This dissertation studies the applications of prodrug strategies in drug delivery. The prodrugs under study are compounds that can deliver carbon monoxide or PROTACs under physiological conditions.

Chapter 1 describes a new structural scaffold of CO prodrugs through the use of an adamantane moiety to afford stabilization of a critical precursor structure, cyclopentadienone, and to allow for optimization of water solubility. The prodrugs are tested in a cell culture model to confirm CO release from such prodrugs and demonstrate their efficacy in anti-inflammation studies.

Chapter 2 reviews the field of using click chemistry in the development of PROTACs, which are hetero-bifunctional molecules designed to mediate the disposal of a target protein via recruitment of the ubiquitination-proteasome degradation machinery. Click chemistry has unique advantages for tethering two or more molecular entities of choice under near-physiological conditions and therefore has been applied to the development of PROTACs in various ways. Chapter 2 provides a succinct summary of this field with a critical analysis of various factors that need to be considered for optimal results.

Chapter 3 describes our effort to develop a reversible assembly approach to the design of PROTACS.