UC San Diego

The first part of this dissertation focuses on new methodology to prepare functionalizable derivatives of polylactic acid (PLA), an important biodegradable and biocompatible polymer often used for drug-delivery applications. Chapter 1 provides a brief background covering the uses and properties of biodegradable polymers and outlines previous strategies to synthesize functionalized PLA. Chapter 2 presents a novel synthetic route to functionalized lactide monomers via a Passerini- type condensation reaction. This methodology provides access to a variety of functionalized PLA molecules, including those with derivatizable alkyne and azide pendant groups. In addition, the chapter explores the preparation of polymeric nanoparticles from these functionalized PLAs for potential use in drug delivery applications. The second part of this dissertation focuses on studies toward the development of a small molecule capable of chemically degrading the Alzheimer's related [beta]-amyloid (A[beta]) peptide. Chapter 3 provides a brief introduction to Alzheimer's disease (AD) and its potential impact on global health. The chapter discusses the amyloid cascade hypothesis (which implicates A[beta] as a causative factor in developing AD) as well as the current drugs and therapeutic strategies used to stop or reverse the progression of this disease. Chapter 4 introduces target-directed degradation of A[beta] with a small molecule as a potential approach for the treatment of AD. The chapter presents the design and synthesis of a small molecule comprised of a cyclic enediyne chemical "warhead" moiety and a benzothiazole aniline (BTA) A[beta] binding group. This designed BTA-enediyne conjugate reduces the toxicity of A[beta], presumably by degrading the amyloid to lower molecular weight fragments that are less harmful than full-length A[beta]. Chapter 5 describes the development of a methodology leading to an improved synthesis of oligoethylene glycol derivatives of BTA and the collaborations made possible because of the increased availability of these molecules. These compounds exhibit many interesting, biomedically relevant properties including the ability to inhibit SEVI and semen-mediated infectivity of HIV-1 and form ion channels in lipid bilayers