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Avaliação biológica de inibidores da monoamina oxidase A e B : síntese de análogos promissores
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As monoamina oxidases, MAO-A e MAO-B, são isoenzimas presentes na membrana das mitocôndrias de células neuronais e não neuronais, cuja principal função in vivo é catalisarem a desaminação oxidativa de diversas aminas biogénicas, como monoaminas neurotransmissoras e neuromoduladoras (dopamina, noradrenalina, adrenalina, serotonina) relacionadas com o movimento, a cognição, o comportamento, e que são essenciais à neurotransmissão no sistema nervoso central. Os subprodutos das reacções mediadas pelas MAO incluem uma variedade de espécies químicas com elevado poder neurotóxico, tais como o peróxido de hidrogénio, amónia e aldeídos. Como tal, especula-se que a actividade excessiva e prolongada destas isoenzimas possa gerar danos a nível mitocondrial e distúrbios neurodegenerativos. Neste contexto, as MAO tornam-se num dos principais alvos terapêuticos para as doenças neurodegenerativas, através do desenvolvimento de inibidores enzimáticos.
O trabalho desenvolvido visa avaliar as potencialidades de diferentes classes de compostos como inibidores da MAO, a fim de seleccionar os compostos mais promissores. Feita esta avaliação foram sintetizadas novas classes de compostos análogos como potenciais inibidores para a MAO-A e MAO-B.
O estudo inicial compreendeu a avaliação biológica dos diferentes compostos, através da determinação da percentagem de inibição e do valor de IC50, pelo método de Amplex®Red. De um modo geral, a avaliação revelou que alguns dos compostos são potenciais inibidores da MAO-B, destacando-se os compostos C7, A3 e A9. O composto C7 apresentou um maior potencial de inibição para a MAO-B com um valor de IC50 de 0,31 ± 0,09 μM, enquanto os compostos A3 e A9 com um valor de IC50 de 1,66 ± 0,35 μM e de 4,27 ± 0,66 μM, respectivamente, mostraram selectividade para esta isoenzima.
Em função da avaliação biológica, procedeu-se à síntese de novas moléculas (compostos 4-12), derivadas de (benzilideno)propanodinitrilo como inibidores da MAO, a partir da reacção de condensação de Knoeveagel de diferentes benzaldeídos com malononitrilo. Todos os compostos sintetizados já se encontravam referenciados na literatura como inibidores de quinases. No entanto, estes compostos não apresentavam a totalidade dos dados espectroscópicos. Assim, optou-se por confirmar as estruturas de todos os compostos, recorrendo a uma análise espectroscópica completa (espectroscopia de infravermelho, massa, e ressonância magnética nuclear unidimensional, 1H-RMN) e ainda à determinação das análises elementares e respectivos pontos de fusão.
Monoamine oxidases A and B are mithocondrial bound isoenzimas of neuronal and non-neuronal cells, whose main function in vivo is to catalyze the oxidative deamination of biogenic amines, such as monoamine neurotransmitters (dopamine, norepinephrine, serotonin) related to the movement, cognitive function, behavior, that are essential to neurotransmission in the central nervous system. The by-products of MAO-mediated reactions include several chemical species with neurotoxic potential, such as hydrogen peroxide, ammonia and aldehydes. As a consequence, it is speculated that excessive and prolonged activity of these isoenzymes may be conducive to mithocondrial damages and neurodegenerative disturbances. In this context, MAO becomes a major therapeutic target for treatment of neurodegenerative diseases, through the development of MAO inhibitors. This work aims to evaluate the potential of different classes of MAO-inhibitors, in order to select the most promising compounds, to guide the synthesis of new class of analogues with inhibitory potential for MAO-A and MAO-B. The initial study included the biological assessment of various compounds, by determining the respective percentage inhibition and IC50 values, using the fluorimetric method Amplex® Red. In general, the evaluation revealed that some of the compounds are potential inhibitors of MAO-B, especially compounds A3, A9 and C7. The most potent MAO-B inhibitor was compound C7 with an IC50 value of 0,31 ± 0,09 μM, while compounds A3 and A9 with an IC50 value of 1,66 ± 0,35 μM and 4,27 ± 0,66 μM, respectively, showed selectivity for this isozyme. According to the analysis of biological assessment, the synthesis of new molecules was carried out (compounds 4-12), (benzylidene)propanedinitrile derivatives as MAO inhibitors, via Knoevenagel reaction, using different benzaldehydes and malononitrile. All the synthesized compounds were already reported in the literature as kinases inhibitors. However, only a few present detailed spectroscopic data. Thus, we chose to confirm the structures of all compounds, using a full spectroscopic analysis (infrared and mass spectroscopy, and 1H-NMR) and microanalysis.
Monoamine oxidases A and B are mithocondrial bound isoenzimas of neuronal and non-neuronal cells, whose main function in vivo is to catalyze the oxidative deamination of biogenic amines, such as monoamine neurotransmitters (dopamine, norepinephrine, serotonin) related to the movement, cognitive function, behavior, that are essential to neurotransmission in the central nervous system. The by-products of MAO-mediated reactions include several chemical species with neurotoxic potential, such as hydrogen peroxide, ammonia and aldehydes. As a consequence, it is speculated that excessive and prolonged activity of these isoenzymes may be conducive to mithocondrial damages and neurodegenerative disturbances. In this context, MAO becomes a major therapeutic target for treatment of neurodegenerative diseases, through the development of MAO inhibitors. This work aims to evaluate the potential of different classes of MAO-inhibitors, in order to select the most promising compounds, to guide the synthesis of new class of analogues with inhibitory potential for MAO-A and MAO-B. The initial study included the biological assessment of various compounds, by determining the respective percentage inhibition and IC50 values, using the fluorimetric method Amplex® Red. In general, the evaluation revealed that some of the compounds are potential inhibitors of MAO-B, especially compounds A3, A9 and C7. The most potent MAO-B inhibitor was compound C7 with an IC50 value of 0,31 ± 0,09 μM, while compounds A3 and A9 with an IC50 value of 1,66 ± 0,35 μM and 4,27 ± 0,66 μM, respectively, showed selectivity for this isozyme. According to the analysis of biological assessment, the synthesis of new molecules was carried out (compounds 4-12), (benzylidene)propanedinitrile derivatives as MAO inhibitors, via Knoevenagel reaction, using different benzaldehydes and malononitrile. All the synthesized compounds were already reported in the literature as kinases inhibitors. However, only a few present detailed spectroscopic data. Thus, we chose to confirm the structures of all compounds, using a full spectroscopic analysis (infrared and mass spectroscopy, and 1H-NMR) and microanalysis.
Descrição
Tese de mestrado, Química Farmacêutica e Terapêutica, Universidade de Lisboa, Faculdade de Farmácia, 2012
Palavras-chave
Monoamina oxidase A e B Inibidores da MAO Doenças neurodegenerativas Depressão Neuroprotecção Teses de mestrado - 2012