Advances in combinatorial chemistry have facilitated the production of large chemical libraries that can be used as tools to discover biological probes and therapeutics. High-throughput screening (HTS) strategies have emerged as the standard method to assess the biological activity of small molecules. These screens involve the individual analysis of each small molecule in multi-well plates, often requiring expensive automated methods and development of robust assays that may not translate to physiologically relevant contexts. This problem of evaluating large numbers of reagents in physiologically relevant cell and animal models has been addressed for genetic reagents such as RNAi, CRISPR, and cDNA by creating barcoded retroviral libraries that can be used to infect target cells in culture or in animal models. Using these tools, effective reagents can be selected and decoded using a rapid and inexpensive procedure compared to testing of individual reagents one at a time in an arrayed fashion. In order to more efficiently analyze small molecules, a pooled approach would similarly be useful. This dissertation describes the studies towards developing a pooled screening strategy for small molecules in cellular contexts. Through an initial screen, we set to phenotypically profile small molecule biological activity in a pooled fashion, while simultaneously gain insight about an individual, active molecule’s mechanism of action. I first describe the design of the pooled screen and define the goals necessary for successful application. Next, I outline the steps taken and challenges encountered during the invention of each component of the technology. Finally, I discuss a computational, target-based approach to design small molecules appropriate for future applications of the new screening technology.

Bibliography: leaves 71-79. Almost 80 percent of plant taxa develop vesicular-arbuscular mycorrhizae (VAM) which are symbiotic associations between plant roots and soil fungi. The fungi are biotropic-obligate symbionts. Identification of VAM fungi is currently based on spore characteristics. Molecular techniques provide tools for better and more accurate identification of species, as well as for the examination of genetic variability occuring between individual spores of a single species.

Thesis (Ph.D.)--Virginia Commonwealth University, 2009. / Prepared for: Dept. of Medicinal Chemistry. Title from title-page of electronic thesis. Bibliography: leaves 141-177.

Thesis (Ph.D. (Biochemistry, Microbiology & Biotechnology)) - Rhodes University, 2008.

Thesis (Ph. D.)--University of Missouri-Columbia, 1997. / Typescript. Vita. Includes bibliographical references (leaves 179-191). Also available on the Internet.

Thesis (Ph. D.)--University of Missouri-Columbia, 1997. / Typescript. Vita. Includes bibliographical references (leaves 179-191). Also available on the Internet.

Thesis (Ph. D.)--University of California, Riverside, 2009. / Includes abstract. Available via ProQuest Digital Dissertations. Title from first page of PDF file (viewed March 10, 2010). Includes bibliographical references. Also issued in print.

Thesis (Ph. D.)--Ohio State University, 2009. / Title from first page of PDF file. Includes vita. Includes bibliographical references (p. 112-122).

While providing non-invasive tissue detection, magnetic resonance imaging (MRI) presently possesses limited sensitivity for protein target recognition. This limitation was addressed for the target beta-galactosidase (beta-gal) by constructing three beta-gal-specific MRI probes. The probes are based on a bipartite design in which a vasoactive moiety known as a diazeniumdiolate (NONOate) is bound to a specifier, specifically galactose. Upon galactose' interaction with beta-gal, the NONOate is cleaved from galactose, and actively generates nitric oxide (NO). The released NO leads to microvascular permeability changes in surrounding tissues affecting localized T1 measurements. These changes serve as a quantitative index of beta-gal detection. The three beta-gal-specific NO-releasing probes constructed include GALPYRNONO, GALPIPNONO and a 'bi-functional' probe, which is similar to the first two but with glucose additionally incorporated so that the third probe may easily cross cellular membranes. Synthesis and characterization of this novel class of MRI probes are described in this work. / Keywords: non-invasive detection, magnetic resonance imaging (MRI), nitric oxide (NO), diazeniumdiolates (NONOates), NO-releasing compounds, novel MRI probes, molecular targets, protein targets, specifier, vasoactive, vasodilation, microvascular permeability, tissue localization, bipartite systems, bifunctional probes, blood-brain barrier, cell membrane trafficking, saccharide-bound NONOates, sugar diazeniumdiolates, glycosylated diazeniumdiolates, galactose, beta-galactosidase, glucose, glucose transporters, thermal & photolytic degradation, half-life optimization, Griess test, rat serum, stability.

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