Síntese e avaliação anti-inflamatória de derivados esteroides da série Lapdesf GL-FT
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Data
2017-02-01
Autores
Machado, Marcella Gabrielle Mendes [UNESP]
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
Os glicocorticoides (GCs) são fármacos utilizados amplamente na terapêutica devido suas atividades anti-inflamatória, imunossupressora e antiangiogênica. Possuem a capacidade de reduzir a transcrição de uma série de enzimas/proteínas inflamatórias como a ciclooxigenase-2 (COX-2), lipoxigenases, fosfolipase A2, óxido nítrico sintase induzida (iNOS) e citocinas pró-inflamatórias como o fator de necrose tumoral alfa (TNF-alfa), super expresso em diversas doenças inflamatórias. Porém o seu uso é limitado devido as diversas reações adversas. Derivados ftalimídicos também têm sido relatados na literatura com importante atividade anti-inflamatória. Dessa forma, no presente trabalho, planejou-se através da estratégia de hibridação molecular, novos derivados anti-inflamatórios esteroides moduladores da citocina TNF-alfa, úteis no tratamento de doenças inflamatórias crônicas. Nesse contexto, foram sintetizados e caracterizados seis compostos derivados da prednisolona e budesonida da série Lapdesf GL-FT 1-6. Os compostos finais foram avaliados quanto à atividade anti-inflamatória em modelo de colite ulcerativa distal, atividade imunossupressora e determinação da viabilidade celular necessária para o ensaio de doseamento da citocina TNF-alfa. Além disso, os compostos GLFT 2 e 3 foram avaliados quanto à atividade anti-inflamatória em modelo de edema de pata. No ensaio de colite ulcerativa os compostos Lapdesf GL-FT 5 e 6 foram iguais estatisticamente ao controle negativo e apresentaram atividade anti-inflamatória com regressão do quadro de ulceração causada pela indução com ácido acético. O composto 5 ainda apresentou melhora nos sinais clínicos com ganho de peso e aumento da sobrevida dos animais e regressão total da ulceração em 83,3% dos animais tratados. Os compostos GLFT 1 e 3 foram diferentes estatisticamente dos grupos controle positivo e negativo. Apresentaram atividade anti-inflamatória com regressão total do quadro de ulceração em 33,3% dos animais em cada grupo, sendo superior ao fármaco padrão, prednisolona, que obteve 16,7% de regressão total da ulceração. A viabilidade celular para os seis compostos da série Lapdesf GL-FT nas concentrações de 50, 25, 12,5, 6,25, 3,12 e 1,65 μM foi superior a 70% indicando baixa citotoxicidade. Porém, os compostos GL-FT 2 e 3 apresentaram viabilidade celular inesperada, chegando a valores de 300 e 400%, respectivamente, nas concentrações avaliadas. Os derivados da série Lapdesf GL-FT 1-6 não apresentaram atividade imunossupressora no ensaio in vitro. Os compostos Lapdesf GL-FT 2 e 3 apresentaram atividade anti-inflamatória no ensaio de edema de pata, não havendo diferença estatística com o fármaco padrão, prednisolona.
