Síntese e avaliação de bioatividades de derivados triazólicos de benzofenonas hidroxiladas
Data
2018-08-10
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Universidade Federal de Viçosa
Resumo
Os compostos sintetizados foram avaliados quanto à sua atividade antioxidante, citotóxica e inibitória de elatase e também foi determinado seu fator de proteção solar (FPS). Foi descrita a síntese de dezesseis derivados de 4,4'-diidroxibenzofenona e doze derivados de 2,4-diidroxibenzofenona contendo em sua estrutura o anel 1,2,3- triazol. Os compostos sintetizados ainda não haviam sido descritos na literatura e a etapa chave envolvida em suas sínteses foi a reação “click” (CuAAC) entre alquinos terminais e azidas benzílicas. Os compostos foram obtidos com rendimentos variando de 35% a 95%. Todos os compostos foram caracterizados utilizando-se as técnicas de Ressonância Magnética Nuclear (RMN) de 1 H e 13 C, Infravermelho (IV) e Espectro de Massas de Alta Resolução (HRMS). Ensaios in vitro revelam que os derivados de benzofenonas hidroxiladas apresentam fator de proteção solar (FPS) similar a fotoprotetores comercialmente disponíveis. Dez dos derivados sintetizados exibem peso molecular superior a 500 Daltons, característica indispensável para que os fotoprotetores não difundam através da pele. Os derivados triazólicos também foram avaliados quanto à capacidade de inibir a serino protease elastase, sendo o derivado bis(4-((1-(4-iodobenzil)-1H-1,2,3-triazol-4- il)metoxi)benzofenona o mais ativo da série, apresentando um IC 50 de 16,6 ± 1,9 µmol/L. Em relação a atividade antioxidante, os derivados obtidos da 2,4- diidroxibenzofenona mostraram-se mais reativos frente ao radical livre 2,2- xxdifenil-1-picrilhidrazilo (DPPH). A presença de uma hidroxila livre nas moléculas pode ser responsável por sua maior atividade antioxidante. Os ensaios in vitro revelaram que cinco dos derivados triazólicos possuem atividade moderada contra linhagens de células cancerígenas. Os derivados 2-hidroxi-(4-((1-benzil- 1H-1,2,3-triazol-4-il)metoxi)benzofenona e 2-hidroxi-(4-((1-(4-clorobenzil)-1H- 1,2,3-triazol-4-il)metoxi)benzofenona, por exemplo, para a linhagem MCF-7 (carcinoma de mama) apresentaram valores de IC 50 iguais a 50,43 e 65,06 µmol/L, respectivamente, menores que o da cisplatina (IC 50 = 75,73 µmol/L) um fármaco antitumoral comercial. Dessa forma, os compostos sintetizados têm grande potencial para serem usados como antioxidantes e inibiores da atividade proteolítica da enzina elastase e ainda em formulações destinadas a proteção da pele contra os raios ultravioletas.
The present investigation aimed at the synthesis of a group derived from hydroxylated benzophenones. The synthesized compounds had theirs antioxidant, cytotoxic and inhibition of elastase activities evaluated and its sun protection factor was determined. It is described the synthesis of sixteen 4,4‟- dihydroxybenzophenone derivatives and twelve 2,4-dihydroxybenzophenone derivatives, both containing 1,2,3-triazole ring. The key step involved in the synthesis of these derivatives corresponded to the click reaction (CuAAC). The synthesized triazoles have not been described in the literature, and they were obtained yields ranging from 35% to 95%. The compounds were characterized using the techniques of IR, 1 H and 13 C NMR and HRMS. In vitro biological assays carried out with the derivatives of hydroxylated benzophenone demonstrate that four of derivatives showed ability to inhibit serine protease elastase. For instance, bis(4-((1-(4-iodobenzyl)-1H-1,2,3-triazol-4-yl)methoxy) benzophenone showed the most active of the series, presenting an IC 50 value of 16.6 μmol L -1 . In relation to the antioxidant activity, the derivatives obtained from 2,4-dihydroxybenzophenone were more reactive to the DPPH free radical. The presence of a free hydroxyl in the molecules may be responsible for its higher antioxidant activity. In vitro assays revealed that five of the triazole derivatives were shown to have moderate activity against cancer cell lines. The (2-hydroxy-4-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)benzophenone and (2- hydroxy-4-((1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)benzophenone, for example, for the MCF-7 cell (breast carcinoma) showed IC 50 values of 50.43 and 65.06 μmol/L, respectively, lower than that of cisplatin (IC 50 =75.73 μmol/L) a commercial antitumor drug. The triazole derivatives have a sun protection factor (SPF) similar to commercially available photoprotectors, ten of the synthesized derivatives exhibit molecular weight above 500 daltons, an essential feature so that photoprotectors do not diffuse through the skin. Thus, the synthesized compounds have potential to be used as antioxidants and xxiiinhibitors of the proteolytic activity of the enzyme elastase and also in formulations intended to protect the skin against ultraviolet rays.
The present investigation aimed at the synthesis of a group derived from hydroxylated benzophenones. The synthesized compounds had theirs antioxidant, cytotoxic and inhibition of elastase activities evaluated and its sun protection factor was determined. It is described the synthesis of sixteen 4,4‟- dihydroxybenzophenone derivatives and twelve 2,4-dihydroxybenzophenone derivatives, both containing 1,2,3-triazole ring. The key step involved in the synthesis of these derivatives corresponded to the click reaction (CuAAC). The synthesized triazoles have not been described in the literature, and they were obtained yields ranging from 35% to 95%. The compounds were characterized using the techniques of IR, 1 H and 13 C NMR and HRMS. In vitro biological assays carried out with the derivatives of hydroxylated benzophenone demonstrate that four of derivatives showed ability to inhibit serine protease elastase. For instance, bis(4-((1-(4-iodobenzyl)-1H-1,2,3-triazol-4-yl)methoxy) benzophenone showed the most active of the series, presenting an IC 50 value of 16.6 μmol L -1 . In relation to the antioxidant activity, the derivatives obtained from 2,4-dihydroxybenzophenone were more reactive to the DPPH free radical. The presence of a free hydroxyl in the molecules may be responsible for its higher antioxidant activity. In vitro assays revealed that five of the triazole derivatives were shown to have moderate activity against cancer cell lines. The (2-hydroxy-4-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)benzophenone and (2- hydroxy-4-((1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)benzophenone, for example, for the MCF-7 cell (breast carcinoma) showed IC 50 values of 50.43 and 65.06 μmol/L, respectively, lower than that of cisplatin (IC 50 =75.73 μmol/L) a commercial antitumor drug. The triazole derivatives have a sun protection factor (SPF) similar to commercially available photoprotectors, ten of the synthesized derivatives exhibit molecular weight above 500 daltons, an essential feature so that photoprotectors do not diffuse through the skin. Thus, the synthesized compounds have potential to be used as antioxidants and xxiiinhibitors of the proteolytic activity of the enzyme elastase and also in formulations intended to protect the skin against ultraviolet rays.
Descrição
Palavras-chave
Benzofenonas, Química click, 1,2,3-triazol, Elastases, adiação solar - Medidas de segurança, Antioxidantes
Citação
DIAS, Maria Cecília Fernandes. Síntese e avaliação de bioatividades de derivados triazólicos de benzofenonas hidroxiladas. 2018. 268 f. Tese (Doutorado em Agroquímica) - Universidade Federal de Viçosa, Viçosa. 2018.