Enhancing the anti-inflammatory activity of chalcones by tuning the Michael acceptor site
| Autor: | Hannelore Rücker, Tobias P. Dick, Sabine Amslinger, Nafisah Al-Rifai, Lidia Brodziak-Jarosz, Clarissa Gerhäuser, Anne Rascle, Eva Gottfried |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Lipopolysaccharides
Chalcone Transcription Genetic NF-E2-Related Factor 2 Stereochemistry medicine.drug_class Cysteamine ddc:540 Anti-Inflammatory Agents Nitric Oxide Synthase Type II Enzyme-Linked Immunosorbent Assay Alkylation Biochemistry Anti-inflammatory Mice chemistry.chemical_compound Chalcones medicine Animals Humans Sulfhydryl Compounds Physical and Theoretical Chemistry Heme Inflammation chemistry.chemical_classification biology Interleukin-6 Macrophages Interleukin-8 Organic Chemistry NF-kappa B Photochemical Processes Glutathione Nitric oxide synthase chemistry 540 Chemie Electrophile Thiol biology.protein Cytokines Signal transduction Heme Oxygenase-1 HeLa Cells |
| Zdroj: | Organic & Biomolecular Chemistry. 13:3040-3047 |
| ISSN: | 1477-0539 1477-0520 |
| DOI: | 10.1039/c4ob02301c |
| Popis: | 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, ��-X-substituted 2���,3,4,4���-tetramethoxychalcones (��-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 ��-X-TMCs activate Nrf2 transcriptional activity and inhibit NF-��B transcriptional activity. For most ��-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. Open Access Komponente aus der Allianzlizenz |
| Databáze: | OpenAIRE |
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