Defense Date
2026
Document Type
Thesis
Degree Name
Master of Science
Department
Chemistry
First Advisor
Dr. Heather R. Lucas
Second Advisor
Dr. Vladimir Sidorov
Third Advisor
Dr. Katherine Belecki
Fourth Advisor
Dr. Zhihua Chen
Abstract
As the population of the United States continues to age, the prevalence of neurodegenerative disorders is rising, increasing the societal and clinical burden of diseases such as Parkinson’s disease and dementia-related conditions. Lewy Body Dementia (LBD), the second most common cause of dementia, shares underlying neuropathological features with Parkinson’s disease, including the aggregation of misfolded α-synuclein into Lewy bodies and Lewy neurites. Current diagnostic approaches rely heavily on cerebrospinal fluid biomarker analysis; however, significant overlap exists among biomarkers associated with Alzheimer’s disease and other neurodegenerative conditions, limiting diagnostic specificity. Emerging evidence suggests that oxidative modifications of α-synuclein, particularly the formation of dityrosine and iso-dityrosine crosslinks, contribute to pathological aggregation and may serve as more selective biomarkers for LBD.
Copper-mediated oxidative stress has been shown to promote intra- and intermolecular dityrosine crosslinking in α-synuclein, leading to conformational changes that favor oligomerization and fibril formation. Elevated levels of dityrosine have been detected in LBD brain tissue and cerebrospinal fluid, while iso-dityrosine has been identified as a potential, yet understudied, oxidative product. Prior synthetic efforts successfully produced dityrosine in sufficient quantities for immunological evaluation; however, synthesis of iso-dityrosine was limited by low yields of a key intermediate (7), restricting further study.
The objective of this work was to improve the synthetic yield of intermediate 7 and, upon optimization, complete the coupling and deprotection steps necessary to generate iso-dityrosine in quantities suitable for downstream investigation. By refining the synthetic route and increasing material accessibility, this research aims to enable further biochemical and immunological evaluation of iso-dityrosine as a potential biomarker and mechanistic contributor to LBD pathology.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
4-24-2026