Synthesis and biological evaluation of 9-(5',5'-difluoro-5'-phosphonopentyl)guanine derivatives for PNP-inhibitors

Bioorg Med Chem. 2006 Mar 1;14(5):1660-70. doi: 10.1016/j.bmc.2005.10.017. Epub 2005 Nov 2.

Abstract

9-(5',5'-Difluoro-5'-phosphonopentyl)guanine (DFPP-G) and its hypoxanthine analogue (DFPP-H) were modified by introducing a methyl group to all possible positions of the linker connecting a purine and difluoromethylenephosphonic acid moiety to evaluate the effects of the methyl group on inhibition against purine nucleoside phosphorylase. The methyl group on the linker affected the inhibition in a positional-dependent manner. Inhibitory potency of alpha-methyl and beta-methyl-substituted analogues of DFPP-H increased by about 600- to 1000-fold upon converting to cyclopropane nucleotide analogue (+/-)-4.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Clodronic Acid / analogs & derivatives
  • Clodronic Acid / chemistry
  • Clodronic Acid / pharmacology
  • Cyclopropanes / chemistry
  • Cyclopropanes / pharmacology
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology
  • Fluorides / chemistry*
  • Fluorides / pharmacology
  • Guanine / analogs & derivatives*
  • Guanine / chemical synthesis*
  • Guanine / pharmacology
  • Hypoxanthines / chemical synthesis*
  • Hypoxanthines / pharmacology
  • Kinetics
  • Methylation
  • Phosphoric Acids / chemistry*
  • Phosphoric Acids / pharmacology
  • Purine-Nucleoside Phosphorylase / antagonists & inhibitors*
  • Purine-Nucleoside Phosphorylase / chemistry
  • Purine-Nucleoside Phosphorylase / metabolism
  • Structure-Activity Relationship
  • Substrate Specificity

Substances

  • 9-(5',5'-difluoro-5'-phosphonopentyl)guanine
  • Cyclopropanes
  • Enzyme Inhibitors
  • Hypoxanthines
  • Phosphoric Acids
  • Clodronic Acid
  • difluoromethylene diphosphonate
  • difluorophosphoric acid
  • Guanine
  • Purine-Nucleoside Phosphorylase
  • Fluorides