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Abstract(s)
A doença de Alzheimer é uma demência neurodegenerativa, caracterizada a nível molecular por misfolding e agregação proteica, stress oxidativo, anomalias mitocondriais e processos inflamatórios. Apesar de ainda existirem incertezas quanto às causas moleculares da doença, algumas hipóteses são consideradas, como a colinérgica, que admite existir uma deficiência da acetilcolina no cérebro que é devido à diminuição da sua produção ou aumento da atividade da acetilcolinesterase (AChE). A AChE está também envolvida na formação de placas amiloides, também associadas com AD. A única terapia existente para a doença são os inibidores da AChE, que facilitam a transmissão colinérgica e interferem com síntese, formação e agregação das placas amiloides.
Compostos naturais ou semissintéticos, como esteroides, têm sido estudados como potenciais inibidores da enzima. Após uma análise dos pontos estruturais comuns desses esteroides, que lhe conferem a atividade inibitória, foram desenhados novos esteroides, partindo do acetato de 16-desidropregnenolona (16-DPA). Assim, modificou-se neste composto o substituinte em C-3 e funcionalizou-se o anel D, na posição 16, com a introdução de aminas.
Os compostos desenhados, foram submetidos a um estudo de docking molecular, do qual se obteve energias de ligação inferiores à tacrina (fármaco de referência), sendo o melhor resultado para o composto 27, com -14,38 kJ/mol. De seguida tentou-se sintetizar os compostos, recorrendo-se a uma hidrólise em C-3 e à adição de Michael, com estudo do catalisador, para a introdução de aminas em C16. Deste modo, foi possível obter dois acetatos de 16a-aminopregnenolonas puros, 20 e 26, e uma 16a-aminopregnenolona (21) hidrolisada em C-3.
Finalmente, submeteram-se os compostos 16-DPA, 20 e 21 ao ensaio de Ellman’s, para a avaliar a sua capacidade inibitória contra a AChE, obtendo-se as seguintes percentagens de inibição 6,58, 15,36 e 15,58, respetivamente, para soluções a 10µM.
Alzheimer´s disease (AD) is a neurodegenerative disorder characterized at a molecular level by protein misfolding and aggregation, oxidative stress, mitochondrial abnormalities, and neuroinflammatory processes. The exact cause of AD is still uncertain, but some hypotheses have been considered, such as the cholinergic hypothesis which states that a deficiency on acetylcholine in brain is observed due to a decreased production of acetylcholine or to amplified acetylcholinesterase (AChE) activity. In addition, this enzyme has a partial involvement in the formation of amyloid plaques and neurofibrillary tangles, also associated with AD. The only therapy available for AD is AChE inhibitors, which facilitates the cholinergic transmission and interferes with amyloid plaques synthesis, formation and aggregation. Natural or semisynthetic compounds, such as steroids have been studied as potential enzyme inhibitors. After an analysis of structural features of those steroids, that provides the inhibitory activity, new steroids were drawn, from 16-dihydropregnnenolone acetate (16-DPA). Modifications were made on C-3 substituent and functionalization of ring D, by amine introduction on C-16. The new compounds were submitted to a molecular docking study, where were obtained binding energies lowers than tacrine (reference drug), the best result was obtained for compound 27, with -14.38 kJ/mol. Then, the compounds were synthesized, using a hydrolysis on C-3 and Michael addition, with the study of the catalyst, for amine introduction. Two 16a-aminopregnenolones acetate 20 and 26, and one hydrolysed on C-3 16a-aminopregnenolone 21, were achieved. Finally, compounds 16-DPA, 20 and 21 were submitted to an Ellman’s assay, to evaluate their inhibitory capacity against AChE. The following inhibition percentage were obtained: 6.58, 15.36 and 15.58, respectively, for 10µM solutions.
Alzheimer´s disease (AD) is a neurodegenerative disorder characterized at a molecular level by protein misfolding and aggregation, oxidative stress, mitochondrial abnormalities, and neuroinflammatory processes. The exact cause of AD is still uncertain, but some hypotheses have been considered, such as the cholinergic hypothesis which states that a deficiency on acetylcholine in brain is observed due to a decreased production of acetylcholine or to amplified acetylcholinesterase (AChE) activity. In addition, this enzyme has a partial involvement in the formation of amyloid plaques and neurofibrillary tangles, also associated with AD. The only therapy available for AD is AChE inhibitors, which facilitates the cholinergic transmission and interferes with amyloid plaques synthesis, formation and aggregation. Natural or semisynthetic compounds, such as steroids have been studied as potential enzyme inhibitors. After an analysis of structural features of those steroids, that provides the inhibitory activity, new steroids were drawn, from 16-dihydropregnnenolone acetate (16-DPA). Modifications were made on C-3 substituent and functionalization of ring D, by amine introduction on C-16. The new compounds were submitted to a molecular docking study, where were obtained binding energies lowers than tacrine (reference drug), the best result was obtained for compound 27, with -14.38 kJ/mol. Then, the compounds were synthesized, using a hydrolysis on C-3 and Michael addition, with the study of the catalyst, for amine introduction. Two 16a-aminopregnenolones acetate 20 and 26, and one hydrolysed on C-3 16a-aminopregnenolone 21, were achieved. Finally, compounds 16-DPA, 20 and 21 were submitted to an Ellman’s assay, to evaluate their inhibitory capacity against AChE. The following inhibition percentage were obtained: 6.58, 15.36 and 15.58, respectively, for 10µM solutions.
Description
Keywords
16a-Aminopregnenolonas Acheis Catalisador. Docking Molecular Reação de Michael