Abstract
Arachidonic acid is an unsaturated fatty acid liberated from phospholipids of cell membranes. NSAIDs are known as targets of cyclooxygenase enzyme (COX-1, COX-2 and COX-3) in arachidonic acid metabolism. This mechanism of COX-2 in carcinogenesis causes cancer. In addition, COX-2 plays a role in the early stages of hepatocarcinogenesis. Hepatitis C virus (HCV) infection is cause of liver cirrhosis and hepatocellular carcinoma (HCC). The aim of our study was to improve effective agents against HCV. A novel series of new etodolac 1,2,4-triazoles derivatives (4a–h) have been synthesized and investigated for their activity against HCV NS5B polymerase. Compound 4a was found to be the most active with IC50 value of 14.8 µM. In accordance with these results, compound 4a was screened for anti-cancer activity on liver cancer cell lines (Huh7, Mahlavu, HepG2, FOCUS). Compound 4a showed anti-cancer activity against Huh7 human hepatoma cell line with IC50 value of 4.29 µM. Therefore, compound 4a could be considered as a new anti-cancer and anti-HCV lead compound.
Highlights
Non-steroidal anti-inflammatory drugs (NSAIDs) have recently gained attention as promising cancer chemopreventive agents
We recently reported on the synthesis of etodolac thiosemicarbazides and identified their anti-Hepatitis C virus (HCV) NS5B polymerase activity[14]
In continuation of our efforts towards developing new anticancer agents with enhanced biological properties and potent antiHCV NS5B polymerase activity, here we report on the synthesis and biological evaluation of novel etodolac 1,2,4-triazole derivatives
Summary
Non-steroidal anti-inflammatory drugs (NSAIDs) have recently gained attention as promising cancer chemopreventive agents. Evidence for a connection between COX-2 activation and carcinogenesis has come from a number of studies[1]. Many epidemiological studies have highlighted COX-2 as an important molecular target for anti-cancer therapy. Overexpression of COX-2 in tumor cell lines affect diverse mechanisms involved in carcinogenesis, such as angiogenesis, inhibition of apoptosis, stimulation of cell growth as well as the invasiveness of tumor cells. Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, accounting for approximately 1 million deaths annually and an estimated 500 000 new cases per year[2]. High levels of COX-2 expression in hepatocytes may be involved in NSAIDs, including selective COX-2 inhibitors, exhibit chemopreventive as well as therapeutic effects.
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