Date of Award
December 2023
Degree Type
Thesis
Degree Name
Master of Science
Department
Chemistry
First Advisor
Alexander E Arnold
Committee Members
Shama P Mirza, Xiaohua Peng, Chris Cunningham
Abstract
PART 1: The GABAA receptor is a pentameric, ligand-gated ion channel which plays a major role in inhibition of the central nervous system. Recent reports have identified GABAAR subunits expression on non-CNS cells such as smooth muscle cells, epithelial cells, and immune cells. Allosteric ligands that bind GABAARs in the presence of gamma-aminobutyric acid (GABA), the endogenous ligand of GABAARs, have been shown to elicit smooth muscle relaxation and anti- inflammatory properties. This includes benzodiazepines, such as asthma drug candidate MIDD0301 which has no measurable CNS effects. The anti-inflammatory effects mediated by GABAARs can prove useful in the treatment of several inflammatory diseases, such as inflammatory bowel disease (IBD). PI320, an analog of drug candidate MIDD0301, was developed which contains a polyethylene oxide substituent to elicit topical effects, which was demonstrated with the improvement of airway function in bronchoconstrictive disorders by inhaled application. The synthesis of novel analogs of PI320 are presented. Derivatizations using varying lengths of (PEG)x-NH2 reagents in the presence of HBTU as a coupling agent were utilized. Compound structures were verified using 1H-NMR and 13C-NMR spectroscopy.
PART 2: Palladium catalyzed reactions have become prominent reactions for creating C-C and C- heteroatom bonds. These types of reactions are widely applicable in areas including pharmaceutical synthesis. Recently, Millipore Sigma has developed a novel class of unsymmetrical ferrocene ligands and corresponding palladium complexes, referred to as Mphos. Using these ligands in palladium catalysis, several amino carbonylation reactions were performed to couple amines and aryl halides in the presence of chloroform and base. The coupling of these compounds was completed using well-known palladium complexes as well as various novel Mphos palladium complexes. Reaction completion was monitored via GC-MS and LC-MS. Chromatography conditions were extensively optimized for the separation of reagents and products. Results showed successful reaction conversion when applied to aryl iodides and aryl bromides but was unsuccessful when applied to aryl chlorides. Multiple benzodiazepines containing an aryl bromide were tested for coupling with various amines. Little to no conversion was observed in amino carbonylation reactions for the tested benzodiazepines. Finally, Buchwald-Hartwig reactions were explored with these novel palladium ligands and various aryl halides. The results showed the novel class of Mphos ligands supported the successful reaction between basic aryl bromides and aryl bromide containing benzodiazepines. The reaction was unsuccessful when applied to aryl bromide containing imidazobenzodiazepines.
Recommended Citation
Lee, Maija, "PART 1: SYNTHESIS OF BENZODIAZEPINES AS GABAAR POSITIVE MODULATORS TO TREAT INFLAMMATORY BOWEL DISEASE. PART 2: UNSYMMETRICAL FERROCENE LIGANDS IN PALLADIUM CATALYZED SYNTHESIS USING ARYL HALIDES" (2023). Theses and Dissertations. 3416.
https://dc.uwm.edu/etd/3416