Title

Part I: Total Synthesis of Novel Dihydroceramids from the Dental Pathogen Porphyromonas gingivalis Part II: Application of Conducting Polymers as Green-Chemistry Reagents in Organic Reactions Part III: Synthesis of Imidazole-Indocyanine Green Conjugates

Date of Completion

January 2011

Keywords

Chemistry, Organic|Chemistry, Polymer

Degree

Ph.D.

Abstract

Part I: Porphyromonas gingivalis is a known periodontal pathogen that produced four classes of novel dihydroceramides with biological activity ranging from inducing pro-inflammatory responses to gingival tissue and bone degeneration. It has been shown that these compounds are capable of induction of multiple sclerosis in mice model systems. GCMS and NMR analysis of these active compounds revealed that a mixture of dihydroceramides existed whose composition was dihydrosphinganine base with an amide linkage to a β-hydroxy fatty acid. The dihydrosphinganine portion contained two stereocenters, odd-carbon chains (C17 and C19), and a terminal isobranch moiety. The β-hydroxy fatty acid had a chain length of C17, a single stereocenter and a terminal isobranch. Due to the complexity of the lipid extracts we have not been able to isolate individual lipid components in pure form, directly from P.gingivalis by using chromatographic method, making their synthesis essential. Apart from the synthesis and verification of the structure, our work is focused on determining the absolute and relative stereochemistry of the most active dihydroceramide. ^ Part II: Conducting polymers are rarely thought of as chemical reagents that promote chemical transformations. Poly(3,4-ethylenedioxythiophene) or PEDOT and Polypyrrole (PP) are some of the most widely used conducting polymers and can be prepared via oxidative chemical using FeCl3 or electrochemical polymerization with a triflate counterion. Chemical reactions induced by PEDOT and PP alone have not been reported prior to our work. The commercial importance of PEDOT, along with the ease of preparation and handling, stability to air and solvents, and its conductive properties led us to choose it for our studies.^ Work in our laboratory disproves the common assumption of chemical inertness by showing that these polymers are capable of facilitating a variety of chemical reactions. Upon exposure to PEDOT or polypyrrole, alcohols are converted to ethers or undergo Friedel-Crafts alkylation. Polyols and ketohexoses undergo cyclodehydrations, dienones undergo Nazarov cyclization, 1,2-diols go through Pinacol rearrangements, and acid-sensitive alcohol and ketone protecting groups can be removed. Their use as a chemical reagent in organic reactions has proved to not only generate equivalent yields when compared to standard literature precedent but also able to complete reactions previously inaccessible by conventional methods.^ Part III: Cancerous solid tumors generate a specific environment that are characterized by a low oxygen partial pressure and low pH. This microenvironment is recognized as a critical factor that makes conventional anti-cancer treatment ineffective while also rapidly advancing the malignant progression. This condition is known as tumor hypoxia. Currently non-invasive imaging methods include Magnetic Resonance Imaging (MRI) and Positron emission tomography (PET). The issue with these methods is the large expense and short half-life of radioactive isotopes required for imaging that is required during chemotherapy treatment. Hence a new, non-invasive, lost cost method to repeatedly monitor changes to hypoxia tumor size and characteristics is an attractive goal. Near-infrared (NIR) fluorescence diffuse optical tomography (FDOT) is low-cost and highly effective technique used to image tumors. However the technique is dependent on an internal fluorochrome to generate a fluorescent signal. Our goal was to combine a biologically safe fluorescent dye (indocyanine green), that could be easily detectable by a topical imaging probe, with a molecule which has an affinity for low-pH, hypoxic areas (2-nitroimidazoles). This involved the formation these new indocyanine green dye conjugates that would specifically target hypoxic tumor and supply imaging at that site. Our work synthesized four generations of dye conjugates with each subsequent generation improving on the previous.^