Chemical reactivity and biological activity of chalcones and other α,β-unsaturated carbonyl compounds

• Published in: Xenobiotica 2013-08, Vol.43 (8), p.711-718
• Main Authors: Maydt, Daniela, De Spirt, Silke, Muschelknautz, Christian, Stahl, Wilhelm, Müller, Thomas J. J.
• Format: Article
• Language: English
• Subjects: Acetylcysteine - pharmacology; Aldehydes - pharmacology; Cell Survival - drug effects; Chalcone; Chalcones - pharmacology; Dithionitrobenzoic Acid - metabolism; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - enzymology; Heme Oxygenase-1 - metabolism; HO-1; Humans; Michael-type reaction; Reactive Oxygen Species - metabolism; Sulfhydryl Compounds - chemistry; Sulfhydryl Compounds - metabolism; thiol reaction
• ISSN: 0049-8254; 1366-5928
• DOI: 10.3109/00498254.2012.754112

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.