Abstract
Cyclooxygenase inhibitors as anti-inflammatory agents can be used in chemoprevention. Many in vitro and in vivo studies on human and animal models have explained the mechanisms of the chemopreventive effect of COX inhibitors such as: induction of apoptosis, inhibition of neoplasia, angiogenesis suppression, induction of cell cycle inhibition and inhibition of the expression of peroxisome proliferator-activated receptors. Here, biological evaluation of twelve different Schiff base derivatives of N-(2-hydrazine-2-oxoethyl)-4,6-dimethyl-2-sulfanylpyridine- 3-carboxamide are presented. Their in vitro anti-COX-1/COX-2, antioxidant and anticancer activities were studied. The molecular docking study was performed in order to understand the binding interaction of compounds in the active site of cyclooxygenases. Compounds PS18 and PS33 showed a significant inhibitory activity on COX-1 at lower concentrations compared to meloxicam and piroxicam. The IC50 of COX-1 of these compounds was 57.3 µM for PS18 and 51.8 µM for PS33. Out of the tested compounds, the highest therapeutic index was demonstrated by PS18, PS19, PS33, PS40 and PS41. Lower molar concentrations of these compounds inhibit the growth of cancer cells while not inhibiting the healthy cells. Compounds PS18, PS19 and PS33 simultaneously demonstrated a statistically-significant inhibition of COX-1 or COX-2. This opens up the possibility of applying these compounds in the chemoprevention of cancer.
Highlights
Cyclooxygenases (COX) are dual-function enzymes, which catalyse the conversion of arachidonic acid to prostaglandins and can occur in two isoforms: COX-1 and COX-2
The compound PS42 inhibited in a statistically-significant manner the activity of COX-1 and COX-2 compared with the inhibitory activity of piroxicam and meloxicam
Out of the tested compounds, the highest therapeutic index, i.e., the difference between the concentrations that inhibit 50% of healthy and cancerous cells, was demonstrated by PS18, PS19, PS33, PS40 and PS41
Summary
Cyclooxygenases (COX) are dual-function enzymes, which catalyse the conversion of arachidonic acid to prostaglandins and can occur in two isoforms: COX-1 and COX-2. The first generation of non-steroidal anti-inflammatory drugs (NSAIDs) inhibits the activity of COX in a non-selective manner and is associated with adverse effects, especially on the mucous membrane of the gastral and intestinal sections of the digestive tract. The discovery of COX-2 inhibitors (coxibs) made it possible to apply them primarily in the treatment of pain caused by neoplastic and non-neoplastic changes (e.g., rheumatoid arthritis, osteosclerosis) This in turn was associated with adverse effects and increased the risk of cardiovascular diseases [2]. Inflammatory cells and cancer cells themselves produce free radicals, pro-inflammatory mediators such as cytokines, chemokines and arachidonic acid metabolites, which generate further production of reactive oxygen species (ROS), activating further series of inflammatory cells. It is important to determine the most rational and effective combination of redox-active and anti-inflammatory compounds with other standard anti-cancer drugs and to identify a low, non-toxic dose thereof. Blocking the enzymatic cascade of arachidonic acid and the production of inflammatory factors pro-inflammatory factors [15,19]
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