Eeyarestatin I derivatives with improved aqueous solubility

Bioorg Med Chem Lett. 2016 Nov 1;26(21):5177-5181. doi: 10.1016/j.bmcl.2016.09.068. Epub 2016 Sep 29.

Abstract

Inhibition of p97 (also known as valosin-containing protein (VCP)), has been validated as a promising strategy for cancer therapy. Eeyarestatin I (EerI) blocks p97 through a novel mechanism of action and has favorable anti-cancer activities against cultured cancer cells. However, its poor aqueous solubility severely limits its in vivo applications. To circumvent this problem, we have identified EerI derivatives that possess improved aqueous solubility by introducing a single solubilizing group. These modified compounds preserved endoplasmic reticulum (ER) stress-inducing and antiproliferative activities as well as generally good in vitro metabolic properties, suggesting that these EerI derivatives could serve as candidates for further optimization.

Keywords: EerI; Eeyarestatin I; Solubility; VCP; Valosin-containing protein; p97.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 3 / metabolism
  • Activating Transcription Factor 4 / metabolism
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Endoplasmic Reticulum / drug effects
  • Humans
  • Hydrazones / chemistry*
  • Hydrazones / pharmacology
  • Hydroxyurea / analogs & derivatives*
  • Hydroxyurea / chemistry
  • Hydroxyurea / pharmacology
  • Mice
  • Solubility
  • Water / chemistry

Substances

  • 1-(4-chlorophenyl)-3-(3-(4-chlorophenyl)-5,5-dimethyl-1-(3-(5-nitrofuran-2-yl)allyldienehydrazinocarbonylmethyl)-2-oxoimidazolidin-4-yl)-1-hydroxyurea
  • Activating Transcription Factor 3
  • Hydrazones
  • Water
  • Activating Transcription Factor 4
  • Hydroxyurea