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Síntese de Catinonas psicoativas e avaliação da sua hepatotoxicidade
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Este trabalho foi realizado no âmbito do protocolo entre a Faculdade de Ciências da Universidade de Lisboa e o Laboratório de Polícia Cientifica da Policia Judiciária (LPC-PJ). Teve como objetivo a sintese de 12 catinonas psicoactivas (N,N-dimetilcatinona (DMC), N,N-dimetilbufedrona (DMB), N,N-dietilpentedrona (DMP), N,N-4-metildimetcatinona (4-MDMC), anfepramona (AFP), N,N-dietilbufedrona (DEB), N,N-dietilpentedrona (DEP), 4’-metilfenilanfepramona (4-MAFP), N-etilcatinona (NEC), N-etilbufedrona (NEB), N-etilpentedrona (NEP), 4’-metil-α-pirrolidinpropiofenona (4-MPPP)) e a avaliação da sua hepatotoxicidade juntamente com a da 3,4-DMMC. Foi ainda efetuada a identificação de uma catinona sintética num produto apreendido em Portugal, a N-etilpentilona (Efilona). A catinona é um β-ceto análogo da anfetamina, um potente estimulante do sistema nervoso central, pelo que diversas catinonas têm surgido no mercado das drogas como substitutos legais das substâncias ilicitas. Estes são categorizados como catinonas sintéticas e enquadram-se na classificação de Novas Substâncias Psicoactivas (NSP), definidas como novas subtâncias psicotrópicas que não são controladas pela Convenção Única de Estupefacientes de 1961 nem pela Convenção de Substâncias Psicotrópicas de 1971. As catinonas sintéticas são o segundo maior grupo de substâncias psicoativas reportadas ao Observatório Europeu da Droga e Toxicodependência (EMCDDA, European Monitoring Centre for Drugs and Drug Addiction) e representam um perigo para a saúde pública, não só pelos seus riscos já reportados mas também devido à facil acessibilidade ao público via internet. Tendo em conta que, o fígado é um dos orgãos alvo das anfetaminas e de já se ter conhecimento de casos de insuficiência hepática nos consumidores de catinonas psicoativas, revela-se importante compreender a relação destas substâncias com a toxicidade no fígado. Estes compostos são sintetizados em laboratórios ilegais, deste modo o conhecimento da sua síntese é importante para prever o aparecimento de novos compostos no mercados e a sua toxicidade. Este trabalho descreve uma síntese de 2 passos para se obter 12 catinonas psicoativas e a sua caracterização por RMN, GC-MS e HR-MS-ESI. Após confirmação da pureza das catinonas foi avaliada a sua toxicidade contra a linha celular do fígado Hep G2. As células foram expostas aos compostos, durante 24 horas, com concentrações a variar entre 0,05 e 16 mM e a viabilidade celular pelo método do MTT (brometo de 3-(4,5-dimetiltiazol-2-il)-2,5-difeniltetrazólio). Através das curvas dose-resposta obteve-se valores de EC50, concentração entre o limite inferior e superior que induz 50 % de morte celular . As catinonas 4-MDMC (0,81 mM) e DMP (1,09 mM) foram as que revelaram maior tóxicidade, enquanto que as catinonas DMC (7,83 mM) e AFP (6,62 mM) foram as menos tóxicas. Tomou-se como referência duas catinonas já designadas como drogas e proibidas, a mefedrona (1,28 mM) e a 4-MEC (1,51 mM). Finalmente, os resultados foram comparados com a hepatoxicidade de 8 catinonas (metcatinona, bufedrona, pentedrona, α-PPP, α-PBP, α-PVP, mefedrona e 4-MEC) sintetizadas e testadas anteriormente. Deste modo, por comparação da toxicidade das 21 catinonas foi possivel comprovar uma relação entre a sua toxicidade hepatocelular e a sua estrutura, mostrando que as catinonas com maior cadeia alquílica exibem maior toxicidade, bem como catinonas que contêm um grupo metilo no seu anel aromático.
