Planejamento e síntese de novos candidatos a inibidores da enzima sn-1-diacilglicerol lipase alfa (DAGL-α)
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Data
2017-02-21
Autores
Okada Junior, Celso Yassuo [UNESP]
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Universidade Estadual Paulista (Unesp)
Resumo
A obesidade tem sido relatada como um processo inflamatório em decorrência da presença de tecido adiposo visceral, promovendo a resistência à insulina, devido a isso, a obesidade é capaz de desencadear um conjunto de doenças. Dentre as formas de tratamento da obesidade, a reeducação alimentar, atividade f´ısica regular e psicoterapia são as mais recomendadas. O presente projeto de pesquisa tem como objetivo o planejamento, síntese e caracterização de novos candidatos a fárrmacos com padrão estrutural ftalimídico para o tratamento da obesidade, por meio da inibição da enzima sn-1-Diacilglicerol Lipase α (DAGL-α), esta enzima é responsável pela produção do sinalizador lipídico 2-araquidonoilglicerol (2-AG), que é diretamente responsável pela modulação de receptores canabinoides do subtipo CB1. Nota-se em pacientes obesos elevada quantidade de 2-AG, dado que sugere uma possével explicação para o descontrole da saciedade alimentar, além disso, observa-se que modulações geradas por antagonistas ao receptor CB1 foram capazes de reduzir a resistência à insulina e a obesidade, todavia, efeitos colaterais como: depressão profunda e descontrole emocional foram relatados. Nesta perspectiva, a estratégia adotada neste trabalho consistiu em inibir a enzima que catalisa a síntese de 2-AG, para isso, foi utilizado o planejamento racional de fármacos adotando-se o ligante sintetizado pelo grupo de pesquisa da universidade de Leiden, ao qual foi relatada atividade biológica promissora frente à enzima DAGL-α. No presente projeto de pesquisa foi possível desenvolver uma rota sintética de quatro etapas, e com isso, sintetizar 12 derivados ftalimídicos que foram enviados para a universidade de Leiden em colaboração científica com o professor Dr. Mário Van der Stelt para execução dos testes de inibição enzimática. Dentro do contexto do CIBFar foram realizados testes biológicos paralelos perante as doenças negligenciadas e o câncer. Os resultados para o derivado CYOJ4 foram promissores para a malária e câncer de mama, proporcionando novas perspectivas para futuros trabalhos.
Obesity has been highlighted as an inflammatory process, this association has been evidenced by visceral adipose tissue. The physiologic response of the inflammation promotes problems in the homeostatic control of food intake. In addition, obesity and metabolic syndrome are capable of triggering a group of disease. Here, we promote the planning, synthesis, and characterization of a novels drug candidates with a phthalimide structural standard for the treatment of obesity, by inhibiting the enzyme sn-1-Diacilglicerol Lipase α (DAGL-α). This protein is responsible for the production of the 2-arachidonoylglycerol a lipid marker (2-AG), which is directly associated with the modulation of cannabinoid receptors called CB1. In obese patients there is a high plasma level of 2-AG, it suggests a possible explanation for high food intake, in addition, has been observed that modulations generated by antagonists to the CB1 receptor were able to reduce insulin resistance and obesity, however, side effects such as profound depression and change in emotional responses were reported. In this perspective, the strategy used in this project was to inhibit the enzyme that catalyzes the synthesis of 2-AG, for this, the rational drug planning has adopted with the ligand synthesized by the research group of the University of Leiden, which show a biological activity promising against the DAGL-α enzyme. In this research project has been possible to develop a synthetic route of four steps, and synthesize 12 phthalimide derivatives which were sent to the university of Leiden in scientific collaboration with the professor Dr. Mario Van Der Stelt to carry out the tests of enzymatic inhibition. Within the context of CIBFar, parallel biological tests have been carried out in the tropical diseases and cancer. The results were promising for malaria and breast cancer, providing novel perspectives for future projects.
Obesity has been highlighted as an inflammatory process, this association has been evidenced by visceral adipose tissue. The physiologic response of the inflammation promotes problems in the homeostatic control of food intake. In addition, obesity and metabolic syndrome are capable of triggering a group of disease. Here, we promote the planning, synthesis, and characterization of a novels drug candidates with a phthalimide structural standard for the treatment of obesity, by inhibiting the enzyme sn-1-Diacilglicerol Lipase α (DAGL-α). This protein is responsible for the production of the 2-arachidonoylglycerol a lipid marker (2-AG), which is directly associated with the modulation of cannabinoid receptors called CB1. In obese patients there is a high plasma level of 2-AG, it suggests a possible explanation for high food intake, in addition, has been observed that modulations generated by antagonists to the CB1 receptor were able to reduce insulin resistance and obesity, however, side effects such as profound depression and change in emotional responses were reported. In this perspective, the strategy used in this project was to inhibit the enzyme that catalyzes the synthesis of 2-AG, for this, the rational drug planning has adopted with the ligand synthesized by the research group of the University of Leiden, which show a biological activity promising against the DAGL-α enzyme. In this research project has been possible to develop a synthetic route of four steps, and synthesize 12 phthalimide derivatives which were sent to the university of Leiden in scientific collaboration with the professor Dr. Mario Van Der Stelt to carry out the tests of enzymatic inhibition. Within the context of CIBFar, parallel biological tests have been carried out in the tropical diseases and cancer. The results were promising for malaria and breast cancer, providing novel perspectives for future projects.
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Palavras-chave
Tratamento da obesidade, Ftalimidas, DAGL-alfa, 2-Aracdonoilglicerol