Synthesis and Analysis of Novel Anti-Inflammatory Conjugates for the Treatment of Inflammatory Bowel Disease

Current aminosalicylic acid (ASA) preparations are used to induce and control the remission of inflammatory bowel diseases (IBOs); however, only partial success has been achi~ved. Hence, in the absence of a satisfactor~ treatment or a cure, there is a need for the development of further therapeutic strategies to combat IBOs. The objective of this study was to explore new therapeutic avenues by developing novel conjugates of the active ASAs pharmacophore. These conjugates were designed to incorporate the ASA with other moieties which show therapeutically useful properties. This report includes the design, synthesis and characterisation of novel ASA and aliphatic amino acid (AA) conjugates with the antioxidant ethylenediaminetetraacetic acid (EOTA). Diglyceride and model polymeric delivery systems were also investigated, although, these two alternative areas were not highly successful. All the EOTA conjugates· described in this study are readily synthesised in two steps using standard methyl ester and amide-bond formation techniques. A wide range of biochemical properties were studied for the conjugates synthesised in this project. These studies determined the effectiveness of the conjugates in the combat against IBOs. These properties included metal ion chelation, reactive oxygen species (ROS) suppression, proteolytic and pH stabilities, as well as anti-cancer activity. Firstly, the chelation of labile transition metal ions has been shown to remove the ion's pro-oxidant activity. The removal of pro-oxidant activities by chelation could assist in the treatment of IBOs, which has been shown to be linked with oxidative stress. Secondly, due to a link between ROS and IBOs, the discovered ROS suppression would also be advantageous in the combat against IBOs. Thirdly, the gastrointestinal stability of these conjugates is favourable; as, reaching the disease site (Le. the colon and terminal ileum) intact would enable the conjugates to function as designed. And fourthly, due to a link between IBOs and cancer, ethylenediaminetetraacetic acid bis-(5-aminosalicylic acid methyl ester) was tested in the National Cancer Institute's 60 cancer cell-line.· The synthesised conjugates showed an ideal 1: 1 binding ratio with the transition metal ions Cu(lI) and Fe(III). ROS suppression was observed for all the synthesised compounds whe~ chelatcd to redox active transition metal ions. In the stability studies, it was found that the ASA conjuga.tes were· stable to proteolytic attack. This was in contrast to the AA conjugates, which were· readily degraded by protease. Additionally, all the studied conjugates showed excellent pH stabilities. And lastly; the 5-ASA-EDTA conjugate showed promising in vitro anti-cancer activity. This study reports novel anti-inflammatory conjugates, which show promising properties for use in the combat against IBOs. Results from this project have shown that the conjugates are able to chelate toxic, unbound transition metal ions, which in turn forms strong ROS suppressors. The work within this report has also shown excellent protease and pH stabilities of the ASA conjugates, which would enable them to travel through the upper gastrointestinal tract intact. Upon reaching the ~ite of disease, they would be able to either act as novel anti-inflammatory, chelating conjugates, or, as prodrugs which would then release the ASA moiety via bacterial reduction, The anti-cancer activity shown for one of the conjugates would also be beneficial in IBO treatment.EThOS - Electronic Theses Online ServiceGBUnited Kingdo