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Synthesis of a boronic acid-based diazo acetate derivative
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Recentemente a investigação em química biológica relativa à descoberta de novos fármacos tem aumentado. Apesar de estes serem necessários, também é preciso identificar novos alvos terapêuticos a nível molecular. Existem vários potenciais alvos ainda por caracterizar, pelo que surgiu a necessidade de desenvolver novas tecnologias para os identificar e explorar as suas funções, tais como as sondas moleculares. Estas consistem em pequenas moléculas concebidas especificamente para se ligarem a um alvo molecular, para estabelecer o papel e os mecanismos de biomoléculas como as proteínas. As moléculas contendo grupos funcionais diazo são uma classe de moléculas que contêm um grupo -N2 ligado a um substituinte contendo carbono. Quando irradiados com luz, do comprimento de onda adequado, podem fragmentar-se em nitrogénio molecular e num carbeno. Este pode ser utilizado para fazer marcação de alvos moleculares. Os ácidos borónicos são uma classe de compostos que contêm um átomo de boro trivalente que possui dois grupos hidroxilo e um substituinte contendo carbono. Estes compostos são conhecidos por formarem complexos reversíveis com compostos hidroxilados em condições fisiológicas, alternando entre uma estrutura trigonal planar sp2 e uma tetraédrica sp3. Esta propriedade permite utilizar estes compostos para efetuar o reconhecimento de alvos específicos, como proteínas ricas em serinas e hidratos de carbono. O objetivo deste trabalho era sintetizar uma nova molécula pertencente à classe dos α-diazocarbonilos com bom rendimento, levando à síntese do 2-diazo-N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (composto 5). Após concluída a síntese da molécula, o objectivo era testar a possibilidade de ser usada como sonda de fotoafinidade. Infelizmente, não foi possível concluir este objectivo. Proteínas ricas em serinas são uma possível aplicação desta sonda. Estas proteínas são expressas à superfície de várias bactérias Gram positivas, e foi provado que possuem um papel vital na adesão destes patogénicos aos tecidos e no desenvolvimento de doença invasiva. Tecnologia que tivesse a capacidade de reconhecer estas proteínas teria um grande valor clínico.
Recently there has been an increased investigative effort in chemical biology towards drug discovery. Not only new medicines are necessary but also new molecular targets. There are innumerous uncharacterized potential targets, from which stems the need to develop new tools that can identify and explore their functions, such as chemical probes. These are small molecules designed to bind tightly to a specific target, to help elucidate the roles and mechanisms of biomolecules, such as proteins. Diazo compounds are a class of molecules that have a -N2 group linked to a carbon-based substituent. When irradiated with light, of the appropriate wavelength, they can fragment into molecular nitrogen and a carbene. This carbene can be used to label molecular targets. Boronic acids are organic compounds characterized by having a trivalent boron atom, which possesses two hydroxyl groups and one carbon-based substituent. In fact, they are known to form reversible complexes with hydroxylated compounds under physiological conditions, shifting from a trigonal planar sp2 structure to a tetrahedral sp3 one. This property allows these compounds to be utilized as a recognition moiety for hydroxylated compounds such as serine-rich proteins and carbohydrates. The objective of this work was to synthesize a novel α-diazocarbonyl molecule within good yield, that could combine the characteristics of both classes of compounds, leading to the synthesis of 2-diazo-N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (compound 5). After synthesizing the molecule, the goal was to verify if it could be used as a photoaffinity probe. Unfortunately, it was not possible to proceed with this objective. Serine-rich repeat proteins are a possible application of this probe. These proteins are expressed at the surface of many Gram-positive pathogens and have been shown to contribute significantly to the adhesion of the bacteria to the tissue and to the development of invasive disease. A tool that could recognize them would have great value in clinical and analytical practice.
Recently there has been an increased investigative effort in chemical biology towards drug discovery. Not only new medicines are necessary but also new molecular targets. There are innumerous uncharacterized potential targets, from which stems the need to develop new tools that can identify and explore their functions, such as chemical probes. These are small molecules designed to bind tightly to a specific target, to help elucidate the roles and mechanisms of biomolecules, such as proteins. Diazo compounds are a class of molecules that have a -N2 group linked to a carbon-based substituent. When irradiated with light, of the appropriate wavelength, they can fragment into molecular nitrogen and a carbene. This carbene can be used to label molecular targets. Boronic acids are organic compounds characterized by having a trivalent boron atom, which possesses two hydroxyl groups and one carbon-based substituent. In fact, they are known to form reversible complexes with hydroxylated compounds under physiological conditions, shifting from a trigonal planar sp2 structure to a tetrahedral sp3 one. This property allows these compounds to be utilized as a recognition moiety for hydroxylated compounds such as serine-rich proteins and carbohydrates. The objective of this work was to synthesize a novel α-diazocarbonyl molecule within good yield, that could combine the characteristics of both classes of compounds, leading to the synthesis of 2-diazo-N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (compound 5). After synthesizing the molecule, the goal was to verify if it could be used as a photoaffinity probe. Unfortunately, it was not possible to proceed with this objective. Serine-rich repeat proteins are a possible application of this probe. These proteins are expressed at the surface of many Gram-positive pathogens and have been shown to contribute significantly to the adhesion of the bacteria to the tissue and to the development of invasive disease. A tool that could recognize them would have great value in clinical and analytical practice.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2019
Palavras-chave
Ácido borónico Diazo Sonda Proteína Mestrado Integrado - 2019