UC San Diego

Prodrugs are derivatives of bioactive molecules that can become activated in vivo by a chemical or enzymatic stimulus. They serve as tools to help improve physicochemical or pharmacokinetic properties of active agents to overcome barriers that effect drug formulation. The work in this thesis explores the development of two novel prodrug strategies.

In Chapter 2, several metalloenzyme inhibitor prodrugs that become activated in the presence of esterase were developed. A study that contrasts differences between directly acetylated drugs and ones appended with an acetylated self-immolative linker were investigated. In this study the activation kinetics, aqueous stability and inhibition profile of the prodrugs was evaluated

Chapter 3 highlights the development of a novel prodrug strategy utilizing thiazolidinones that mask carboxylic acids. The prodrugs developed were reactive in the presence of hydrogen peroxide. Specific activation by hydrogen peroxide may allow for targeted activation of these prodrugs. These strategies were applied to an FDA approved anti-inflammatory drug and a known metalloenzyme inhibitor. Their responsiveness to hydrogen peroxide was investigated, as well as their aqueous stability in the presence of biologically relevant nucleophiles. Lastly, their inhibition profile was evaluated as well as the cytotoxicity of the promoiety.