UC San Diego
Prodrug Strategies for Metalloenzyme Inhibitors and Molecular Imaging Agents
- Author(s): Daniel, Kevin Brett
- et al.
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 inhibitor