Synthesis and properties of molecular probes for the rescue site on mutant cystic fibrosis transmembrane conductance regulator

J Med Chem. 2011 Dec 22;54(24):8693-701. doi: 10.1021/jm201335c. Epub 2011 Nov 21.

Abstract

Cystic fibrosis is a genetic disease caused by mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. In vitro experiments have demonstrated that 4-methyl-2-(5-phenyl-1H-pyrazol-3-yl)phenol (VRT-532, 1) is able to partially restore the function of mutant CFTR proteins. To help elucidate the nature of the interactions between 1 and mutant CFTR, molecular probes based on the structure of 1 have been prepared. These include a photoreactive aryl azide derivative 11 and a fluorescent dansyl sulfonamide 15. Additionally, a method for hydrogen isotope exchange on 1 has been developed, which could be used for the incorporation of radioactive tritium. Using iodide efflux assays, the probe molecules have been demonstrated to modulate the activity of mutant CFTR in the same manner as 1. These probe molecules enable a number of biochemical experiments aimed at understanding how 1 rescues the function of mutant CFTR. This understanding can in turn aid in the design and development of more efficacious compounds which may serve as therapeutic agents in the treatment of cystic fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azides / chemical synthesis
  • Azides / chemistry
  • Azides / pharmacology
  • Cell Line
  • Cresols / pharmacology
  • Cricetinae
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
  • Dansyl Compounds / chemical synthesis
  • Dansyl Compounds / chemistry
  • Dansyl Compounds / pharmacology
  • Fluorescent Dyes / chemical synthesis*
  • Fluorescent Dyes / chemistry
  • Fluorescent Dyes / pharmacology
  • Isotope Labeling
  • Molecular Probes / chemical synthesis*
  • Molecular Probes / chemistry
  • Molecular Probes / pharmacology
  • Mutation
  • Photoaffinity Labels / chemical synthesis*
  • Photoaffinity Labels / chemistry
  • Photoaffinity Labels / pharmacology
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology
  • Structure-Activity Relationship
  • Tritium

Substances

  • Azides
  • Cresols
  • Dansyl Compounds
  • Fluorescent Dyes
  • Molecular Probes
  • Photoaffinity Labels
  • Pyrazoles
  • VRT 532
  • Tritium
  • Cystic Fibrosis Transmembrane Conductance Regulator