Abstract of the Dissertation
Rational Design, Synthesis and Evaluation of Benzothiazole Amphiphiles with Applications in Neurodegenerative Diseases
Jessica Lynn Cifelli
Doctor of Philosophy in Chemistry
University of California, San Diego, 2016
Professor Jerry Yang, Chair
Neurodegenerative diseases (NDDs), or disorders with progressive neuronal or nervous system dysfunction, affect millions of people worldwide each year. With a steadily increasing aging population, the amount of people affected is projected to exponentially increase unless there are significant advances made in research. As such, this dissertation will explore small molecule therapeutics that can potentially alleviate common pathological features of NDDs, with a focus on Alzheimer’s disease (AD). First, this dissertation will describe the rational design strategy towards improving the biocompatibility, of a class of amyloid-binding benzothiazoles particularly, with focus on decreasing toxicity. Here, novel benzothiazole amphiphiles or BAMs were designed, synthesized and evaluated to have a decreased toxicity over the parent compound when observed in various cell lines. In the subsequent chapters, these improved derivatives were further evaluated and modified for use in NDDs diagnostics or therapeutics. Specifically, BAMs capability to protect cells against the pathological hallmark of AD, β-amyloid (Aβ), its related toxicity and oxidative stress, was examined. Next, charged derivatives of BAM1-EG6 were synthesized for use in improving the binding to several NDD associated amyloids, including Aβ and α-synuclein (αS). This non-covalent strategy has potential future applications to differentiate between amyloids for diagnostics, or in therapeutics if metal chelation was utilized instead of charge-charge interactions.
The last two chapters of this dissertation, analyzes the ability of BAMs to increase dendritic spine density. Since decreased synaptic density and function is associated with many NDDs, particularly as one of the initial pathologies, small molecules that could alleviate or even reverse these effects would be quite valuable. Here, the BAMs spinogenic properties were evaluated in both primary hippocampal neurons as well as human induced pluripotent stem cell (hiPSC)-derived neurons. Importantly, the ability of BAMs to counteract Aβ-induced dendritic spine loss was also examined in primary culture. Lastly, the possibility of these effects translating into humans was evaluated utilizing hiPSC-derived neurons. Collectively, this dissertation presents on small molecules with a dual-modality (i.e amyloid binding capabilities and spinogenic activity), which may find use as part of a therapeutic regiment for AD and other NDDs.