2-Alkoxycarbonyl Allyl Ester Conjugates of NSAIDs as Potential Anticancer Agents

Abstract

Enzyme cyclooxygenase (COX) inhibition with non-steroidal anti-inflammatory drugs (NSAIDs) has long been utilized to treat inflammation and relieve pain. Several studies have shown that NSAIDs have also cancer preventative and tumor regressive effects. Prostaglandin E2 which acts as an inflammatory mediator influences many mechanisms that plays a significant role in tumorigenesis such as cell proliferation, angiogenesis, and metastasis. COX overexpression is a characteristic feature of most malignant tumors and contributes to poor outcomes in multiple malignancies. It has been reported that cancer incidence can be reduced by 25-40% in patients regularly taking low dose COX inhibitor aspirin on a daily basis, with the most compelling evidence acquired for colorectal cancer. We envisioned that NSAID conjugates derived from 2-alkoxycarbonyl allyl esters would have cytotoxicity enhancing prodrug properties with dual anti-inflammatory and intracellular alkylation. In the current work, 2-alkoxycarbonyl allyl ester conjugates of several common NSAIDs have been synthesized and tested for their cell proliferation inhibition properties in breast (MDA-MB-231, 4T1), pancreatic (MIA PaCa-2), and colorectal adenocarcinoma (WiDr) cell lines. Several of the synthesized derivatives exhibit good potency against all four cancer cell lines. The synthesized compounds have also been tested for their COX inhibition properties.