1 |
A novel iterative reducible ligation strategy for the synthesis of homogeneous gene delivery polypeptidesEricson, Mark David 01 December 2012 (has links)
The ability to safely delivery efficacious amounts of nucleic acids to cells and tissues remains an important goal for the gene therapy field. Viruses are very efficient at delivering DNA, but safety concerns limit their clinical use. Nonviral vectors are not as efficient at DNA delivery, but have a better safety profile. Limiting the efficaciousness of nonviral vectors are the numerous extra and intracellular barriers that must be overcome for successful DNA delivery in vivo. While single polymers can successfully transfect immortalized cell lines in vitro, multicomponent gene delivery systems are required for delivery in vivo. Key in the development of multicomponent systems is their syntheses. Optimization of a nonviral gene delivery system requires the development of methodologies that incorporate the different components in a controlled fashion, generating homogeneous gene delivery vectors. Such syntheses ensure every polymer has the different components required for successful delivery. The amount of each component and location within the gene delivery system can also be varied systemically, allowing optimization of the vector.
The overall scope of this thesis is to develop a chemical method to iteratively couple gene delivery peptides through reducible disulfide bonds. The synthesis of such polypeptides allows the triggered disassembly of a polypeptide polyplexed with DNA upon cellular uptake. To synthesize homogeneous gene delivery polypeptides, a novel iterative reducible ligation strategy was developed, based upon the use of a thiazolidine masked cysteine. Initial studies demonstrated that a thiazolidine could be unmasked to a cysteine in the presence of a disulfide bond without side reaction, though the reported thiazolidine hydrolysis conditions of aqueous methoxyamine were insufficiently robust for high yielding ligations. Discovery of a novel silver trifluoromethanesulfonate hydrolysis led to an efficient process for generating reducible polypeptides, as evidenced in the synthesis of a 4 component polypeptide.
Due to the success of the thiazolidine mediated iterative ligation strategy, cysteines were replaced by penicillamines to produce more stable disulfide bonds. The mild thiazolidine hydrolysis and subsequent peptide conjugation reactions led to attempt the iterative ligation strategy on a solid support, eliminating purification steps that lowered the yields in the solution phase methodology. Initial progress at generating gene delivery peptides that could be incorporated into the synthetic strategy included the generation of a tri-orthogonal cysteine protecting scheme that allowed a third cysteine to be derivatized with a targeting ligand or stealthing polymer. Due to the use of terminal cysteines in the iterative ligation strategy, a PEG stealthing polymer could be placed in the center of a polyacridine gene delivery peptide with only a small decrease in the ability to condense and protect DNA during systemic circulation. A convergent synthesis was also developed that was able to synthesize large polypeptides in fewer linear steps. The synthetic methodology of thiazolidine mediated iterative reducible ligation developed in this thesis is important in the gene therapy field as it allows the construction of polypeptides that can be systemically optimized, potentially resulting in highly efficacious nonviral gene delivery.
|
2 |
Metal triflate catalysed organic transformationsLawton, Michelle Claire 28 October 2010 (has links)
Ph.D. / The research described in this thesis was directed at advancing the application of metal triflates, Al(OTf)3 in particular, in organic synthesis, on the one hand and to contribute to the understanding of the underlying basis for their catalytic activity. The study was undertaken against the background and on the bases of a detailed literature study of metal triflates, their chemical and catalytic properties and applications thereof. Amongst others, it deals with the possible role of metal-bound water that give rise to Brønsted type acidity and that this induced Brønsted acidity may be responsible for the catalytic activity that is observed. The study was prompted by the realisation that Al(OTf)3 was largely neglected as a potential reusable catalyst. This is in marked contrast to the attention paid to other metal triflates, the rare earth metals in particular. Earlier work in this laboratory has shown that Al(OTf)3 is stable in water from which it can be recovered easily for reuse. In addition it showed promise as a Lewis acid catalyst and is relatively soluble in several organic solvents. New applications for the use of Al(OTf)3 have now been demonstrated. These include the efficient formation of acetals from aldehydes and ketones. The conversions can be carried out in an alcohol/orthoester mixture or preferably in neat orthoester. Other metal triflates, notably Sc(OTf)3 and In(OTf)3, are useful alternative catalysts. Al(OTf)3 can be easily recycled without loss of activity. This methodology also can be applied to aldehydes and ketones containing TBDMS groups without effecting deprotection of the ethers. In view of the sensitivity of the TBDMS groups to hydrolysis in the presence of triflic acid the results suggest little hydrolysis (or alcoholysis) of the metal triflates in the protic solvents used, which would generate trifluoromethanesulfonic acid as a consequence of such metal based hydrolysis. Al(OTf)3 was also found to be a good catalyst for the formation of THP ethers. It proved to be excellent for Friedel Crafts reactions using alkynes as substrates. Al(OTf)3 together with other triflates offers a mild alternative to the more traditional water sensitive Lewis acids, e.g. BF3, AlCl3 and TiCl4, which are difficult to recover and require the use of extremely dry solvents.
