Evaluation of synthetic naphthalene derivatives as novel chemical chaperones that mimic 4-phenylbutyric acid

Bioorg Med Chem Lett. 2015 Feb 15;25(4):811-4. doi: 10.1016/j.bmcl.2014.12.080. Epub 2015 Jan 5.

Abstract

The chemical chaperone 4-phenylbutyric acid (4-PBA) has potential as an agent for the treatment of neurodegenerative diseases. However, the requirement of high concentrations warrants chemical optimization for clinical use. In this study, novel naphthalene derivatives with a greater chemical chaperone activity than 4-PBA were synthesized with analogy to the benzene ring. All novel compounds showed chemical chaperone activity, and 2 and 5 possessed high activity. In subsequent experiments, the protective effects of the compounds were examined in Parkinson's disease model cells, and low toxicity of 9 and 11 was related to amphiphilic substitution with naphthalene.

Keywords: 4-Phenylbutyric acid (4-PBA); Chemical chaperone; Endoplasmic reticulum (ER) stress; Naphthalene; Parkinson’s disease (PD).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Endoplasmic Reticulum Stress / drug effects
  • Humans
  • Molecular Chaperones / chemistry*
  • Naphthalenes / chemical synthesis
  • Naphthalenes / chemistry*
  • Parkinson Disease / drug therapy
  • Phenylbutyrates / chemistry*
  • Signal Transduction

Substances

  • Molecular Chaperones
  • Naphthalenes
  • Phenylbutyrates
  • 4-phenylbutyric acid