  • Substrate Specificity


  • Enzyme Inhibitors
  • Clodronic Acid
  • difluoromethylene diphosphonate
  • Guanine
  • 9-deazaguanine
  • Purine-Nucleoside Phosphorylase