Date of Completion

1-6-2017

Embargo Period

1-6-2017

Major Advisor

Smith, Michael

Associate Advisor

Peczuh, Mark

Associate Advisor

Neth, Edward

Associate Advisor

Nichols, Frank

Associate Advisor

Brueckner, Christian

Field of Study

Chemistry

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Mankind’s greatest attribute is the capability of higher order intellect being applied to prolonging life and improving one’s overall health. Modern medicine and the research therein has created opportunities to understand and combat disease at incredible levels. Yet, some of the most befuddling diseases are ones that our own bodies inheritably produce. Autoimmune disease is a condition in which the body’s own defense mechanisms begin to target healthy cells as if they were foreign threats. Cancer is a condition in which abnormal cell growth can spread throughout the body and begin to shut down vital bodily functions. Medicinal chemistry has difficulty combating and understanding such diseases due to the fact that intervention targets of the disorders are derived from human anatomy. The research presented within aims to aid in the scientific understanding of the two diseases discussed.

Part I: Lipids isolated for Porphyromonas gingivalis have been recently implicated in possible development and/or progression of multiple sclerosis. The lipids are produced in bacteria, which are found throughout the GI track, and are shown to invade into the body. First, this study is intended as a structural proof and stereochemical elucidation of the proposed lipid compounds labeled lipid 430 and 654. Second, synthesis of stereochemically pure material is needed for further biological testing to establish a greater understanding of disease implications. We present the details of the convergent synthesis of lipids 430 and 654, which confirm the proposed structure of P. gingivalis lipid 654 to be (3R and 3S)-L-serine. The bis(fatty acid) (3R)-L-serine 2 was prepared as well as the synthetic precursor, serine dipeptide mono-fatty acid (3R)-L-serine 1, which is the structure of lipid 430. We also synthesized the (3S)-L-serine diastereomer 2 as well as (3S)-L-serine 1. Using these synthetic standards, we confirmed that phospholipase A2 (PLA2)-mediated hydrolysis of lipid 654 is enantioselective in that only the (3R)-L-serine 2, but not (3S)-L-serine 2 is enzymatically hydrolyzed.

Part II: Cancerous tumors have been shown to have a hypoxic microenvironment that creates resistance to radiation therapy and ineffectiveness of common chemotherapy drugs. There is a need for improved noninvasive imaging techniques that detect hypoxic tumors and monitor the effects of administered cancer treatments. To do this we have synthesized hypoxic targeting fluorescence probes derived from FDA approved Indocyanine green dye to be used for optical imaging. Extending our previous work with 2-nitroimidazole-piperazine-indocyanine dye-conjugate 3, we prepared the 4-nitroimidazole-piperazine-indocyanine derivative 12. We also prepared imidazole derivative 14 as a control. We compared the in vivo hypoxia targeting performance of both with the previously tested 2-nitro dye conjugate, and the 4-nitro derivative showed a higher fluorescent intensity after 15 min post-injection. All findings were supported with fluorescence images of histological sections of tumor samples an immunohistochemistry technique for tumor hypoxia. New generations of the dyes are being created to increase the efficiency of the imaging technique.

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