Rational Design, Preparation, and Analysis of Chemical Reagents for Investigating Multiple Pathological Factors in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is the most common form of neurodegenerative disease that is currently affecting over 28 million people worldwide. Even after more than a century of research, there still is no cure or even effective, long-term therapeutics for AD. As a result, AD continues to increase in prevalence and presents a major socioeconomic burden for today’s society. The absence of a cure is most certainly a result of our limited understanding of the cause(s) of AD. For example, due to the involvement of many pathological factors, such as misfolded and aggregated proteins, dysregulated metal ions, and overproduced reactive oxygen species, it is very difficult to unravel and identify the most up-stream causative factors of AD to which a drug can be designed to correct. Therefore, it is clear that in order to begin to determine the underlying cause of AD, we first must develop tools that can be used to probe and investigate the interconnections between these pathological facets. The work presented in this dissertation highlights our efforts toward this goal. Following a detailed introduction given in Chapter 1, a structure-reactivity study is presented in Chapter 2 to determine key pharmacophores that have potential applications for the development of multifunctional chemical tools for AD. In Chapter 3, a small, compact redox-active molecule is identified as a potential anti-amyloidogenic agent for AD that relies on the formation of intramolecular ligand–peptide crosslinks and represents a novel strategy for amyloid management. The applicability of transition metal complexes to control the self-assembly of amyloid-β (Aβ) peptides is further probed in Chapter 4 with the use of tetramethylcyclam metal complexes which are shown to hydrolytically cleave amide bonds of Aβ peptides. Finally, Appendix A proposes a novel method to synthetically generate specific diastereomers of our tetramethylcyclam metal complexes based on a newly identified anion effect. Overall, our findings presented herein offer significant contributions toward advancing the development of chemical tools and therapeutics for AD, and our particular emphasis on establishing reaction mechanisms and biological applicability gives us further directions to improve our next-generation reagents.