Development and Activation of Novel Metalloenzymes Proinhibitors

Metalloenzymes such as matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that play a crucial role in the cleavage of extracellular proteins. Overexpression of MMPs has been associated with a number of pathologies such as arthritis and cancer. The activity of these metalloenzymes can be controlled with inhibitors that coordinate to the catalytic metal. Several MMP inhibitors have been developed, but have had little success in clinical trials due to systemic inhibition. To obtain an inhibitor that is highly specific, a pro-drug approach has emerged as a way to control metal binding. For the use of prodrugs, ester groups are an ideal protecting group since they improve the properties of small-molecule drugs including solubility, stability, and bioavailability. In addition, ester-protected drugs are easily synthesized and can be readily cleaved by the presence of ubiquitous esterases. This work explores the development of inactive MMP proinhibitors (proMMPi) that can become activated, releasing a metal binding group (MBG), after deprotection by a specific stimulus, esterase.  This project will also explore the responsiveness of protected metal binding groups (proMBGs) to esterase by monitoring the cleavage of the proMBG through UV-Vis spectroscopy and high pressure liquid chromatography (HPLC). Through these methods the kinetic efficiency of the MBG release will be determined.