Conformationally constrained analogues of diacylglycerol. 18. The incorporation of a hydroxamate moiety into diacylglycerol-lactones reduces lipophilicity and helps discriminate between sn-1 and sn-2 binding modes to protein kinase C (PK-C). Implications for isozyme specificity

J Med Chem. 2001 Dec 6;44(25):4309-12. doi: 10.1021/jm0103965.

Abstract

An approach to reduce the log P in a series of diacylglycerol (DAG)-lactones known for their high binding affinity for protein kinase C (PK-C) is presented. Branched alkyl groups with reduced lipophilicity were selected and combined with the replacement of the ester or lactone oxygens by NH or NOH groups. Compound 6a with an isosteric N-hydroxyl amide arm represents the most potent and least lipophilic DAG analogue known to date.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Butyrolactone / analogs & derivatives
  • 4-Butyrolactone / chemistry*
  • Diglycerides / chemical synthesis*
  • Diglycerides / chemistry
  • Drug Design
  • Hydroxamic Acids / chemistry*
  • Isoenzymes / chemistry
  • Lactones / chemical synthesis*
  • Lactones / chemistry
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Protein Binding
  • Protein Kinase C / chemistry*
  • Structure-Activity Relationship

Substances

  • 4-((N-hydroxy(tert-butylcarbonyl)amino)methyl)-4-hydroxy-3-(3-(2-methylpropyl)hexylidene)-2-oxotetrahydrofuran
  • Diglycerides
  • Hydroxamic Acids
  • Isoenzymes
  • Lactones
  • Ligands
  • Protein Kinase C
  • 4-Butyrolactone