title: Enhancing the anti-inflammatory activity of chalcones by tuning the Michael acceptor site.
abstract: Inflammatory signaling pathways orchestrate the cellular response to infection and injury. These pathways are known to be modulated by compounds that alkylate cysteinyl thiols. One class of phytochemicals with strong thiol alkylating activity is the chalcones. In this study we tested fourteen chalcone derivatives, α-X-substituted 2',3,4,4'-tetramethoxychalcones (α-X-TMCs, X = H, F, Cl, Br, I, CN, Me, p-NO2-C6H4, Ph, p-OMe-C6H4, NO2, CF3, COOEt, COOH), for their ability to modulate inflammatory responses, as monitored by their influence on heme oxygenase-1 (HO-1) activity, inducible nitric oxide synthase (iNOS) activity, and cytokine expression levels. We confirmed that the transcriptional activity of Nrf2 was activated by α-X-TMCs while for NF-κB it was inhibited. For most α-X-TMCs, anti-inflammatory activity was positively correlated with thiol alkylating activity, i.e. stronger electrophiles (X = CF3, Br and Cl) being more potent. Notably, this correlation did not hold true for the strongest electrophiles (X = CN and NO2) which were found to be ineffective as anti-inflammatory compounds. These results emphasize the idea that chemical fine-tuning of electrophilicity is needed to achieve and optimize desired therapeutic effects.
authors.affiliation: Institute of Organic Chemistry, University of Regensburg, Universitätsstraße 31, 93053 Regensburg, Germany. sabine.amslinger@chemie.uni-regensburg.de.
authors.forename: Hannelore
authors.initials: H
authors.lastname: Rücker
authors.forename: Nafisah
authors.initials: N
authors.lastname: Al-Rifai
authors.forename: Anne
authors.initials: A
authors.lastname: Rascle
authors.forename: Eva
authors.initials: E
authors.lastname: Gottfried
authors.forename: Lidia
authors.initials: L
authors.lastname: Brodziak-Jarosz
authors.forename: Clarissa
authors.initials: C
authors.lastname: Gerhäuser
authors.forename: Tobias P
authors.initials: TP
authors.lastname: Dick
authors.forename: Sabine
authors.initials: S
authors.lastname: Amslinger
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry*; D047188:Chalcones / Q000737:chemistry*; D003543:Cysteamine / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005978:Glutathione / Q000737:chemistry; D006367:HeLa Cells; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000737:chemistry; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D055668:Photochemical Processes; D013438:Sulfhydryl Compounds / Q000737:chemistry; D014158:Transcription, Genetic
chemical_list: D000893:Anti-Inflammatory Agents; D047188:Chalcones; D016207:Cytokines; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; D013438:Sulfhydryl Compounds; D003543:Cysteamine; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1; D005978:Glutathione