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

The tetra(ethylene glycol) derivative of benzothiazole aniline, BTA-EG4, is a novel amyloid-binding small molecule that can penetrate the blood-brain barrier and protect cells from Aβ-induced toxicity. However, the effects of Aβ-targeting molecules on other cellular processes, including those that modulate synaptic plasticity, remain unknown. We report here that BTA-EG4 decreases Aβ levels, alters cell surface expression of amyloid precursor protein (APP), and improves memory in wild-type mice. Interestingly, the BTA-EG4-mediated behavioral improvement is not correlated with LTP, but with increased spinogenesis. The higher dendritic spine density reflects an increase in the number of functional synapses as determined by increased miniature EPSC (mEPSC) frequency without changes in presynaptic parameters or postsynaptic mEPSC amplitude. Additionally, BTA-EG4 requires APP to regulate dendritic spine density through a Ras signaling-dependent mechanism. Thus, BTA-EG4 may provide broad therapeutic benefits for improving neuronal and cognitive function, and may have implications in neurodegenerative disease therapy.

Our recent study demonstrated that an amyloid-β binding molecule, BTA-EG4, increases dendritic spine number via Ras-mediated signaling. To potentially optimize the potency of the BTA compounds, we synthesized and evaluated an amyloid-β binding analog of BTA-EG4 with increased solubility in aqueous solution, BTA-EG6. We initially examined the effects of BTA-EG6 on dendritic spine formation and found that BTA-EG6-treated primary hippocampal neurons had significantly increased dendritic spine number compared to control treatment. In addition, BTA-EG6 significantly increased the surface level of AMPA receptors. Upon investigation into the molecular mechanism by which BTA-EG6 promotes dendritic spine formation, we found that BTA-EG6 may exert its effects on spinogenesis via RasGRF1-ERK signaling, with potential involvement of other spinogenesis-related proteins such as Cdc42 and CDK5. Taken together, our data suggest that BTA-EG6 boosts spine and synapse number, which may have a beneficial effect of enhancing neuronal and synaptic function in the normal healthy brain.