Tailoring the structure of aminobisphosphonates to target plant P5C reductase

J Agric Food Chem. 2008 May 14;56(9):3193-9. doi: 10.1021/jf800029t. Epub 2008 Apr 10.

Abstract

Using the structure of (3,5-dichlorophenyl)aminomethylenebisphosphonic acid as a lead compound, 25 new phosphonates were synthesized and evaluated as possible inhibitors of Arabidopsis thaliana delta1-pyrroline-5-carboxylate (P5C) reductase. Derivatives substituted in the phenyl ring retained the inhibitory potential, though to a different extent. On the contrary any variation in the scaffold, i.e., the replacement of the second phosphonate moiety with a hydroxyl or an amino residue, resulted in a significant loss of biological activity. The availability of several structures capable of interfering with the catalytic mechanism in the micromolar to millimolar range allowed a proper structure-activity relationship analysis, leading us to hypothesize about the steric and electronic requirements for maintenance or enhancement of the inhibitory properties. Reversal experiments with suspension cultured cells provided evidence for the occurrence of enzyme inhibition in vivo. Because in higher plants the step catalyzed by P5C reductase is shared by all pathways leading to proline synthesis, these compounds may be exploited for the design of new substances endowed with herbicidal activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arabidopsis Proteins
  • Diphosphonates / chemistry*
  • Diphosphonates / pharmacology*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Herbicides
  • Models, Molecular
  • Pyrroline Carboxylate Reductases / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Arabidopsis Proteins
  • Diphosphonates
  • Enzyme Inhibitors
  • Herbicides
  • Pyrroline Carboxylate Reductases
  • delta-1-pyrroline-5-carboxylate reductase