|
3 |
Catalyzed Synthesis of Aromatic Esters / Katalyserad syntes av aromatiska estrarDalla-Santa, Oscar January 2019 (has links)
No description available.
|
4 |
Estudo dos parâmetros operacionais de uma célula a combustível de glicerol direto utilizando uma membrana de polibencimidazol impregnada com ácido fosfórico (PBI/H3PO4) ou 1-hexil-3-metilimidazol trifluorometanosulfo / Study of the operating parameters of a direct glycerol fuel cell using a polibenzimidazole membrane impregnated with phosphoric acid (PBI/H3PO4) or 1-hexyl-3-methylimidaolium trifluoromethanesulfonate (PBI/HMI-Tf)Barrientos, Wilner Valenzuela 16 July 2015 (has links)
Com o aumento da população mundial, o desenvolvimento de novas fontes e conversores de energia tornou-se uma necessidade. As células a combustível mostram-se como uma alternativa viável devido principalmente a duas razões, sua alta eficiência e a utilização de combustíveis renováveis. No presente trabalho se estuda a influência da temperatura de operação e o conteúdo de álcali no combustível sobre a densidade de potencia para uma célula a combustível de glicerol direto. Como combustível foi utilizado uma solução de glicerol:KOH (1M:xM, x=0, 1, 3, 5), como membranas foram utilizados filmes de polibencimidazol impregnado com ácido fosfórico (PBI/H3PO4, relação molar 1:11) ou 1-hexil-3-metilimidazol trifluorometanosulfonato (PBI/HMI-Tf relação molar 1:1.5), e finalmente, nano partículas de Pt suportadas em carbono (60% w/w) como catalizador no ânodo e no cátodo. Em geral, o incremento da temperatura e conteúdo de álcali no combustível mostra um efeito favorável na densidade de potencia do sistema. Numa célula a combustível unitária de glicerol direto utilizando membranas de PBI/ H3PO4 e PBI/HMI-Tf foram obtidas densidades de potencia de 0.54mW.cm-2 a 175°C e 0.599mW.cm-2 a 130°C, respectivamente, para uma solução de glicerol de (1M); enquanto que, para uma solução com um conteúdo maior de álcali, glicerol:KOH (1M:5M), foram obtidas densidades de potencia maiores, 44.1mW.cm-2 a 175°C e 29mW.cm-2 a 130°C, respectivamente. O efeito combinado do incremento da temperatura e concentração de álcali no combustível mostra um efeito maior em relação ao efeito só da temperatura. / With the increasing world population, the development of new energy sources or energy converters has become a necessity. Fuel cells show up as a viable alternative due mainly to two reasons, their high efficiency and the use of renewable fuels. In the present work we study the influence of operating temperature and alkali content in the fuel on the power density for a direct glycerol fuel cell. A glycerol:KOH (1M: xM, x = 0, 1, 3, 5) solution was used as fuels, as membranes were used polibencimidazol films impregnated with phosphoric acid (PBI/H3PO4, molar ratio of 1:11) or 1-hexyl-3-methylimidazolium trifluoromethanesulfonate (PBI/HMI-Tf), and finally, Pt nanoparticles supported on carbon (60% w / w) as catalyst in the anode and cathode. In general, increasing the temperature and alkali content in the fuel shows a favorable effect in the system power density. In a direct glycerol fuel cell using PBI/H3PO4 and PBI /HMI-Tf membranes were obtained power density of 0.54mW.cm-2 at 175°C and 0.599mW.cm-2 at 130°C, respectively, for a 1M glycerol solution; while for a glycerol solution with a higher content of alkali, glycerol:KOH (1M: 5M), were obtained higher power densities, 44.1mW.cm-2 at 175 ° C and 29mW.cm-2 at 130 ° C, respectively. The combined effect of increased temperature and alkali concentration in the fuel shows a greater effect compared to the effect of temperature only.
