Synthesis and evaluation of the anti-inflammatory properties of selenium-derivatives of celecoxib
| Autor: | Karam El-Bayoumy, Gang Chen, Christopher A. D'Souza, Dhimant Desai, Ryan J. Arner, Ujjawal H. Gandhi, Hema Vunta, Naveen Kaushal, Shantu Amin, K. Sandeep Prabhu |
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| Rok vydání: | 2010 |
| Předmět: |
Lipopolysaccharides
GPX1 medicine.drug_class Anti-Inflammatory Agents Bone Marrow Cells Pharmacology Toxicology Gene Expression Regulation Enzymologic Article Anti-inflammatory Cell Line Mice Selenium Glutathione Peroxidase GPX1 Gene expression medicine Animals Humans chemistry.chemical_classification Glutathione Peroxidase Sulfonamides Cyclooxygenase 2 Inhibitors biology Macrophages NF-kappa B General Medicine In vitro Rats chemistry Celecoxib Cyclooxygenase 2 biology.protein Pyrazoles Tumor necrosis factor alpha Selenoprotein Cyclooxygenase Signal Transduction medicine.drug |
| Zdroj: | Chemico-Biological Interactions. 188:446-456 |
| ISSN: | 0009-2797 |
| DOI: | 10.1016/j.cbi.2010.09.021 |
| Popis: | Celecoxib is a selective cyclooxygenase (COX)-2 inhibitor used to treat inflammation, while selenium is known to down-regulate the transcription of COX-2 and other pro-inflammatory genes. To expand the anti-inflammatory property, wherein celecoxib could inhibit pro-inflammatory gene expression at extremely low doses, we incorporated selenium (Se) into two Se-derivatives of celecoxib, namely; selenocoxib-2 and selenocoxib-3. In vitro kinetic assays of the inhibition of purified human COX-2 activity by these compounds indicated that celecoxib and selenocoxib-3 had identical K(I) values of 2.3 and 2.4μM; while selenocoxib-2 had a lower K(I) of 0.72μM. Furthermore, selenocoxib-2 inhibited lipopolysaccharide-induced activation of NF-κB leading to the down-regulation of expression of COX-2, iNOS, and TNFα more effectively than selenocoxib-3 and celecoxib in RAW264.7 macrophages and murine bone marrow-derived macrophages. Studies with rat liver microsomes followed by UPLC-MS-MS analysis indicated the formation of selenenylsulfide conjugates of selenocoxib-2 with N-acetylcysteine. Selenocoxib-2 was found to release minor amounts of Se that was effectively inhibited by the CYP inhibitor, sulphaphenazole. While these studies suggest that selenocoxib-2, but not celecoxib and selenocoxib-3, targets upstream events in the NF-κB signaling axis, the ability to effectively suppress NF-κB activation independent of cellular selenoprotein synthesis opens possibilities for a new generation of COX-2 inhibitors with significant and broader anti-inflammatory potential. |
| Databáze: | OpenAIRE |
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