Glucocorticoids (GCs) are drugs widely used in therapy due their anti-inflammatory, immunosuppressive and antiangiogenic activities. They have the ability to reduce the transcription of a series of inflammatory enzymes / proteins such as cyclooxygenase-2 (COX-2), lipoxygenases, phospholipase A2, induced nitric oxide synthase (iNOS) and proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha), over expressed in several inflammatory diseases. However, its use is limited due to the various adverse reactions. Phthalimide derivatives have also been reported in the literature with important anti-inflammatory activity. Thus, in the present work, new steroid anti-inflammatory derivatives as TNF-alpha cytokine modulators, useful in the treatment of chronic inflammatory diseases, have been designed through the molecular hybridization strategy. In this context, six compounds prednisolone and budesonide derivatives, Lapdesf GL-FT series, were synthesized and characterized. The final compounds were evaluated for anti-inflammatory activity in a model of distal ulcerative colitis, immunosuppressive activity and cell viability assay required for the TNF-alpha assay. In addition, GLFT 2 and 3 compounds were evaluated for anti-inflammatory activity in paw edema model. In the ulcerative colitis test, Lapdesf GL-FT 5 and 6 compounds were statistically equal to the negative control and showed anti-inflammatory activity with regression of the ulceration caused by the induction with acetic acid. Compound 5 also showed improvement in clinical signs such as weight gain and increased survival of animals and total regression of ulceration in 83.3% of treated animals. GLFT 1 and 3 compounds were statistically different from the positive and negative control groups. They presented anti-inflammatory activity with total regression of ulceration in 33.3% of the animals in each group, being superior to the standard drug, prednisolone, which obtained 16.7% of total ulceration regression. Cell viability for all Lapdesf GL-FT compounds at the concentrations of 50, 25, 12.5, 6.25, 3.125 and 1.65 μM was higher than 70% indicating low cytotoxicity. However, GL-FT 2 and 3 compounds showed unexpected cell viability, reaching values of 300 and 400%, respectively, at the concentrations evaluated. Lapdesf GL-FT 1-6 did not present immunosuppressive activity in the in vitro assay. Lapdesf GL-FT 2 and 3 compounds showed anti-inflammatory activity in the paw edema test, and there was no statistical difference with the standard drug, prednisolone.
Glucocorticoids (GCs) are drugs widely used in therapy due their anti-inflammatory, immunosuppressive and antiangiogenic activities. They have the ability to reduce the transcription of a series of inflammatory enzymes / proteins such as cyclooxygenase-2 (COX-2), lipoxygenases, phospholipase A2, induced nitric oxide synthase (iNOS) and proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha), over expressed in several inflammatory diseases. However, its use is limited due to the various adverse reactions. Phthalimide derivatives have also been reported in the literature with important anti-inflammatory activity. Thus, in the present work, new steroid anti-inflammatory derivatives as TNF-alpha cytokine modulators, useful in the treatment of chronic inflammatory diseases, have been designed through the molecular hybridization strategy. In this context, six compounds prednisolone and budesonide derivatives, Lapdesf GL-FT series, were synthesized and characterized. The final compounds were evaluated for anti-inflammatory activity in a model of distal ulcerative colitis, immunosuppressive activity and cell viability assay required for the TNF-alpha assay. In addition, GLFT 2 and 3 compounds were evaluated for anti-inflammatory activity in paw edema model. In the ulcerative colitis test, Lapdesf GL-FT 5 and 6 compounds were statistically equal to the negative control and showed anti-inflammatory activity with regression of the ulceration caused by the induction with acetic acid. Compound 5 also showed improvement in clinical signs such as weight gain and increased survival of animals and total regression of ulceration in 83.3% of treated animals. GLFT 1 and 3 compounds were statistically different from the positive and negative control groups. They presented anti-inflammatory activity with total regression of ulceration in 33.3% of the animals in each group, being superior to the standard drug, prednisolone, which obtained 16.7% of total ulceration regression. Cell viability for all Lapdesf GL-FT compounds at the concentrations of 50, 25, 12.5, 6.25, 3.125 and 1.65 μM was higher than 70% indicating low cytotoxicity. However, GL-FT 2 and 3 compounds showed unexpected cell viability, reaching values of 300 and 400%, respectively, at the concentrations evaluated. Lapdesf GL-FT 1-6 did not present immunosuppressive activity in the in vitro assay. Lapdesf GL-FT 2 and 3 compounds showed anti-inflammatory activity in the paw edema test, and there was no statistical difference with the standard drug, prednisolone.
Descrição
Palavras-chave
Anti-inflamatório, Ftalimida, Glicocorticoides, Hibridação molecular, Anti-inflammatory, Phthalimide, Glucocorticoids, Molecular hybridization