N-Oxide derivatives of 3-(3-pyridyl)-2-phosphonopropanoic acids as potential inhibitors of Rab geranylgeranylation

Bioorg Med Chem Lett. 2015 Jun 1;25(11):2331-4. doi: 10.1016/j.bmcl.2015.04.021. Epub 2015 Apr 17.

Abstract

The N-oxide derivatives of [2-(3-pyridinyl)-1-hydroxyethylidene-1,1-phosphonocarboxylic acid (or PEHPC) and [2-(3-pyridinyl)-1-ethylidene-1,1-phosphonocarboxylic acid (or PEPC) have been prepared and evaluated for their activity against several enzymes which utilize isoprenoids. The parent pyridines are known inhibitors of GGTase II, but the N-oxide derivatives show no improvement in biological activity in assays with the isolated enzyme. However, the PEHPC N-oxide did induce significant accumulation of intracellular light chain in myeloma cells, consistent with inhibition of Rab geranylgeranylation.

Keywords: Apoptosis; Bioassay; GGTase II; Myeloma; Pyridyl N-oxides; Rab GGTase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkyl and Aryl Transferases / antagonists & inhibitors*
  • Cell Line, Tumor
  • Drug Discovery
  • Humans
  • Molecular Structure
  • Multiple Myeloma
  • Propionates / chemistry
  • Propionates / pharmacology*
  • Structure-Activity Relationship

Substances

  • Propionates
  • Alkyl and Aryl Transferases
  • Rab geranylgeranyltransferase