Design, synthesis and testing of biologically active small molecules

The enzyme inhibitor studies reported in this thesis target protein tyrosine phosphatases (PTPases) and matrix metalloproteinase-1 (MMP-1). Hydroxamic acids are good inhibitors of MMP-1. However, they lack specificity and as a result have not successfully passed clinical trials. To address this issue we have designed a hybrid between squaric acid and a hydroxamic acid to create a vinylogous hydroxamic acid inhibitor for MMP-1.;High levels of PTP-1B activity impair the signaling cascade initiated by insulin. Knock out studies in mice show that PTP-1B is a negative regulator of glucose metabolism and is a contributing factor in Type II diabetes. The PTP Yop H contributes to the virulence of the plague-causing bacterium Yersinia pestis. We have designed a series of inhibitors based on squaric acid to inhibit these PTPases. We have also designed multidentate bis-alpha-ketoacids as PTP inhibitors to address issues of specificity. This can be a significant challenge since many biologically important PTPases are structurally homologous in their active site regions.