Design, síntese e atividade antiplaquetária in vitro da taiwanina C
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Data
2021-10-08
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Universidade Estadual Paulista (Unesp)
Resumo
As plaquetas são ativadas quando há rompimento do epitélio vascular pela exposição a uma série de fatores que mudam sua forma e levam ao processo de agregação. A ativação e agregação das plaquetas forma o trombo (coágulo) que impede o extravasamento do sangue. Após o estancamento do sangue a desativação das plaquetas é feita pela ação de prostaciclinas, mas quando o processo de ativação e desativação é descontrolado ocorre a formação de trombos que afetam o fluxo sanguíneo nas artérias e veias que podem levar a inúmeras patologias. A fim de controlar esse processo inúmeros fármacos têm sido desenvolvidos, porém muitos apresentam limitações quanto a efeitos colaterais, idade do paciente e alto custo. Portanto, o desafio de muitos pesquisadores é obter moléculas que possam ser eficientes, seguras e mais acessíveis. Dentro deste contexto os produtos naturais têm sido uma fonte inesgotável de moléculas com potencial biológico. Desta forma, o objetivo deste trabalho foi sintetizar a taiwanina C, uma lignana arilnaftalênica extraída da Taiwania cryptomerioides, de forma mais eficiente do que relatado por outros autores, avaliar sua atividade antiplaquetária usando como agonistas o ácido araquidônico e o TRAP-6, além de estudar o mecanismo de ação sobre as COXs e PAR-1 que são, respectivamente, as proteínas envolvidas nas vias de ativação plaquetária mediadas por esses agonistas. Foram avaliadas duas rotas sintéticas nas quais a taiwanina C foi obtida em rendimento total de 40,4% e 52%, portanto maiores do que aqueles descritos na literatura. Nos ensaios usando plaquetas humanas a taiwanina C inibiu significativamente a agregação plaquetária na presença de ácido araquidônico com CI50 = 0,46 µM e na presença de TRAP-6 com CI50 = 0,56 µM. Esses estudos indicaram maior atividade da taiwanina C do que a indometacina usada como controle positivo. Estudos de docking molecular usando as COX-1 e COX-2 sugerem que a taiwanina C interage em ambas as COX, porém com maior afinidade com a COX-1. Em relação a PAR-1 os estudos sugerem que a taiwanina C apresenta mecanismo de interação diferente da indometacina e do vorapaxar (medicamento referência). Esses resultados demonstram que a taiwanina C atua em duas vias de sinalização da agregação plaquetária o que não é comum para a maioria dos fármacos utilizados. Embora preliminares, esses resultados indicam que a taiwanina C pode ser uma molécula alvo para o desenvolvimento de novos fármacos antiplaquetários.
Platelets are activated when there is disruption of the vascular epithelium due to exposure to a series of factors, changing their shape and initiating a process of aggregation. Platelet activation and aggregation form the thrombus (clot) that prevents blood leakage. After the blood is stopped, platelets are deactivated by the action of prostacyclins, but when the activation and deactivation process is uncontrolled, thrombi can form, which affect the blood flow in the arteries and veins, which can lead to numerous pathologies. In order to control this process, many drugs have been developed, but many have limitations in terms of side effects, patient age and high cost. Therefore, the challenge for many researchers is to obtain molecules that can be efficient, safe and more accessible. Within this context, natural products have been an inexhaustible source of molecules with biological potential. Thus, the objective of this work was to synthesize taiwanin C, an arylnaphthalene lignan extracted from Taiwania cryptomerioides, more efficiently than reported by other authors, to evaluate its antiplatelet activity using arachidonic acid and TRAP-6 as agonists, in addition to study the mechanism of action on COXs and PAR-1, which are, respectively, the proteins involved in platelet activation pathways mediated by these agonists. Two synthetic routes were evaluated in which taiwanin C was obtained in total yields of 40.4% and 52%, therefore in higher than those described in the literature. In assays using human platelets, taiwanin C significantly inhibited platelet aggregation in the presence of arachidonic acid with IC50 = 0.46 µM and in the presence of TRAP-6 with IC50 = 0.56 µM. These studies indicated greater activity of taiwanin C than indomethacin used as a positive control. Molecular docking studies using COX-1 and COX-2 suggest that taiwanin C interacts with both COX, but with greater affinity with COX-1. Regarding PAR-1, studies suggest that taiwanin C has an interaction mechanism different from that of indomethacin and vorapaxar (reference drug). These results demonstrate that taiwanin C acts on two signaling pathways for platelet aggregation, which is no common for most drugs used. Although preliminary, these results indicate that taiwanin C may be a target molecule for the development of new antiplatelet druso.
Platelets are activated when there is disruption of the vascular epithelium due to exposure to a series of factors, changing their shape and initiating a process of aggregation. Platelet activation and aggregation form the thrombus (clot) that prevents blood leakage. After the blood is stopped, platelets are deactivated by the action of prostacyclins, but when the activation and deactivation process is uncontrolled, thrombi can form, which affect the blood flow in the arteries and veins, which can lead to numerous pathologies. In order to control this process, many drugs have been developed, but many have limitations in terms of side effects, patient age and high cost. Therefore, the challenge for many researchers is to obtain molecules that can be efficient, safe and more accessible. Within this context, natural products have been an inexhaustible source of molecules with biological potential. Thus, the objective of this work was to synthesize taiwanin C, an arylnaphthalene lignan extracted from Taiwania cryptomerioides, more efficiently than reported by other authors, to evaluate its antiplatelet activity using arachidonic acid and TRAP-6 as agonists, in addition to study the mechanism of action on COXs and PAR-1, which are, respectively, the proteins involved in platelet activation pathways mediated by these agonists. Two synthetic routes were evaluated in which taiwanin C was obtained in total yields of 40.4% and 52%, therefore in higher than those described in the literature. In assays using human platelets, taiwanin C significantly inhibited platelet aggregation in the presence of arachidonic acid with IC50 = 0.46 µM and in the presence of TRAP-6 with IC50 = 0.56 µM. These studies indicated greater activity of taiwanin C than indomethacin used as a positive control. Molecular docking studies using COX-1 and COX-2 suggest that taiwanin C interacts with both COX, but with greater affinity with COX-1. Regarding PAR-1, studies suggest that taiwanin C has an interaction mechanism different from that of indomethacin and vorapaxar (reference drug). These results demonstrate that taiwanin C acts on two signaling pathways for platelet aggregation, which is no common for most drugs used. Although preliminary, these results indicate that taiwanin C may be a target molecule for the development of new antiplatelet druso.
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Palavras-chave
Atividade antiplaquetária, COX-1, Lignana arilnaftalênica, PAR-1, Antiplatelet activity, Arylnaphthalene lignan