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Master's Dissertation
DOI
https://doi.org/10.11606/D.46.2013.tde-05082013-092818
Document
Author
Full name
Thiago de Souza Freire
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2013
Supervisor
Committee
Machini, Maria Teresa (President)
Etchegaray Júnior, Augusto
Santos, Alcindo Aparecido dos
Title in Portuguese
Solvólise da ligação peptidil-resina mediada por íons metálicos divalentes: método alternativo de obter peptídeos modificados no C-terminal
Keywords in Portuguese
Alcoólise
Aminoácido esterificado
Peptídeo esterificado
Peptídeos
Resina HMBA
Zn2+
Abstract in Portuguese
Este estudo enfocou a mediação por íons metálicos divalentes da solvólise da ligação éster formada entre peptídeos e resinas, método desenvolvido por nós para a preparação de peptídeos C-modificados. Os objetivos foram: i) adaptá-lo para a estratégia Fmoc de síntese, ii) buscar resinas adequadas para tal propósito, iii) verificar qual íon metálico é mais eficiente para mediar tal reação; iv) investigar o possível mecanismo pelo qual os íons metálicos mediam as reações estudadas. Para isso, foram testadas as resinas derivadas do ácido p-hidroximetilbenzóico (HMBA-AM, HMBA-PEGA, HMBA-TG) e do álcool p-benziloxibenzílico (Wang), os mediadores metálicos Ca2+ e Zn2+, condições reacionais determinadas em estudos anteriores do nosso grupo de pesquisa (50% nucleófilo/ DMF) e os solventes nucleófilos metanol, etanol, propan-1-ol, propan-2-ol, butan-1-ol, álcool benzílico, butilamina e hexilamina. O desligamento de aminoácidos e peptídeos esterificados das resinas ocorreu com altos rendimentos (72 - 98%). A resina HMBA-AM e o íon Zn2+ demonstraram ser a combinação mais eficiente. Análises de espectroscopia de infravermelho na presença e ausência do íon metálico indicaram um mecanismo de reação no qual a coordenação do íon Zn2+ com o álcool facilita a formação do íon alcóxido, o qual é um nucleófilo melhor que o álcool e com capacidade de atacar o carbono da carbonila da ligação éster entre o peptídeo e a resina.
Title in English
Solvolysis of peptidyl-resin linkage promoted by divalent metal ions: alternative method to obtain C-terminal modified peptides
Keywords in English
Alcoholysis
Esterified amino acid
Esterified peptide
Peptides
Resin HMBA
Zn2+
Abstract in English
The present study was focused on divalent metal ions-mediated solvolysis of the ester linkage formed between peptides and resins, a method developed by us for the preparation of C-modified peptides. The aims were: i) to adapt it for the Fmoc synthesis strategy; ii) to search resins suitable for such purpose; iii) to determine which divalent metal ion is the most efficient reaction mediator; iv) to investigate the mechanism by which the metal ion mediates the solvolysis reactions studied. Therefore, we employed the resins p-hydroxymethylbenzoic acid (HMBA-AM, HMBA-PEGA, HMBA-TG) and p-benzyloxybenzyl (Wang) alcohol, the metal ions Ca2+ and Zn2+, the optimized solvolysis conditions found in our previous studies (50% nucleophile/DMF) and the nucleophilic solvents methanol, ethanol, propan-1-ol, propan-2-ol, butan-1-ol, benzyl alcohol, butylamine and cyclohexylamine. Detachment of esterified amino acids or peptides from resins gave high yields (72-98%). HMBA-AM resin and Zn2+ ion showed to be the most effective combination of resin and metal ion. Infrared spectroscopy analysis of the peptide-resins in absence and presence of such metal ion suggested a mechanism of reaction where the coordination of Zn2+ ion with the alcohol promotes its deprotonation to give the alkoxide ion, which is a better nucleophile and can attack the carbonyl carbon of the ester linkage formed between the amino acid and the resin.
 
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Publishing Date
2013-08-23
 
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