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Síntese e avaliação in vitro de novos derivados de tiossemicarbazonas como compostos biologicamente ativos
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A produção de radicais livres é uma consequência normal do metabolismo celular. O equilíbrio entre a produção destas espécies e o sistema de defesa antioxidante é fundamental na manutenção das funções fisiológicas, uma vez que um excesso de oxidantes leva a uma situação de stress oxidativo. Devido a este fenómeno, a procura por antioxidantes exógenos tem-se intensificado. As tiossemicarbazonas têm sido estudadas em Química Medicinal devido às suas inúmeras propriedades biológicas, destacando-se as promissoras atividades antioxidante e anticancerígena.
Neste trabalho construiu-se uma pequena biblioteca de quinze derivados de tiossemicarbazonas (4.a - 4.o), dez dos quais novos (4.a – 4.e, 4.h, 4.l, 4.m – 4.o). Os compostos foram caracterizados por RMN (1H, 13C-APT, COSY, HSQC, HMBC e, no caso de 4.b, 4.h, 4.m e 4.o por NOESY), IV e ESI-HRMS.
Avaliou-se a atividade antioxidante de todos os compostos segundo o método de sequestro do radical livre DPPH. Sete compostos (4.a, 4.d, 4.f, 4.g, 4.m - 4.o) revelaram uma capacidade antioxidante boa a moderada, com valores de EC50 compreendidos entre 51,34 ± 1,93 μM e 252,16 ± 3,61 μM. O composto mais promissor foi a (E)-2-((3-metil-1H-indole-2-il)metileno)-N-fenil-hidrazinacarbotioamida (4.o) com um EC50 de 51,34 ± 1,93 μM, comparável ao da rutina 11,36 ± 0,38 μM e ácido ascórbico 23,66 ± 0,82 μM.
A citotoxicidade in vitro dos compostos (4.b e 4.f – 4.o), foi avaliada em células de hepatocarcinoma humano Hep-G2, para uma indicação preliminar do potencial hepatotóxico e, células de cancro da mama hormono-dependente MCF-7, segundo o método colorimétrico do MTT. Os resultados demonstraram que, em ambas as linhas celulares, para uma concentração de 100 μM, não se obteve uma percentagem de morte celular significativa, portanto nenhum dos compostos testados é citotóxico.
Em suma, com os resultados obtidos foi possível concluir que as tiossemicarbazonas sintetizadas não apresentam citotoxicidade, nem para as células Hep-G2 nem para as MCF-7. Contudo, sustentam que alguns dos compostos apresentam um promissor potencial antioxidante, com destaque para o 4.o, que poderá representar uma lead para o desenvolvimento de novos antioxidantes.
The production of free radicals is a common consequence of cellular metabolism. The balance between these species and the antioxidant defense system is essential in maintaining physiological functions since an excess of oxidants, leads to a situation of oxidative stress. Due to this phenomenon, the search for exogenous antioxidants has intensified. Thiosemicarbazones have been the subject of studies in medicinal chemistry due to their numerous biological properties, highlighting their promising antioxidant and anticancer activity. In this project, a small library of fifteen thiosemicarbazones derivatives (4.a - 4.o) was built, ten of which were new (4.a – 4.e, 4.h, 4.l, 4.m – 4.o). All compounds were characterized by NMR (1H, 13C-APT, COSY, HSQC, HMBC, and in the case of 4.b, 4.h, 4.m and 4.o NOESY was used), IV and ESI-HRMS. The antioxidant activity of all compounds was evaluated according to the DPPH free radical scavenging method. Seven compounds (4.a, 4.d, 4.f, 4.g, 4.m - 4.o) showed an antioxidant capacity from good to moderate, with EC50 values between 51,34 ± 1,93 μM and 252,16 ± 3,61 μM. Compound (E)-2-((3-methyl-1H-indole-2-yl)methylene)-N-phenyl-hydrazinecarbothioamide (4.o) was the most promising with an EC50 of 51,34 ± 1,93 μM, comparable to the rutin 11,36 ± 0,38 μM and ascorbic acid 23,66 ± 0,82 μM. The in vitro cytotoxicity of the compounds (4.b and 4.f – 4.o) was evaluated in Hep-G2 human hepatocarcinoma cells, for a preliminary indication of hepatotoxic potential and, hormone-dependent breast cancer cells MCF-7, according to the MTT colorimetric assay. The results demonstrated that, in both cell lines, at a 100 μM concentration, a significant percentage of cell death wasn’t obtained, therefore none of the tested compounds is cytotoxic. In summary, with the results obtained it was possible to conclude that the synthesized thiosemicarbazones don’t show cytotoxicity, either for Hep-G2 cells or for MCF-7. Nonetheless, they support that some of the compounds have promising antioxidant potential, with emphasis on the 4.o, which may represent a lead for developing new antioxidants.
The production of free radicals is a common consequence of cellular metabolism. The balance between these species and the antioxidant defense system is essential in maintaining physiological functions since an excess of oxidants, leads to a situation of oxidative stress. Due to this phenomenon, the search for exogenous antioxidants has intensified. Thiosemicarbazones have been the subject of studies in medicinal chemistry due to their numerous biological properties, highlighting their promising antioxidant and anticancer activity. In this project, a small library of fifteen thiosemicarbazones derivatives (4.a - 4.o) was built, ten of which were new (4.a – 4.e, 4.h, 4.l, 4.m – 4.o). All compounds were characterized by NMR (1H, 13C-APT, COSY, HSQC, HMBC, and in the case of 4.b, 4.h, 4.m and 4.o NOESY was used), IV and ESI-HRMS. The antioxidant activity of all compounds was evaluated according to the DPPH free radical scavenging method. Seven compounds (4.a, 4.d, 4.f, 4.g, 4.m - 4.o) showed an antioxidant capacity from good to moderate, with EC50 values between 51,34 ± 1,93 μM and 252,16 ± 3,61 μM. Compound (E)-2-((3-methyl-1H-indole-2-yl)methylene)-N-phenyl-hydrazinecarbothioamide (4.o) was the most promising with an EC50 of 51,34 ± 1,93 μM, comparable to the rutin 11,36 ± 0,38 μM and ascorbic acid 23,66 ± 0,82 μM. The in vitro cytotoxicity of the compounds (4.b and 4.f – 4.o) was evaluated in Hep-G2 human hepatocarcinoma cells, for a preliminary indication of hepatotoxic potential and, hormone-dependent breast cancer cells MCF-7, according to the MTT colorimetric assay. The results demonstrated that, in both cell lines, at a 100 μM concentration, a significant percentage of cell death wasn’t obtained, therefore none of the tested compounds is cytotoxic. In summary, with the results obtained it was possible to conclude that the synthesized thiosemicarbazones don’t show cytotoxicity, either for Hep-G2 cells or for MCF-7. Nonetheless, they support that some of the compounds have promising antioxidant potential, with emphasis on the 4.o, which may represent a lead for developing new antioxidants.
Descrição
Palavras-chave
radicais livres antioxidantes tiossemicarbazonas atividade antioxidante citotoxicidade