|
5 |
Estudo dos parâmetros operacionais de uma célula a combustível de glicerol direto utilizando uma membrana de polibencimidazol impregnada com ácido fosfórico (PBI/H3PO4) ou 1-hexil-3-metilimidazol trifluorometanosulfo / Study of the operating parameters of a direct glycerol fuel cell using a polibenzimidazole membrane impregnated with phosphoric acid (PBI/H3PO4) or 1-hexyl-3-methylimidaolium trifluoromethanesulfonate (PBI/HMI-Tf)Wilner Valenzuela Barrientos 16 July 2015 (has links)
Com o aumento da população mundial, o desenvolvimento de novas fontes e conversores de energia tornou-se uma necessidade. As células a combustível mostram-se como uma alternativa viável devido principalmente a duas razões, sua alta eficiência e a utilização de combustíveis renováveis. No presente trabalho se estuda a influência da temperatura de operação e o conteúdo de álcali no combustível sobre a densidade de potencia para uma célula a combustível de glicerol direto. Como combustível foi utilizado uma solução de glicerol:KOH (1M:xM, x=0, 1, 3, 5), como membranas foram utilizados filmes de polibencimidazol impregnado com ácido fosfórico (PBI/H3PO4, relação molar 1:11) ou 1-hexil-3-metilimidazol trifluorometanosulfonato (PBI/HMI-Tf relação molar 1:1.5), e finalmente, nano partículas de Pt suportadas em carbono (60% w/w) como catalizador no ânodo e no cátodo. Em geral, o incremento da temperatura e conteúdo de álcali no combustível mostra um efeito favorável na densidade de potencia do sistema. Numa célula a combustível unitária de glicerol direto utilizando membranas de PBI/ H3PO4 e PBI/HMI-Tf foram obtidas densidades de potencia de 0.54mW.cm-2 a 175°C e 0.599mW.cm-2 a 130°C, respectivamente, para uma solução de glicerol de (1M); enquanto que, para uma solução com um conteúdo maior de álcali, glicerol:KOH (1M:5M), foram obtidas densidades de potencia maiores, 44.1mW.cm-2 a 175°C e 29mW.cm-2 a 130°C, respectivamente. O efeito combinado do incremento da temperatura e concentração de álcali no combustível mostra um efeito maior em relação ao efeito só da temperatura. / With the increasing world population, the development of new energy sources or energy converters has become a necessity. Fuel cells show up as a viable alternative due mainly to two reasons, their high efficiency and the use of renewable fuels. In the present work we study the influence of operating temperature and alkali content in the fuel on the power density for a direct glycerol fuel cell. A glycerol:KOH (1M: xM, x = 0, 1, 3, 5) solution was used as fuels, as membranes were used polibencimidazol films impregnated with phosphoric acid (PBI/H3PO4, molar ratio of 1:11) or 1-hexyl-3-methylimidazolium trifluoromethanesulfonate (PBI/HMI-Tf), and finally, Pt nanoparticles supported on carbon (60% w / w) as catalyst in the anode and cathode. In general, increasing the temperature and alkali content in the fuel shows a favorable effect in the system power density. In a direct glycerol fuel cell using PBI/H3PO4 and PBI /HMI-Tf membranes were obtained power density of 0.54mW.cm-2 at 175°C and 0.599mW.cm-2 at 130°C, respectively, for a 1M glycerol solution; while for a glycerol solution with a higher content of alkali, glycerol:KOH (1M: 5M), were obtained higher power densities, 44.1mW.cm-2 at 175 ° C and 29mW.cm-2 at 130 ° C, respectively. The combined effect of increased temperature and alkali concentration in the fuel shows a greater effect compared to the effect of temperature only.
|
Page generated in 0.0937 seconds