Title : Prodrugs of non-steroidal anti-inflammatory drugs (NSAIDs) and Amino acid esters as novel non-cyclooxygenase inhibitors for colorectal cancer chemoprevention
A structure-based medicinal chemistry strategy was applied to design new NSAID prodrugs that show growth inhibitory activity against human colon tumor cells through cyclooxygenase (COX)-independent mechanism. In vitro testing of the synthesized compounds against the human HT-29 colon tumor cell line revealed enhanced growth inhibitory activity compared to the parent drugs. Selectivity of the most active tested molecules was investigated against a panel of three tumor and one normal colon cell lines and showed up to six times less toxicity against normal colonocytes. The tested molecules was shown to induce dose-dependent apoptosis of HT116 colon tumor cells as evidenced by measuring the activity of caspases-3 and 7. None of the synthesized prodrugs showed activity against COX-1 or COX-2 isozymes, con?rming a COX-independent mechanism of action. The synthesized prodrugs were found to have no ulcerogenic effect in rats as indicated by electron microscope scanning of the stomach after oral administration. A pharmacophore model was developed for elucidating structure-activity relationships and subsequent chemical optimization for this series of compounds as colorectal cancer chemopreventive drugs.