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Chemical synthesis and biological evaluation of circular, branched and lariat oligonucleotidesCarriero, Sandra January 2003 (has links)
This thesis highlights novel synthetic routes towards the facile synthesis of lariat DNA and RNA oligonucleotides, and the utilities of branched (bNAs) and circular (i.e. dumbbell-shaped) nucleic acids for targeting biologically relevant processes (i.e. HIV proliferation, alternative RNA splicing) with potential therapeutic applications. / An innovative synthetic strategy for the synthesis and cyclization of a medium-sized (21-nucleotide) DNA lariat starting from a CPG-tethered, convergently synthesized branched DNA (bDNA) molecule was devised in Chapter 2. This synthetic route exploited the differential cleavage rates of two CPG-oligonucleotide tethers, namely the base-labile hydroquinone-O,O'-diacetate (Q-linker) and the more robust succinate (S-linker ) linkages, as well as phosphitylation of the 5'-oligonucleotide terminus and cyclization under standard phosphoramidite coupling conditions to effect new phosphodiester bond construction. The results clearly indicate a disadvantageous correlation between high branching efficiency on a densely loaded CPG and the production of dendrimeric (i.e. hyperbranched) oligonucleotide species rather than effective cyclization. / Given the entropic disadvantage of synthesizing medium-sized DNA lariats on solid-support using the method described in Chapter 2, unique intermolecular (i.e. DNA dumbbells) and intermolecular template-mediated approaches for lariat cyclization commencing with convergently and divergently synthesized bDNAs and bRNAs were developed in Chapter 3. Both methods lead to the exclusive and high-yielding formation of medium sized (46--57 nucleotides) DNA and RNA lariats. Parameters for successful phosphodiester bond construction were also elucidated in both systems. / A novel class of highly specific and potent oligonucleotide-based HIV-1 reverse transcriptase inhibitors, RNA dumbbells, comprising of a 10 base-pair stem and two flanking UUCG hairpin-loop motifs are described in Chapter 4. Explicitly, such constructs were capable of selectively hampering the RNase-H mediated activity of the retroviral enzyme without consequence to its DNA polymerase function with an IC50 in the 3 muM range. Its precise interaction with the RNase H domain of RT was authenticated via a UV-crosslinking assay. Furthermore, the RNA dumbbells did not inflict any effect on mammalian RNase H activity, suggesting that such compounds would not obstruct cellular RNase H function. / Chapter 5 describes the utility of synthetic bRNA for the inhibition and modulation of pre-mRNA splicing in yeast and mammalian in vitro systems. Most notably, synthetic bNAs can be suitably exploited as agents for the study of branchpoint recognition during in vitro splicing of a pre-mRNA transcript. The results clearly indicate the requirement for a fully formed branchpoint (i.e. 5 '-, 2'- and 3'-extensions; Y-shaped molecules) off the conserved branchpoint adenosine for efficient splicing inhibition. Specific methods for stabilizing bNAs against ubiquitous cellular exo- and endonucleases as well as the 2'-scissle (2'-debranching) activity present in the HeLa extract milieu are also described.
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Pseudo-dynamic combinatorial libraries : a receptor-assisted combinatorial chemistry approach to drug recoveryCheeseman, Jeremy D. January 2004 (has links)
Emerging methods of combinatorial chemistry involve receptor assistance to combine synthesis and screening. Binding to the receptor alters either the thermodynamics or kinetics of synthesis. Dynamic combinatorial chemistry uses reversible synthesis where binding to the receptor shifts the equilibrium to make more of the best binders. In target-accelerated synthesis, binding of the starting materials to the receptor speeds up the synthesis of the best-binding compounds. We report a new receptor-assisted method---pseudo-dynamic combinatorial chemistry---where binding to a receptor slows the destruction of the best-binding compounds. In pseudo-dynamic libraries, synthesis and destruction of library members are separate, irreversible reactions. Extending the destruction reaction amplifies binding differences similar to a kinetic resolution of enantiomers. Initial libraries of two to eight dipeptides, some containing an aryl sulfonamide moiety that binds to carbonic anhydrase, showed that a ratio of >100:1 of the best binding dipeptide over the next best was possible. These experiments also suggested that the selectivity is related to the number of compounds in a library, with more library members producing higher selectivity (a highly desirable result opposite that seen in traditional dynamic libraries). Expansion of these libraries to include compounds containing sulfonamides, aryl sulfonamides, sulfamates and hydroxamic acids further support postulations as to the origins of the high selectivity of these systems, and take the number of compounds screened by a pseudo-dynamic library closer to practical levels for drug discovery.
