Structure-activity relationships of methoxychalcones as inducers of heme oxygenase-1

Philip Sawle, Benjamin E Moulton, Magdalena Jarzykowska, Colin J Green, Roberta Foresti, Ian J S Fairlamb, Roberto Motterlini

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45 Citations (Scopus)


Chalcones are naturally occurring flavonoids composed of two aromatic rings connected by a three-carbon unit forming an alpha-beta unsaturated carbonyl group. They are pharmacologically relevant because of their ability to exert anticarcinogenic, antimicrobial, and anti-inflammatory activities. Recent evidence indicates that the bioactivity of hydroxy-chalcones is correlated with their intrinsic property to induce the antioxidant and cytoprotective enzyme heme oxygenase-1 (HO-1). In the present study, we assessed how the methoxy substituents positioned on the two aromatic rings affect the anti-inflammatory action of different chalcones in relation to their ability to increase heme oxygenase in RAW246.7 macrophages. Structure-activity relationships of methoxychlacones were qualitatively and quantitatively examined and correlated with inhibition of endotoxin-mediated nitrite production and cytotoxic effects. Our data indicate that (i) a progressive increase in heme oxygenase activity is obtained by sequentially increasing the number of methoxy substituents in the 3,4,5- and 3',4',5'-positions of the aromatic rings; (ii) methoxy substituents placed either in the 2,4,6-positions or alone in the 4- or 4'-position are ineffective; (iii) increased heme oxygenase activity by chalcones is lost when the alpha-beta double bond and the carbonyl group are reduced or protected; (iv) the anti-inflammatory activity and cytotoxicity profiles of the chalcones examined correlate with their potency as HO-1 inducers; and (v) chalcone-mediated HO-1 induction is reduced by thiols or inhibitors of phosphatidylinositol-3 kinase (PI3K) pathway. This study provides additional information on the structural features that methoxychalcones and natural antioxidants need to possess to be considered as therapeutic agents for maximizing HO-1 expression and activity.

Original languageEnglish
Pages (from-to)1484-94
Number of pages11
JournalChemical Research in Toxicology
Issue number7
Publication statusPublished - Jul 2008


  • Animals
  • Antioxidants
  • Biomarkers
  • Chalcones
  • Enzyme Induction
  • Heme Oxygenase-1
  • Macrophages
  • Mice
  • Structure-Activity Relationship
  • Journal Article
  • Research Support, Non-U.S. Gov't


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