Synthesis and evaluation of carbocyanine dyes as PRMT inhibitors and imaging agents

Eur J Med Chem. 2012 Aug;54:647-59. doi: 10.1016/j.ejmech.2012.06.017. Epub 2012 Jun 21.

Abstract

Protein arginine methylation regulates multiple biological processes. Deregulation of protein arginine methyltransferase (PRMT) activities has been observed in many disease phenotypes. Small molecule probes that target PRMTs with strong affinity and selectivity can be used as valuable tools to dissect biological mechanisms of arginine methylation and establish the role of PRMT proteins in a disease process. In this work, we report synthesis and evaluation of a class of carbocyanine compounds containing indolium, benz[e]indolium or benz[c,d]indolium heterocyclic moieties that bind to the predominant arginine methyltransferase PRMT1 and inhibit its methyltransferase activity at low micromolar potencies. In particular, the developed molecules have long wavelength colorimetric and fluorometric photoactivities, which can be used for optical and near-infrared fluorescence imaging in cells or biological tissues. Together, these new chemical probes have potential application in PRMT studies both as enzyme inhibitors and as fluorescent dyes for microscope imaging.

Publication types

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

MeSH terms

  • Carbocyanines / chemical synthesis*
  • Carbocyanines / chemistry
  • Carbocyanines / metabolism
  • Carbocyanines / pharmacology*
  • Chemistry Techniques, Synthetic
  • Coloring Agents / chemical synthesis*
  • Coloring Agents / chemistry
  • Coloring Agents / metabolism
  • Coloring Agents / pharmacology*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • HeLa Cells
  • Humans
  • Molecular Docking Simulation
  • Molecular Imaging
  • Mutagenesis, Site-Directed
  • Protein Conformation
  • Protein-Arginine N-Methyltransferases / antagonists & inhibitors*
  • Protein-Arginine N-Methyltransferases / chemistry
  • Protein-Arginine N-Methyltransferases / genetics
  • Protein-Arginine N-Methyltransferases / metabolism
  • Substrate Specificity

Substances

  • Carbocyanines
  • Coloring Agents
  • Enzyme Inhibitors
  • Protein-Arginine N-Methyltransferases