Thesis (Ph. D.)--Ohio State University, 2004. / Title from first page of PDF file. Document formatted into pages; contains xiii, 195 p.; also includes graphics Includes bibliographical references (p. 177-195). Available online via OhioLINK's ETD Center

Thesis (Ph. D.)--Ohio State University, 2004. / Title from first page of PDF file. Document formatted into pages; contains xiii, 196 p.; also includes graphics (some col). Includes abstract and vita. Advisor: Robert W. Bruegemeier, Dept. of Pharmacy. Includes bibliographical references (p. 176-196).

The drawbacks of nonactin, the current commercial standard receptor for ammonium ion necessitate the development of new ammonium ionophores. We have designed and attempted to synthesize fluoroionophores, I- III. Molecular modeling of I suggests superior selectivity over that of nonactin. III was synthesized as a selective ionophore for optical detection of ammonium ion. The synthetic strategies for III are two-fold: solid phase and solution phase. Solution phase synthesis was performed with two different protecting groups (t-butyl ester and benzyl ester). A methyl-amino substituted anthracene molecule will be covalently coupled to the secondary amine group to provide an optical signaling moiety that operates on the basis of an“off-on" fluorescence emission mechanism. Compound IV was also synthesized in order to provide a sample reaction for the covalent coupling of the chromophore and to provide a fast route to an ammonium fluoroionophore.

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Le développement de composés permettant le passage de molécules à travers la membrane cellulaire constitue un domaine de grand intérêt de la chimie et de la biochimie. Certaines maladies, comme la fibrose kystique, sont le résultat d'un dysfonctionnement du transport d'ions chlorure et bicarbonate à travers la bicouche lipidique. Ces dernières années, de nouvelles familles de transporteurs synthétiques ont fait leur apparition comme solution de remplacement aux transporteurs naturels. Cependant, la synthèse de systèmes supramoléculaires permettant le transport de larges molécules de part et d’autre de la bicouche lipidique reste, quant à elle, un défi. Ainsi nous présentons dans cette thèse deux systèmes différents: l’un permettant le transport d’ions chlorures et le second capable de combiner transport anionique et transport de macrocycles biologiquement actifs. Dans un premier temps, nous avons étudié le potentiel ionophore d’un dérivé benzimidazole. Des études mécanistiques ont été menées sur le 2,4,7-triphénylbenzimidazole afin de déterminer son mode d’assemblage dans la membrane phospholipidique, responsable de son efficacité à transporter les anions. Basé sur ces résultats, des analogues de cette molécule possédant des sites de complexation métallique ont été synthétisés afin d’augmenter l’efficacité de ces transporteurs benzimidazole et de contrôler leur auto-assemblage. Ces complexes ont été testés dans des membranes bactériennes afin d’étudier leur capacité à inhiber la croissance des bactéries et à diminuer la tolérance d’une souche bactérienne résistante envers les antibiotiques. Dans le second volet de cette thèse, nous avons étudié l’utilisation de dérivés parapluies capables de changer de conformation dépendamment de la polarité du solvant, pour le transport d’anions et de macrocycles. La synthèse et la caractérisation d’un nouvel axe et son dimère parapluie sont rapportées dans cette partie. Leur capacité à transporter les anions à travers la membrane des liposomes ou leur insertion dans des membranes bactériennes ont été étudiées. Les premiers essais de synthèses de rotaxanes à partir de ces dérivés parapluies pour le transport de macrocycle biologiquement actif sont rapportés. / The development of compounds able to transport molecules through cellular membranes is an emerging area of chemistry and biochemistry. Several diseases, such as cystic fibrosis, are the result of a dysfunction of chloride and bicarbonate transport across cellular membranes. In the last few years, new families of synthetic transmembrane transporters were developed in order to restore chloride transport. However, the synthesis of supramolecular systems for the transport of large molecules from one side to the other one of the lipid bilayer remains a challenge. Herein we present two different systems: one for chloride transport and a second one that combines the transport of ions and biologically active macrocycles through cellular membranes. We first present the anionophoric potential of benzimidazole derivatives. Mechanistic studies were conducted on 2,4,7-triphenylbenzimidazole to determine its self-assembly in a phospholipid membrane and its capacity to transport anions. Two analogues possessing metal coordination sites were also developed and studied for their anion transport properties, as well for the formation of metal-organic assemblies. These complexes were studied in bacterial membranes for their ability to inhibit bacterial growth and to reduce the tolerance of a resistant strain to antibiotics. In the second part of this thesis, we present the use of umbrella compounds that are able to change their conformation depending on the polarity of the environment. The synthesis and characterization of a new umbrella thread and its dimer are reported in this section. Their ability to transport anions through liposomal membranes or their insertion into more complex bacterial membranes are studied. The first attempts to assemble rotaxanes with the umbrella compounds and an active macrocycle are presented.