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Application of the [2,3] Wittig rearrangement to synthetic studies toward the total synthesis of (+)-discodermolideLiang, Guohua. January 2007 (has links)
Thesis (Ph. D.)--Syracuse University, 2007. / "Publication number AAT 3266298."
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Discovery and characterization of small molecule inhibitors of biofilm formation in Pseudomonas aeruginosa /Musk, Dinty Joe, January 2006 (has links)
Thesis (Ph. D.)--University of Illinois at Urbana-Champaign, 2006. / Source: Dissertation Abstracts International, Volume: 68-02, Section: B, page: 0980. Adviser: Paul J. Hergenrother. Includes bibliographical references (leaves 110-121). Available on microfilm from Pro Quest Information and Learning.
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Development of a diastereoselective [4+2]-annulation of vinyl carbodiimides with chiral N-alkyl imines and its application to the synthesis of the batzelladine alkaloids : total synthesis of (+)-batzelladine A and ( - )-batzelladine D /Arnold, Michael A., January 2007 (has links)
Thesis (Ph. D.)--University of Illinois at Urbana-Champaign, 2007. / Source: Dissertation Abstracts International, Volume: 68-11, Section: B, page: 7342. Adviser: David Y. Gin. Includes bibliographical references. Available on microfilm from Pro Quest Information and Learning.
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The development of new carbon-nitrogen bond forming reactions towards the synthesis of mitomycin C /Williams, Amie L. January 2004 (has links)
Thesis (Ph.D.)--Indiana University, Dept. of Chemistry, 2004. / Title from PDF t.p. (viewed Nov. 10, 2008). Source: Dissertation Abstracts International, Volume: 67-02, Section: B, page: 0900. Adviser: Jeffrey N. Johnston.
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Chemistry under the sea: Secondary metabolites from marine sponges of Papua New GuineaWegerski, Christopher John. Unknown Date (has links)
Thesis (Ph. D.)--University of California, Santa Cruz, 2007. / (UMI)AAI3265741. Source: Dissertation Abstracts International, Volume: 68-05, Section: B, page: 3063. Adviser: Joseph P. Konopelski.
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I. Total synthesis of stemonine. II. Studies towards the total synthesis of kendomycinShamim, Khalida. January 2006 (has links)
Thesis (Ph. D.)--Indiana University, Dept. of Chemistry, 2006. / Title from PDF t.p. (viewed Nov. 18, 2008). Source: Dissertation Abstracts International, Volume: 67-12, Section: B, page: 7099. Adviser: David R. Williams.
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Progress toward the total synthesis of the Lycopodium alkaloid, (+)-serratezomine APigza, Julie Alana. January 2008 (has links)
Thesis (Ph. D.)--Indiana University, Dept. of Chemistry, 2008. / Title from PDF t.p. (viewed May 13, 2009). Source: Dissertation Abstracts International, Volume: 69-08, Section: B, page: 4762. Adviser: Jeffrey N. Johnston.
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Chiral proton catalysis design and development of enantioselective aza-Henry and Diels-Alder reactions /Yoder, Ryan A. January 2008 (has links)
Thesis (Ph. D.)--Indiana University, Dept. of Chemistry, 2008. / Title from PDF t.p. (viewed May 14, 2009). Source: Dissertation Abstracts International, Volume: 69-09, Section: B, page: 5420. Adviser: Jeffrey N. Johnston.
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