Abstract
The traditional nonsteroidal anti‐inflammatory drugs (NSAIDs) exert their effect by inhibition of cyclooxygenase‐1 (COX‐1) as well as COX‐2 enzymes. As COX‐1 is responsible for maintaining normal biological functions, the nonselective inhibition of these enzymes caused side effects including gastrointestinal (GI) problems. Recently developed selective COX‐2 inhibitors could reduce these adverse effects, but the evidence of cardiovascular side effects including an increased risk of myocardial infarction began to emerge, and some of the COX‐2 inhibitors were eventually withdrawn from the market and this led to the downfall of this research. So, the discovery of novel COX‐2 inhibitors with their safety profile became the biggest challenge in pharmaceutical research. However, recent mechanistic and clinical studies revolutionized this area by indicating the fact that COX‐2 is involved in apoptosis resistance, angiogenesis, and tumor progression. Epidemiological data suggest that selective COX‐2 inhibitors might prevent the development of cancers. Moreover, COX‐2 is found to be overexpressed in many cancers thus making it an attractive therapeutic target for the prevention and treatment of a number of malignancies. The purpose of this review is to focus on the medicinal chemistry aspects of COX‐2 inhibitors in cancer chemotherapy and recent reports on these inhibitors as anticancer agents. We attempted to cover only the COX inhibitors that showed anticancer activity, although a number of potent COX‐2 inhibitors have been reported without their anticancer effects. Furthermore, structure–activity relationships (SAR) of different classes of compounds for COX‐2 inhibition as well as anticancer activity, and their future applications are discussed. © 2009 Wiley Periodicals, Inc. Med Res Rev, 31, No. 2, 161–201, 2011