Synthesis and evaluation of the anti-inflammatory properties of selenium-derivatives of celecoxib

• Published in: Chemico-biological interactions Vol. 188; no. 3; pp. 446 - 456
• Main Authors: Desai, Dhimant, Kaushal, Naveen, Gandhi, Ujjawal H., Arner, Ryan J., D'Souza, Christopher, Chen, Gang, Vunta, Hema, El-Bayoumy, Karam, Amin, Shantu, Prabhu, K. Sandeep
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 05.12.2010
• Subjects: Animals; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Bone Marrow Cells - cytology; Celecoxib; Cell Line; Cyclooxygenase 2 - metabolism; Cyclooxygenase 2 Inhibitors - chemical synthesis; Cyclooxygenase 2 Inhibitors - chemistry; Cyclooxygenase 2 Inhibitors - pharmacology; Cyclooxygenase-2; Gene Expression Regulation, Enzymologic - drug effects; Glutathione Peroxidase - metabolism; Glutathione Peroxidase GPX1; Humans; Lipopolysaccharides - pharmacology; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Mice; NF-kappa B - metabolism; Nuclear factor-κB; PGE 2; Proinflammatory genes; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Rats; Selenium - chemistry; Signal Transduction - drug effects; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Transcription; NF-κB; GPX1; COX-2; Transcription; PGE 2; Proinflammatory genes; iNOS; Cyclooxygenase-2; Nuclear factor-κB
• ISSN: 0009-2797; 1872-7786; 1872-7786
• DOI: 10.1016/j.cbi.2010.09.021

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 2.4 μM; while selenocoxib-2 had a lower K I of 0.72 μM. 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.