Design and synthesis of protein kinase C epsilon selective diacylglycerol lactones (DAG-lactones)

Eur J Med Chem. 2015 Jan 27:90:332-41. doi: 10.1016/j.ejmech.2014.11.025. Epub 2014 Nov 13.

Abstract

DAG-lactones afford a synthetically accessible, high affinity platform for probing structure activity relationships at the C1 regulatory domain of protein kinase C (PKC). Given the central role of PKC isoforms in cellular signaling, along with their differential biological activities, a critical objective is the design of isoform selective ligands. Here, we report the synthesis of a series of DAG-lactones varying in their side chains, with a particular focus on linoleic acid derivatives. We evaluated their selectivity for PKC epsilon versus PKC alpha both under standard lipid conditions (100% phosphatidylserine, PS) as well as in the presence of a nuclear membrane mimetic lipid mixture (NML). We find that selectivity for PKC epsilon versus PKC alpha tended to be enhanced in the presence of the nuclear membrane mimetic lipid mixture and, for our lead compound, report a selectivity of 32-fold.

Keywords: Diacylglycerol lactone; PKC-ε; Protein kinase C.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Diglycerides / chemical synthesis
  • Diglycerides / chemistry
  • Diglycerides / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Lactones / chemical synthesis
  • Lactones / chemistry
  • Lactones / pharmacology*
  • Molecular Structure
  • Protein Kinase C-epsilon / antagonists & inhibitors*
  • Protein Kinase C-epsilon / metabolism
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • 1,2-diacylglycerol
  • Diglycerides
  • Lactones
  • Protein Kinase Inhibitors
  • Protein Kinase C-epsilon