Carbohydrates as Scaffolds For Bioactive Agents
Item
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Title
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Carbohydrates as Scaffolds For Bioactive Agents
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Identifier
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d_2009_2013:bf7a02b047c6:11193
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identifier
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11649
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Creator
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Bachan, Stewart,
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Contributor
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David R. Mootoo
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Date
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2012
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biochemistry | Organic chemistry | acetogenin | Carbohydrates | cytotoxicity | GalCer | HIV | metathesis
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Abstract
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Carbohydrates are attractive templates for drug design because of their accessibility, highly functionalized structures and rich synthetic chemistry. The goal of this research was to design mimetics of two classes of biologically interesting molecules using carbohydrate scaffolds. These are beta-D-galactosylceramide (GalCer) and the tetrahydrofuran (THF) containing AAs.;The emergence of multi-drug resistant (MDR) strains of HIV-1 has created a need for new therapeutic agents. The glycolipid GalCer has been shown to be a cofactor in HIV-1 infection as it mediates the binding of the HIV envelope protein gp120 in CD4+ cells. Mimics of GalCer can serve as potential entry inhibitors of HIV-1. 1,1-Linked galactose-mannose (Gal-Man) and glucose-mannose (Glu-Man) disaccharides with an ester on the Man subunit were found to bind to the V3 loop peptide of gp120 and inhibit HIV infectivity in single round infection assays with the TZM-b1 cell line (a derivative of the HeLa cell line that express CD4, CXCR4, and CCR5). IC50 values were in the 50 micromolar range with no toxicity to the cells at concentrations up to 200 micromolar. These compounds appear to inhibit virus entry at early steps in viral infection since they were inactive if added post viral entry. Although these compounds were found to bind to the V3 loop peptide of gp120, it is not clear that this interaction is responsible for their anti-HIV activity because the binding affinity of closely related analogs did not correlate with their antiviral behavior. The low cytotoxicity of these 1,1-linked disaccharide fatty acid esters, combined with their easy accessibility to structurally diverse analogs, make these molecules attractive leads for new anti-viral agents.;The THF-containing AAs have drawn much attention because of their potent antitumor activities. Their mode of action involves the inhibition of the NADH: ubiquinone oxidoreductase, Complex 1, of the mitochondrial electron transport chain. Their generally high cytotoxicity to both normal and tumor cells has hampered their development as anti-cancer agents. Thus acetogenin analogs that show increased specificity towards cancer cells are of interest as new therapeutic agents. Acetogenin analogs in which the THF core was replaced with either a monosaccharide or disaccharide framework were synthesized and evaluated against various cancer cell lines. The monosaccharide analogs showed antitumor activity in the low micromolar range and were generally more active than their disaccharide counterparts. It is also noteworthy that varying the degree of oxygenation on the monosaccharide ring did not show any significant effect on cytotoxicity. These structure activity observations open up possibilities for the design of tumor selective monosaccharide analogs that target carbohydrate receptors that are overexpressed on tumor cells.
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Type
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dissertation
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Source
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2009_2013.csv
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degree
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Ph.D.
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Program
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Chemistry
