Journal article
Synthesis and evaluation of the anti-inflammatory properties of selenium-derivatives of celecoxib
Chemico-biological interactions, Vol.188(3), pp.446-456
12/05/2010
Handle:
https://hdl.handle.net/2376/108043
PMCID: PMC3004533
PMID: 20883674
Abstract
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.
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Details
- Title
- Synthesis and evaluation of the anti-inflammatory properties of selenium-derivatives of celecoxib
- Creators
- Dhimant Desai - Department of Pharmacology, Penn State University College of Medicine, Hershey, PA 17033, USA. ddesai@psu.eduNaveen KaushalUjjawal H GandhiRyan J ArnerChristopher D'SouzaGang ChenHema VuntaKaram El-BayoumyShantu AminK Sandeep Prabhu
- Publication Details
- Chemico-biological interactions, Vol.188(3), pp.446-456
- Academic Unit
- Pharmaceutical Sciences, Department of
- Publisher
- Ireland
- Grant note
- R03 CA128045-02 / NCI NIH HHS R01 DK077152 / NIDDK NIH HHS R01 DK 077152 / NIDDK NIH HHS N02CB56603 / NCI NIH HHS N02-CB-56603 / NCI NIH HHS R01 DK077152-04 / NIDDK NIH HHS R03 CA128045 / NCI NIH HHS
- Identifiers
- 99900547204901842
- Language
- English
- Resource Type
- Journal article