title: Chemical reactivity and biological activity of chalcones and other α,β-unsaturated carbonyl compounds.
abstract: Abstract 1. Chalcones are structural analogues of benzalacetophenone (BAP). Several derivatives have been identified in plants and anticarcinogenic and anti-inflammatory properties were attributed to the compounds, probably related to their direct antioxidant activity or stimulatory effects on the expression of endogenous defence enzymes like hemeoxygenase-1 (HO-1). HO-1 expression is triggered by the Nrf2-Keap1 signalling pathway, initiated by the addition of chalcones to thiol groups of Keap1 via Michael-type reaction. 2. The present study used a model system estimating the reactivity of different synthetic chalcones and other α,β-unsaturated carbonyl compounds with thiols and compared the chemical reactivity with the biological activity, measured by HO-1 expression in human dermal fibroblasts. 3. Chemical reactivity with the thiol group of N-acetylcysteine was determined with 5,5'-dithiobis-(2-nitrobenzoic acid) and followed chemical principles of structure-reactivity relationship. Most reactive were sulforaphane, dimethylfumarate, chalcone 3 ((2E)-1-phenyl-3-pyrimidin-2-ylprop-2-en-1-one) and chalcone 7 (1,3-diphenylprop-2-yn-1-one). This result demonstrates that α,β-unsaturated carbonyl derivatives react with thiols differently. All compounds were also biologically active; however, expression of HO-1 was not only related to the chemical reactivity but also to the lipophilicity of the molecules which likely affected transmembrane uptake. Most efficient inducers of HO-1 expression were BAP, 4-hydroxynonenal and chalcone 1 (4-[(1E)-3-oxo-3-phenylprop-1-en-1-yl]benzonitrile), chalcone 5 ((2E)-1-phenyl-3-[4-(trifluoromethyl)-phenyl]prop-2-en-1-one) and chalcone 7.
authors: Medical Faculty, Institute of Biochemistry and Molecular Biology I, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.
authors: Daniela
authors: D
authors: Maydt
authors: Silke
authors: S
authors: De Spirt
authors: Christian
authors: C
authors: Muschelknautz
authors: Wilhelm
authors: W
authors: Stahl
authors: Thomas J J
authors: TJ
authors: Müller
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000447:Aldehydes / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D047188:Chalcones / Q000494:pharmacology*; D004228:Dithionitrobenzoic Acid / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D017382:Reactive Oxygen Species / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000378:metabolism
chemical_list: D000447:Aldehydes; D047188:Chalcones; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D004228:Dithionitrobenzoic Acid; D051547:Heme Oxygenase-1; D000111:Acetylcysteine