Synthesis, conformational analysis, and biological evaluation of 1-hexylindolactam-V10 as a selective activator for novel protein kinase C isozymes

J Med Chem. 2008 Jan 10;51(1):46-56. doi: 10.1021/jm0706719. Epub 2007 Dec 12.

Abstract

Conventional and novel protein kinase C (PKC) isozymes are the main targets of tumor promoters. We developed 1-hexylindolactam-V10 ( 5) as a selective activator for novel PKC isozymes that play important roles in various cellular processes related to tumor promotion, ischemia--reperfusion injury in the heart, and Alzheimer's disease. The compound existed as a mixture of three conformers. The trans-amide restricted analogues of 5 ( 14 and 15) hardly bound to PKC isozymes, suggesting that the active conformation of 5 could be that with a cis-amide. Compound 5 selectively translocated novel PKC isozymes over conventional PKC isozymes in HeLa cells at 0.1-1 microM. These results suggest that 5 could be useful for the functional analysis of novel PKC isozymes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Membrane / enzymology
  • Enzyme Activators / chemical synthesis*
  • Enzyme Activators / chemistry
  • Enzyme Activators / pharmacology
  • HeLa Cells
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Lactams / chemical synthesis*
  • Lactams / chemistry
  • Lactams / pharmacology
  • Models, Molecular
  • Molecular Conformation
  • Mutation
  • Protein Binding
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism*
  • Protein Transport
  • Structure-Activity Relationship

Substances

  • 1-hexylindolactam-V10
  • Enzyme Activators
  • Indoles
  • Isoenzymes
  • Lactams
  • indolactam V
  • Protein Kinase C