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Item Diethyl zinc mediated intramolecular metalloamination of N,N-dimethylhydrazines: expanding a novel approach to functionalized pyrrolidines and piperidines. Utilizing synthesis as a tool for medicinal chemistry, environmental remediation, and nonlinear optical chromophore construction(Montana State University - Bozeman, College of Letters & Science, 2017) Mickelsen, Ky James; Chairperson, Graduate Committee: Thomas S. Livinghouse; Dissertation contains an article of which Ky James Mickelsen is not the main author.; Sean Zabawa and Tom Livinghouse were co-authors of the article, 'Diethylzinc mediated metalloamination-alkylation of N,N-dimethylhydrazinoalkenes. Catalysis of carbon-zinc alkylation using simple copper(I) salts' in the journal 'Synlett' which is contained within this thesis.When attempting to develop a novel material for increased second-order nonlinear activity, a strategy was devised to rationally design an architecture that would allow for optimized acentric supramolecular organization. By coupling a liquid crystal tolane to a well-understood NLO chromophore via strategic synthesis, a set of novel chromophores was created. The ferroelectric liquid crystal-like molecules intrinsically favor unidirectional chromophore order while simultaneously containing a high beta chromophore along the polar axis. This system has shown potential for high terminal stability as well as increased nonlinear optical susceptibilities. Carbon tetrachloride poses a large threat to the environment and is the focus of ongoing remediation efforts. It is a well-known carcinogenic pollutant that has contaminated groundwater beneath former grain storage and industrial sites, such as the Department of Energy's Hanford site. Remediation through the use of a small molecule, PDTC, when complexed with copper has been shown to lead to complete dechlorination, resulting in conversion to non-toxic end-products (mostly CO 2) and complete removal of the problematic carbon-chlorine bonds. Synthetic chemistry was employed to develop a modified procedure for large-scale production of PDTC that eliminates harmful byproducts and excess toxic reagents used. Additionally, structural derivatives for increased water solubility have been envisaged from citrazinic acid, which could allow for aqueous destruction of carbon tetrachloride. In medicinal and pharmaceutical chemistry, routes to nitrogenous heterocycles are of great importance due to their prevalence in bioactive molecules. Diethylzinc mediated metalloamination/cyclization of unsaturated N,N-dimethylhydrazines with subsequent electrophilic functionalization could prove to be a powerful tool for constructing pyrrolidines and piperidines. This method was extended to the use of 1,2-disubstituted alkenes as N-Zn migratory insertion acceptors, including various vinylcyclopropyl hydrazines. The potential behind the irreversible cyclopropane scission and development of a new alkene make this class of substrates extremely desirable. The metalloamination-alkylation of N,N-dimethylhydrazinoalkenes was shown to be effectively catalyzed by CuBr x SMe 2, CuCN and CuI. This novel method obviates the prior methodology involving use of stoichiometric CuCN(LiCl) 2 as a promoter for the electrophilic functionalization.Item Glycodendrimer mediation of galectin-3 cancer processes and indium(III) as a glycosylation promoter(Montana State University - Bozeman, College of Letters & Science, 2014) Michel, Anna Kaczmarek; Chairperson, Graduate Committee: Mary J. CloningerGalectin-3 is a carbohydrate-binding protein that is found inside and at the surface of most healthy cells, where it plays a role in cellular differentiation, proliferation, and death. Galectin-3 is also overexpressed in many forms of cancer, where it interacts with beta-galactosides on the surface of the transmembrane protein Mucin 1 (MUC1), which is also upregulated in many cancers. The interaction between MUC1 and galectin-3 leads to enhanced tumor formation, invasion, and metastasis. Glycodendrimers were synthesized and used as tools to probe the galectin- 3/MUC1 mediated cancer cellular aggregation. Cellular aggregation assays were designed and performed using three different cancer cell lines. Results indicate that cellular aggregation can either be inhibited or intensified depending on the size of the dendrimer and on the number of carbohydrate endgroups present. Confocal micrographs of cancer cells confirm that the pattern of galectin-3 on the outside of the cell is altered in the presence of glycodendrimers. These finding indicate that glycodendrimers mediate cellular aggregation properties, giving insight into the mechanism of action. The results also establish glycodendrimers as potential targeting agents and prodrug delivery systems when considering cancer drug design. A dendrimer bearing a matrix metalloproteinase (MMP) substrate was synthesized to explore dendritic potential as drug delivery systems. Results show that the substrate can be cleaved from the dendrimer when incubated with cancer cells known to overexpress MMP, indicating a potential for glycodendrimers as a prodrug carrier. A novel method for glycosylation was also explored. Indium(III) provides many advantages over standard glycosylation promoters (such as BF 3 x OEt 2) in that it is not air-or water-sensitive, and there is no need for additional purification of In(III) before use. Carbohydrate donors with a variety of protecting groups were tested against a range of glycosyl acceptors, including a carbohydrate. Results show that using In(III) as a glycosylation promoter gives comparable yields in less time when compared to a common glycosylation promoter.Item Putting Tuberculosis (TB) To Rest: Transformation of the Sleep Aid, Ambien, and “Anagrams” Generated Potent Antituberculosis Agents(2014-12) Moraski, Garrett C.; Miller, Patricia; Bailey, Mai Ann; Ollinger, Juliane; Parish, Tanya; Boshoff, Helena I.; Cho, Sanghyun; Anderson, Jeffery; Mulugeta, Surafel; Franzblau, Scott G.; Miller, Marvin J.Zolpidem (Ambien, 1) is an imidazo[1,2-a]pyridine-3-acetamide and an approved drug for the treatment of insomnia. As medicinal chemists enamored by how structure imparts biological function, we found it to have strikingly similar structure to the antitubercular imidazo[1,2-a]pyridine-3-carboxyamides. Zolpidem was found to have antituberculosis activity (MIC of 10–50 μM) when screened against replicating Mycobacterium tuberculosis (Mtb) H37Rv. Manipulation of the Zolpidem structure, notably, to structural isomers (“anagrams”), attains remarkably improved potency (5, MIC of 0.004 μM) and impressive potency against clinically relevant drug-sensitive, multi- and extensively drug-resistant Mtb strains (MIC < 0.03 μM). Zolpidem anagrams and analogues were synthesized and evaluated for their antitubercular potency, toxicity, and spectrum of activity against nontubercular mycobacteria and Gram-positive and Gram-negative bacteria. These efforts toward the rational design of isomeric anagrams of a well-known sleep aid underscore the possibility that further optimization of the imidazo[1,2-a]pyridine core may well “put TB to rest”.