This work was carried out under the protocol between the Faculty of Sciences of the University of Lisbon and the Laboratory of Scientific Police of the Judicial Police (LPC-PJ). The main purpose of this work was to synthetize 12 psychoactive cathinones (dimethylcathinone, dimethylbuphedrone, diethylpentedrone, N,N-4-methyldimethcathinone, anfepramone, diethylbuphedrone, diethylpentedrone, 4’-methylphenilanfepramone, N-ethylcathinone, N-ethylbuphedrone, N-ethylpentedrone, 4’-methyl-α-pirrolidinpropiophenone) and evaluate their hepatotoxicity along with the 3,4-DMMC. A synthetic cathinone was also identified in a product seized in Portugal, N-ethylpentilone (Ephylone). Since cathinone, a β-keto analogue of amphetamine, is a potent central nervous system stimulant, several synthetic analogues have emerged in the market of recreational drugs as legal substitutes of illicit substances. Synthetic cathinones are classified as New Psychoactive Substances (NPS), which englob substances that are not controlled by the 1961 Single Convention on Narcotic Drugs or by the 1971 Convention on Psychotropic Substances. Synthetic cathinones are the second largest group of psychoactive substances reported do the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) and they represent a public health issue, not only due to the already reported secondary effects, but also because of their easy availability to the public through the internet. Considerente that the liver is the main target for amphetamines, and that liver failure has already been reported in psychoactive cathinone users, it is important to understand the relationship of these substances to liver toxicity. This compounds are synthetized illegall laboratories, the knowledge of a simple synthetic route that resembles the one used in those labs became important to predict new compounds appearing into the market and their toxicity. This work describes a two-step pathway to synthetize 12 psychoactive cathinones and their characterization by NMR, GC-MS and HR-MS-ESI. After confirming the purity of the cathinones, their toxicity was evaluated against the Hep G2 liver cell line. The cells were exposed to the compounds, for 24 hours, to concentrations between 0,05 and 16 mM and the cellular viability was evaluated through the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Through the dose-response curves the EC50 values were determinated, concentration between the bottom and top limits that induces 50 % of cellular death. The toxicity was higher to cathinones 4-MDMC (0,81 mM) and DMP (1,09 mM), while to cathinones DMC (7,83 mM) and AFP (6,62 mM) the toxicity was the lowest. As reference two cathinones considered as prohibited drugs were chosen, mephedrone (1,28 mM) and 4-MEC (1,51 mM). Finally, the results were compared with the hepatotoxicity of 8 cathinones (methcathinone, buphedrone, pentedrone, α-PPP, α-PBP, α-PVP, mephedrone and 4-MEC) synthetized and tested before. Thus by comparision oh the toxicity of 21 cathinones it is possible to prove the relation between the hepatocellular toxicity of cathinones and their chemical structure, showing a toxicity enhancement with the increase of the alkyl chain length of the ketone moiety, as well as with the substitution of an Aromatic-H by a methyl group.
This work was carried out under the protocol between the Faculty of Sciences of the University of Lisbon and the Laboratory of Scientific Police of the Judicial Police (LPC-PJ). The main purpose of this work was to synthetize 12 psychoactive cathinones (dimethylcathinone, dimethylbuphedrone, diethylpentedrone, N,N-4-methyldimethcathinone, anfepramone, diethylbuphedrone, diethylpentedrone, 4’-methylphenilanfepramone, N-ethylcathinone, N-ethylbuphedrone, N-ethylpentedrone, 4’-methyl-α-pirrolidinpropiophenone) and evaluate their hepatotoxicity along with the 3,4-DMMC. A synthetic cathinone was also identified in a product seized in Portugal, N-ethylpentilone (Ephylone). Since cathinone, a β-keto analogue of amphetamine, is a potent central nervous system stimulant, several synthetic analogues have emerged in the market of recreational drugs as legal substitutes of illicit substances. Synthetic cathinones are classified as New Psychoactive Substances (NPS), which englob substances that are not controlled by the 1961 Single Convention on Narcotic Drugs or by the 1971 Convention on Psychotropic Substances. Synthetic cathinones are the second largest group of psychoactive substances reported do the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) and they represent a public health issue, not only due to the already reported secondary effects, but also because of their easy availability to the public through the internet. Considerente that the liver is the main target for amphetamines, and that liver failure has already been reported in psychoactive cathinone users, it is important to understand the relationship of these substances to liver toxicity. This compounds are synthetized illegall laboratories, the knowledge of a simple synthetic route that resembles the one used in those labs became important to predict new compounds appearing into the market and their toxicity. This work describes a two-step pathway to synthetize 12 psychoactive cathinones and their characterization by NMR, GC-MS and HR-MS-ESI. After confirming the purity of the cathinones, their toxicity was evaluated against the Hep G2 liver cell line. The cells were exposed to the compounds, for 24 hours, to concentrations between 0,05 and 16 mM and the cellular viability was evaluated through the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Through the dose-response curves the EC50 values were determinated, concentration between the bottom and top limits that induces 50 % of cellular death. The toxicity was higher to cathinones 4-MDMC (0,81 mM) and DMP (1,09 mM), while to cathinones DMC (7,83 mM) and AFP (6,62 mM) the toxicity was the lowest. As reference two cathinones considered as prohibited drugs were chosen, mephedrone (1,28 mM) and 4-MEC (1,51 mM). Finally, the results were compared with the hepatotoxicity of 8 cathinones (methcathinone, buphedrone, pentedrone, α-PPP, α-PBP, α-PVP, mephedrone and 4-MEC) synthetized and tested before. Thus by comparision oh the toxicity of 21 cathinones it is possible to prove the relation between the hepatocellular toxicity of cathinones and their chemical structure, showing a toxicity enhancement with the increase of the alkyl chain length of the ketone moiety, as well as with the substitution of an Aromatic-H by a methyl group.
Descrição
Tese de mestrado, Química (Química) Universidade de Lisboa, Faculdade de Ciências, 2017
Palavras-chave
Catinonas Novas substâncias psicoativas Hepatotoxicidade HepG-2 Teses de mestrado - 2017