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Title
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Design, synthesis, and anti-tumor activities of benzopolysulfane compounds that mimics a tunicate-derived natural product
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Identifier
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d_2009_2013:d96fceae13f7:11071
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identifier
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11304
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Creator
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Mahendran, Adaikapillai,
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Contributor
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ALEXANDER GREER
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Date
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2011
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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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Organic chemistry | Pharmacy sciences | ANTI-TUMOR | BENZOPOLYSULFANE | PEGylation | pentathiepin | solubility | Synthesis
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Abstract
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Benzopolysulfanes are untapped potential therapeutic compounds, which possess an impressive array of biological activities. By developing an entirely new class of compounds (polysulfanes) drug resistance can be evaded due to the lack of exposure of organisms to these compounds. However, polysulfanes are challenging compounds to prepare, and usually have very poor water-solubility. New synthetic methods and studies on solubility and cell-directed delivery are needed to explore the range of possibilities of this novel class of compounds. This thesis outlines (1) synthesis and biological activities of benzopolysulfane conjugates namely, PEGylated benzopoylsulfanes; and (2) mechanistic aspects on mode of introduction of sulfur atom to the catechol core;;Benzopolysulfanes, 4-CH3(OCH2CH2) 3NHC(O)-C6H4-1,2-Sx (x = 3-7, and 9) were synthesized with a PEG group attached through an amide bond and examined for water solubility, antitumor activity, and propensity to equilibrate and desulfurate. LCMS and HPLC data show the PEG pentasulfane ring structure predominates, and the tri-, tetra-, hexa-, hepta-, and nonasulfanes were present at very low concentrations. The presence of the PEG group improved water solubility by 50-fold compared to the unsubstituted benzopolysulfanes, C 6H4Sx (x = 3, 5, and 7), based on intrinsic solubility measurements. Polysulfur linkages in the PEG compounds decomposed in the presence of ethanethiol and hydroxide ion. The PEG pentathiepin desulfurated rapidly and an S3 transfer reaction was observed in the presence of norbornene, no S2 transfer reaction was observed with 2,3-dimethylbutadiene. The antitumor activities of the PEG-substituted benzopolysulfane mixtures were analyzed against four human tumor cell lines PC3 (prostate), DU145 (prostate), MDA-MB-231 (breast), and Jurkat (T-cell leukemia). The PEG conjugated polysulfanes had IC50 values 1.2-5.8 times lower than the parent "unsubstituted" benzopolysulfanes. Complete cell killing was observed for the PEG polysulfanes with 4 microM for PC3 and DU145 cells, and with 12 microM for MDA-MB-231 cells. The results suggest that solubilization of the polysulfur linkage is a key parameter to the success of these compounds as drug leads.;A mechanism is proposed for the formation of cyclic 5,6,7,8,9-pentathiabenzo-cycloheptene-1,2-diol, 4, from the reaction of o-benzoquinone with reduced elemental sulfur, H2Sx. 1,6-Conjugate addition to the quinone is favored over 1,4-conjugate addition. Hydrogen bonding to the quinone oxygen enhances the nucleophilicity of H2Sx by facilitating the removal of the S-H proton. We propose that initially formed 3-polysulfidobenzene-diol intermediates, 5, are oxidized to their corresponding quinones, 13, and closure of the polysulfur ring subsequently takes place at the C3-C4 bond leading to 4. A possible mechanism for the formation of pentasulfur linkage in 4 is discussed, which the key moiety is found in a number of natural products.
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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
