Prodrug Strategies for Metalloenzyme Inhibitors and Molecular Imaging Agents

Prodrugs are effective tools in overcoming drawbacks typically associated with drug properties in vivo. This dissertation will first discuss prodrug approaches and how they have been successfully applied to a variety of pharmacological agents. Metalloenzymes will then be introduced with an emphasis on matrix metalloproteinases (MMPs) as therapeutic targets. A survey of reported prodrugs of metalloenzymes will be presented, highlighting the limited number of strategies previously explored. A discussion of the benefits of site-selective prodrugs that target metalloenzymes will follow. In Chapter 2, the development of MMP inhibitor prodrugs (proinhibitors) that incorporate acetate promoieties appended directly to the metal-binding pharmacophore (MBP) of MMP inhibitors will be explored, for activation in the presence of esterases. Additionally, sulfonate ester-based MMP proinhibitors will be explored, activated in the presence of hydrogen peroxide (H₂O₂), a marker of many diseases when present in high concentrations. The exploration of novel prodrug strategies, activated in either the presence of esterases or H₂O₂, wherein the triggering moiety is appended to the MMP inhibitor via a cleavable linker will be discussed in Chapter 3. The optimal design of promoieties for MMPs incorporating boronic ester triggers will then be detailed. Chapter 4 will discuss the application of the boronic ester-based promoiety for MMPi to fluorophores. These fluorophores are designed to image H₂O₂ in biological settings. The application of the optimal H₂O₂- sensitive prodrug strategies to nanoparticle drug delivery systems will be detailed in Chapter 5. Here nanoparticles are comprised of a hydrophobic MMP proinhibitor and a quenched fluorophore that are activated in the presence of H₂O₂. Additionally, a hydrophilic ligand that targets high levels of MMP activity will be incorporated into the nanoparticle. Upon delivery, the MMP inhibitor will be released, which can be detected as a function of fluorescence. Finally, in Chapter 6, the development of a thiol-activated histone deacetylase (HDAC) proinhibitor will be discussed that functions to deliver both a covalent and a competitive inhibito