title: Sulforaphane homologues: Enantiodivergent synthesis of both enantiomers, activation of the Nrf2 transcription factor and selective cytotoxic activity.
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.
authors.affiliation: Instituto de Investigaciones Químicas, C.S.I.C-Universidad de Sevilla, C/. Américo Vespucio, 49, Isla de la Cartuja, 41092 Sevilla, Spain.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Elhalem
authors.affiliation: Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad de Sevilla, 41012 Sevilla, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Recio
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: Werner
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Franziska
authors.initials: F
authors.lastname: Lieder
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Universidad de Sevilla, 41012 Sevilla, Spain.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Calderón-Montaño
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Universidad de Sevilla, 41012 Sevilla, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: López-Lázaro
authors.affiliation: Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad de Sevilla, 41012 Sevilla, Spain. Electronic address: inmaff@us.es.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Fernández
authors.affiliation: Instituto de Investigaciones Químicas, C.S.I.C-Universidad de Sevilla, C/. Américo Vespucio, 49, Isla de la Cartuja, 41092 Sevilla, Spain. Electronic address: khiar@iiq.csic.es.
authors.forename: Noureddine
authors.initials: N
authors.lastname: Khiar
mesh_terms: D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D017879:Isothiocyanates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D013237:Stereoisomerism; D013454:Sulfoxides
chemical_list: D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D013454:Sulfoxides; C016766:sulforaphane
keywords: (R)- and (S)-Sulforaphane and homologues; Activation of Nrf2 factor; Cytotoxic activity; DAG-methodology; Enantiodivergent synthesis