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Novel peptide cyclization systems: biomass-derived, bifunctional cyclopentenones as peptide cyclization linkers (ciclização de péptidos terapêuticos)
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inoácidos proteogénicos. Neste trabalho foram utilizadas ciclopentenonas derivadas de biomassa como agentes para a ciclização de péptidos, os aminoácidos reativos utilizados foram a cisteína e a lisina. Observou-se que a ciclopentenona funcionalizada com uma lactona era capaz de realizar a ciclização de péptidos de forma eficiente apenas quando ambos os aminoácidos reativos se encontravam diretamente adjacentes um ao outro. A bromo-diamino-ciclopentenona testada neste estudo não revelou a mesma seletividade, mas mostrou bastante versatilidade e foi capaz de induzir a ciclização de péptidos (com taxas de conversão superiores a 95%) independentemente da distância entre os dois aminoácidos reativos. Ciclopentenonas foram também usadas neste trabalho para a síntese de Aductos Doador-Aceitador de Stenhouse (DASA), a partir de 3-bromofurfural. Embora já se tenham efetuado várias modificações neste tipo de compostos, o trieno conjugado permanece pouco estudado. Ao sintetizar DASA a partir do 3-bromofurfural, o átomo de bromo poderia mais tarde ser explorado através de acoplamento de Suzuki, por exemplo, para formar novas ligações carbono-carbono na estrutura do DASA e explorar novas funcionalidades. Neste trabalho foram sintetizados DASA de primeira e segunda geração. Existe também uma enorme necessidade para o desenvolvimento da própria síntese de péptidos. Neste trabalho é apresentado um novo ciclo de síntese de péptidos em fase líquida. Foi concebido um novo grupo de proteção explorando as características de solubilidade dos compostos de amónio quaternário. Para sintetizar este composto, o sistema aromático do 9-fluerenemetanol (Fmoc-OH) é nitrado com um rendimento de 45%, depois é então reduzido ao grupo amino com um rendimento de 88% e por fim quaternizado com um rendimento de 51%. Embora as condições experimentais para as etapas seguintes ainda não tenham sido definidas é também proposta uma rota sintética para as mesmas.
As peptide drugs are further explored for the development of novel drugs there is a constant demand for the development of novel peptide cyclization methods. The most used peptide cyclization methods generally require non-canonical amino acids which cannot be easily incorporated in biological peptide/protein synthesis and tend to be more expensive to produce than proteogenic amino acids. In this work, cyclopentenones derived from biomass residues were used as linkers for peptide cyclization, the reactive amino acids used were cysteine and lysine. Both cyclopentenones revealed remarkable results. It was observed that the cyclopentenone containing a fused lactone moiety would be efficient at peptide cyclization only when both reactive amino acids were directly adjacent to each other. The bromo-diamino-cyclopentenone tested in this study did not reveal the same selectivity, it proved to be, however, quite versatile and was able to induce peptide cyclization (with conversion rates over 95%) independently of the distance between both reactive amino acids tested. Cyclopentenones were also used in this work for the synthesis of Donnor-Acceptor Stenhouse Adducts (DASA) from 3-bromofurfural. Although several modifications have been performed on these photoswitching compounds the conjugated triene backbone remains unaltered. By synthesizing DASA from 3-bromofurfural the bromine atom could later be explored via Suzuki coupling to form novel carbon-carbon bonds on the triene backbone of the DASA and achieve novel functionalities. In this work DASA from the first and second generation were effectively synthesized. There has also been a growing demand for the development of peptide synthesis itself. In this work an innovative liquid-phase peptide synthesis cycle is presented. A novel protecting group for peptide synthesis is theorized where the characteristic solubility of quaternary ammonium compounds is explored. To produce this new protecting group the aromatic system in Fmoc-OH (9-fluerenemethanol) is first nitrated with a yield of 45%, the newly added nitro group is then reduced to the amino group with a yield of 88% and afterwards the amino group is successfully quaternized with a yield of 51%. Although the experimental conditions for the following steps were not yet determined, a synthetic strategy is also proposed.
As peptide drugs are further explored for the development of novel drugs there is a constant demand for the development of novel peptide cyclization methods. The most used peptide cyclization methods generally require non-canonical amino acids which cannot be easily incorporated in biological peptide/protein synthesis and tend to be more expensive to produce than proteogenic amino acids. In this work, cyclopentenones derived from biomass residues were used as linkers for peptide cyclization, the reactive amino acids used were cysteine and lysine. Both cyclopentenones revealed remarkable results. It was observed that the cyclopentenone containing a fused lactone moiety would be efficient at peptide cyclization only when both reactive amino acids were directly adjacent to each other. The bromo-diamino-cyclopentenone tested in this study did not reveal the same selectivity, it proved to be, however, quite versatile and was able to induce peptide cyclization (with conversion rates over 95%) independently of the distance between both reactive amino acids tested. Cyclopentenones were also used in this work for the synthesis of Donnor-Acceptor Stenhouse Adducts (DASA) from 3-bromofurfural. Although several modifications have been performed on these photoswitching compounds the conjugated triene backbone remains unaltered. By synthesizing DASA from 3-bromofurfural the bromine atom could later be explored via Suzuki coupling to form novel carbon-carbon bonds on the triene backbone of the DASA and achieve novel functionalities. In this work DASA from the first and second generation were effectively synthesized. There has also been a growing demand for the development of peptide synthesis itself. In this work an innovative liquid-phase peptide synthesis cycle is presented. A novel protecting group for peptide synthesis is theorized where the characteristic solubility of quaternary ammonium compounds is explored. To produce this new protecting group the aromatic system in Fmoc-OH (9-fluerenemethanol) is first nitrated with a yield of 45%, the newly added nitro group is then reduced to the amino group with a yield of 88% and afterwards the amino group is successfully quaternized with a yield of 51%. Although the experimental conditions for the following steps were not yet determined, a synthetic strategy is also proposed.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2024, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
Cyclopentenone Biomass valorization Peptide cyclization LPPS DASA Mestrado integrado - 2024