Abstract
The cyclooxygenase-2 (COX-2) enzyme binds to arachidonic acid resulting in the release of metabolites that induce pain and inflammatory responses. Recent studies have shown that strong COX-2 expression is highly correlated with increased tumor risk. Therefore, the development of potent COX-2 inhibitors to relieve pain and treat cancers requires further investigation. We used virtual screening to find three COX-2 inhibitors (Phar-95239, T0511-4424 and Zu- 4280011) from a huge zinc database containing 2000000 compounds. The effects of the compounds on COX-2 were compared to those on COX-1 using a colorimetric COX (ovine) screening assay kit. The selectivity index, the ratio of IC50 for COX-1 inhibition to that of COX-2, calculated were MTT assay was used to evaluate the cytotoxic activity of the compounds using different dilutions. The IC50 values were calculated. Based on the results of the MTT assay, the IC50 values for compounds Phar-95239, T0511-4424 and Zu-4280011 were 178.52, 143 and 97.61 µM, respectively, and the selectivity indices of the compounds were 11.36, 12.20 and 20.03, respectively. These results indicated a relationship between the selectivity index and anticancer activity. Zu-4280011 displayed the highest selectivity index and the best results in the MTT assay among selected componds.
Highlights
The use of nonsteroidal anti-inflammatory drugs (NSAIDs) for the treatment of inflammation and pain is often accompanied by adverse gastrointestinal and renal side effects [1]
The anti-inflammatory activities of these drugs are mediated by the inhibition of cyclooxygenases (COXs), which catalyze the bioconversion of arachidonic acid to prostaglandins[2]
As part of our program to discover novel types of selective COX-2 inhibitors, we report a methodology to find a new group of COX-2 inhibitory compounds and evaluate their anti-inflammatory and anticancer activities [18]
Summary
The use of nonsteroidal anti-inflammatory drugs (NSAIDs) for the treatment of inflammation and pain is often accompanied by adverse gastrointestinal and renal side effects [1]. The indirect inhibition of prostacyclin production by selective COX2 inhibitors might account for their adverse cardiovascular effects [7, 8]. As part of our program to discover novel types of selective COX-2 inhibitors, we report a methodology to find a new group of COX-2 inhibitory compounds and evaluate their anti-inflammatory and anticancer activities [18]. The ability of the test compounds to inhibit ovine COX-1 and COX-2 was determined using a colorimetric COX (ovine) inhibitor-screening assay (Cayman Chemical, Item Number 760111) that utilizes the peroxidase component of cyclooxygenase.
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