Sulforaphane homologues: Enantiodivergent synthesis of both enantiomers, activation of the Nrf2 transcription factor and selective cytotoxic activity

Eur J Med Chem. 2014 Nov 24;87:552-63. doi: 10.1016/j.ejmech.2014.09.052. Epub 2014 Sep 16.

Abstract

Reported is an enantiodivergent approach for the synthesis of both enantiomers of sulforaphane (SFN) homologues with different chain lengths between the sulfinyl sulfur and the isothiocyanate groups and different substituents on the sulfinyl sulfur. The homologues were designed in order to unravel the effect of all the diversity elements included in sulforaphane's structure. The key step of the approach is the diastereoselective synthesis of both sulfinate ester epimers at sulfur, using as single chiral auxiliary the sugar derived diacetone-d-glucose. The approach allows the first synthesis of both enantiomers of 5-methylsulfinylpentyl isothiocyanate, and the biologically important 6-methylsulfinylhexyl isothiocyanate (6-HITC) found in Japanese horseradish, wasabi (Wasabia japonica). The ability of the synthesized compounds as inductors of phase II detoxifying enzymes has been studied by determining their ability to activate the cytoprotective transcription factor Nrf2. The cytotoxic activity of all the synthesized compounds against human lung adenocarcinoma (A549) and foetal lung fibroblasts (MRC-5) is also reported.

Keywords: (R)- and (S)-Sulforaphane and homologues; Activation of Nrf2 factor; Cytotoxic activity; DAG-methodology; Enantiodivergent synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor*
  • Humans
  • Isothiocyanates / chemical synthesis
  • Isothiocyanates / chemistry
  • Isothiocyanates / pharmacology*
  • NF-E2-Related Factor 2 / metabolism*
  • Stereoisomerism

Substances

  • Isothiocyanates
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • sulforafan