TY - JOUR
T1 - Synthesis and evaluation of the anti-inflammatory properties of selenium-derivatives of celecoxib
AU - Desai, Dhimant
AU - Kaushal, Naveen
AU - Gandhi, Ujjawal H.
AU - Arner, Ryan J.
AU - D'Souza, Christopher
AU - Chen, Gang
AU - Vunta, Hema
AU - El-Bayoumy, Karam
AU - Amin, Shantu
AU - Prabhu, K. Sandeep
N1 - Funding Information:
We would like to thank: Dr. Jyh-Ming Lin, Penn State Hershey Cancer Institute, for NMR analysis; Nino Giambrone Jr., Department of Public Health Sciences, Penn State Hershey College of Medicine, for LC–MS analysis; Dr. V.R. Padala for help with kinetic analysis. This study was supported, in part, by National Cancer Institute contract N02-CB-56603 and Penn State Hershey Cancer Institute (SGA) and PHS grants R01 DK 077152 and R03 CA128045 (KSP).
PY - 2010/12/5
Y1 - 2010/12/5
N2 - 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 KI values of 2.3 and 2.4μM; while selenocoxib-2 had a lower KI 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.
AB - 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 KI values of 2.3 and 2.4μM; while selenocoxib-2 had a lower KI 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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U2 - 10.1016/j.cbi.2010.09.021
DO - 10.1016/j.cbi.2010.09.021
M3 - Article
C2 - 20883674
AN - SCOPUS:78149471569
SN - 0009-2797
VL - 188
SP - 446
EP - 456
JO - Chemico-Biological Interactions
JF - Chemico-Biological Interactions
IS - 3
ER -