Discovery of a crystalline sulforaphane analog with good solid-state stability and engagement of the Nrf2 pathway in vitro and in vivo

Bioorg Med Chem. 2019 Feb 15;27(4):579-588. doi: 10.1016/j.bmc.2018.12.026. Epub 2018 Dec 21.

Abstract

The antioxidant natural product sulforaphane (SFN) is an oil with poor aqueous and thermal stability. Recent work with SFN has sought to optimize methods of formulation for oral and topical administration. Herein we report the design of new analogs of SFN with the goal of improving stability and drug-like properties. Lead compounds were selected based on potency in a cellular screen and physicochemical properties. Among these, 12 had good aqueous solubility, permeability and long-term solid-state stability at 23 °C. Compound 12 also displayed comparable or better efficacy in cellular assays relative to SFN and had in vivo activity in a mouse cigarette smoke challenge model of acute oxidative stress.

Keywords: COPD; Isothiocyanate; KEAP1; Nrf2; Sulforaphane.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / chemical synthesis
  • Antioxidants / pharmacokinetics
  • Antioxidants / pharmacology*
  • Cell Line
  • Cyclobutanes / chemical synthesis
  • Cyclobutanes / pharmacokinetics
  • Cyclobutanes / pharmacology*
  • Drug Discovery*
  • Gene Expression
  • Heme Oxygenase-1 / genetics
  • Humans
  • Isothiocyanates / chemical synthesis
  • Isothiocyanates / pharmacokinetics
  • Isothiocyanates / pharmacology*
  • Kelch-Like ECH-Associated Protein 1 / metabolism
  • Mice, Inbred C57BL
  • Molecular Structure
  • NF-E2-Related Factor 2 / metabolism*
  • Oxidative Stress / drug effects
  • Rats
  • Signal Transduction / drug effects*
  • Solubility
  • Structure-Activity Relationship
  • Sulfoxides
  • Thiocarbamates / chemical synthesis
  • Thiocarbamates / pharmacokinetics
  • Thiocarbamates / pharmacology

Substances

  • Antioxidants
  • Cyclobutanes
  • Isothiocyanates
  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Sulfoxides
  • Thiocarbamates
  • HMOX1 protein, human
  • Heme Oxygenase-1
  • sulforaphane