The first half of this dissertation describes the synthesis and biological activities of a series of amino aldehydes; which were derivatives of the basic amino acids, arginine, lysine and ornithine. The synthesis of the amino aldehydes was complicated by the difficulty of producing an intermediate oxidation state (the aldehyde) in the presence of two other functional groups (the α-amino, and the side chain functionality). The amino aldehydes were of biological interest due to the fact that they were inhibitors of the proteolytic enzymes called kallikreins. The kallikreins are known to be involved with the renin-angiotensin system, arginine vasopressin, and the prostaglandins, in the regulation of blood pressure. The aldehydes were assayed for their ability to inhibit the kallikrein-mediated production of kinins, and by the inhibition of the cleavage of Nᵅ-tosyl arginine methyl ester (TAME) to the carboxylic acid. Two of the amino aldehydes (Nᵅ-t-Boc-Nᴳ-nitro-L-argininal and Nᵅ-t-Boc-Nᴳ-tosyl-L-argininal) were effective inhibitors in both bioassays at micromolar concentrations. The second part of the dissertation details the development of two syntheses of β-substituted analogues of cysteine. The first method was based on sulfenylation of Nᵅ-formyl-α, β-dehydro amino acid esters, followed by protection of the sulfhydryl group as the benzyl or para-methylbenzyl thioether. The Nᵅ-formyl and ester groups were cleaved by acidic hydrolysis, and the amino group was then blocked as the t-butyloxycarbonyl derivative. This procedure gave cysteine analogues which were suitable for direct use in solid phase peptide synthesis. A second, more efficient preparation of the cysteine analogues was based on the conjugate addition of lithium benzylthiolate (or lithium para-methylbenzylthiolate) to the Nᵅ-formyl-α, β-dehydroamino acid esters. This synthesis was more efficient since the cysteine analogues were generated directly in S-protected form. The fully protected intermediates were deprotected at the amino and carboxyl groups, followed by treatment with di-tert-butyl dicarbonate. The Nᵅ- t-Boc-β-S-benzyl cysteine analogues (or Nᵅ -t-Boc-β-S-para-methylbenzyl) also were suitable for direct use in solid phase peptide synthesis.

Thesis (PhD (Chemistry and Polymer Science))--University of Stellenbosch, 2008. / This dissertation can be broken into two parts comprising different strategies to synthesise novel poly-amino acid based polymers. The use of recently developed nickel(0) and cobalt(0) metal catalysts for the living polymerization of α-amino acid-N-carboxyanhydrides (NCAs) to synthesise novel poly-amino acid polymers, comprising a polar, hydrophilic block and a neutral hydrophobic block, were investigated in the first part of this study. The hydrophilic block was made up of a random sequence of arginine (Arg, R), glycine (Gly, G) and aspartic acid (Asp, D) - poly-RGD. This was followed by a polyleucine (Leu, L) hydrophobic block. Success was limited with this system due to polymer precipitation during the polymerization reaction. Because of this precipitation, the amino acid composition of the hydrophilic block was changed to a random sequence of glutamic acid (Glu, E), cystein (Cys, C) and aspartic acid – poly-ECD. Here also, the success was limited because of polymer precipitation. A novel approach to the synthesis of hybrid poly-amino acid – synthetic polymer materials constitutes the second part of this study. The final polymeric structure can be described as a carboxylic acid functionalized polyethylene glycol (PEG) sheathed polylysine polymer. The technology involves the synthesis of a lysine NCA functionalized at the ε-amino group with an α,ω-bis(carboxymethyl) ether PEG. The distal carboxylic acid group was protected as a benzyl ester during synthesis and subsequent polymerization of the PEG-lysine-NCA macro-monomer. The polymerization was successfully initiated using n-butyl amine to form short homopolymer strands. Copolymerization with lysine-NCA was also achieved as well as the successful initiation using a generation 1.0 dendritic amine initiator, N,N,N’,N’-tetrakis(3-aminopropyl)-1,4-butanediamine (DAB-Am-4). These polymers were characterized by 1H NMR.

Orientador: Roberto Rittner Neto / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-27T10:22:25Z (GMT). No. of bitstreams: 1 Duarte_ClaudimarJunker_D.pdf: 13121295 bytes, checksum: 3401d9f1581d3385c70c6c859f152c76 (MD5) Previous issue date: 2015 / Resumo: Neste trabalho, o equilíbrio conformacional de alguns ésteres metílicos de aminoácidos não acetilados (L-Serina, L-Treonina e L-Triptofano) e N-acetilados (Glicina, L-Alanina, L-Serina, L-Treonina e L-Triptofano) foi avaliado através de cálculos teóricos e técnicas experimentais de espectroscopia no Infravermelho e de RMN. A metodologia aplicada baseou-se em RMN de 1H (através do comportamento da constante de acoplamento spin-spin 3JHH) e deconvolução analítica do espectro de infravermelho na região de estiramento da carbonila. Os resultados obtidos foram utilizados para determinar a variação populacional de cada derivado de aminoácido em vários solventes. Além disso, cálculos teóricos em fase isolada e também considerando o efeito do solvente foram realizados para determinar os valores de 3JHH e a frequência de estiramento C=O. Os resultados calculados estão em boa concordância com os valores experimentais e proporcionam informações sobre o comportamento conformacional induzido por cada solvente. Adicionalmente, a análise dos Orbitais Naturais de Ligação e a Teoria Quântica dos Átomos em Moléculas foram empregadas para investigar a importância de efeitos clássicos e não clássicos sobre o equilíbrio conformacional dos sistemas supracitados. Diferente de várias propostas da literatura, foi demonstrado que efeitos estéricos e de hiperconjugação são interações importantes para o equilíbrio conformacional para o equilíbrio conformacional dos diversos derivados de aminoácidos avaliados, enquanto que ligações de hidrogênio apresentam contribuição secundária / Abstract: In this work, the conformational equilibrium of some methyl esters of amino acids non-acetylated (L-Serine, L-Threonine and L-Tryptophan) e N-acetylated (Glycine, L-Alanine, L-Serine, L-Threonine and L-Tryptophan) was evaluated by theoretical calculations and Infrared and 1H NMR spectroscopies. The applied methodology was based on the 1H NMR data (through the behavior of the 3JHH spin spin coupling constant) and analytical deconvolution of infrared spectra on the C=O stretching region. The obtained results were used to determine the populational variation of each amino acid derivative in several solvents. In addition, theoretical calculations in isolated phase and taking into account the solvent effect were carried out in order to obtain the values of 3JHH and C=O stretching vibration. The calculated results are in good agreement with the experimental data and provide insights into the conformational behavior induced by each solvent. Additionally, Natural Bond Orbital analysis and the Quantum Theory Atoms In Molecules were employed to investigate the importance of classic and non-classic effects over the conformational isomerism of aforementioned systems. In disagreement of several publications in the literature, it was found that steric effect and hyperconjugation are interactions important to conformational preferences of all amino acid derivatives evaluated whereas H-bonding plays a secondary role / Doutorado / Quimica Organica / Doutor em Ciências