CHEMICAL SYNTHESIS AND BIOLOGICAL EVALUATION OF INHIBITORS AND SUBSTRATE OF CYTOSOLIC PHOSPHOLIPASE A2

Abstract

Cytosolic phospholipase A2 (cPLA2) is an important class of enzyme involved in the inflammatory pathway. In various disease states such as arthritis and neuroinflammation models, cPLA2 was found to have elevated expression or increased activity. As a result, this influenced the production of inflammatory markers such as prostaglandins and eicosanoids which in long-term would be detrimental to the disease state. Suitable pharmacological interventions for identifying cPLA2 as a target have been shown to relieve the effects of inflammation. In this thesis, arachidonyl trifluoromethyl ketone was chosen as the scaffold and a library of analogues was synthesized as inhibitors of cPLA2. Structure activity relationship (SAR) study was conducted with the use of a biochemical assay to identify new leads and effectiveness of cPLA2 inhibition in which the successfully developed compound was evaluated on a neuroinflammatory model. In addition, a set of fluorogenic inhibitors and substrate of cPLA2 were synthesized and demonstrated to be potential imaging tools for detecting cPLA2.