Síntese e avaliação farmacológica de novos derivados da pomalidomida para o tratamento da anemia falciforme
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Data
2018-02-02
Autores
Melo, Thais Regina Ferreira de [UNESP]
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
A Anemia Falciforme (AF) é uma anemia hemolítica genética caracterizada por uma mutação no gene da globina beta. Além do quadro vaso-oclusivo, os pacientes com AF apresentam processo inflamatório crônico caracterizado pelo aumento de diversas citocinas pró-inflamatórias, a exemplo do Fator de Necrose Tumoral alfa (TNF-α). Atualmente, a hidroxiureia (HU) é o único fármaco disponível para o tratamento e seus efeitos benéficos estão associados ao óxido nítrico (NO), gerado após biotransformação. O NO desempenha efeitos benéficos na doença tais como: vasodilatação, inibição da agregação plaquetária e aumento na produção de hemoglobina fetal (HbF). Nesse contexto, foram sintetizados os compostos 3(a-b); 4(a-b) e 5(a-b) obtidos através da estratégia de hibridação molecular da subunidade inibidora de TNF-α presente na pomalidomida com o núcleo furoxânico (1,2,5-oxadiazol-2-N-óxido) com propriedades doadores de NO. Os compostos sintetizados foram obtidos em rendimentos que variaram entre 13 e 30%. As moléculas do estudo demonstraram capacidade de liberar NO em níveis que variaram entre 1 e 30%. Em cultura de células CD34+, o composto 4b (2,5 μM) foi capaz de induzir gobina γ, enquanto HU foi ativa apenas em concentrações 4 vezes superiores (10 μM). Estudos preliminares do possível mecanismo de ação mostraram que o composto 4b não interefe na expressão de fatores de transcrição a exemplo do BCL11A, IKAROS, LRF e nos níveis de acetilação de histona H3. O composto 4b foi capaz de induzir o aumento dos níveis de monofostato de guanosina cíclico (GMPc) em células HUVEC e diminuir a produção de TNF-α em monócitos. Os resultados aqui obtidos sugerem que o composto 4b seja um novo protótipo para o desenvolvimento de fármacos para anemia falciforme.
Sickle cell anemia (SCA) is a inherited hemolitical anemia characterized by a mutation in the β-globin gene. In addition to the vaso-occlusive condition, there is a chronic inflammatory process in the patients characterized by the increase of several pro-inflammatory cytokines, such as TNF-α. Currently, hydroxyurea (HU) is the only drug available for treatment and its beneficial effects are associated with nitric oxide (NO), generated after biotransformation. NO has beneficial effects on the disease such as vasodilatation, inhibition of platelet aggregation and fetal hemoglobin (HbF) production. In this context, the compounds 3 (a-b), 4(a-b) and 5(a-b) were synthesized using molecular hybridization approach of the pomalidomide TNF-α inhibitor subunit with the furoxan ring (1,2,5-oxadiazol-2-N-oxide) as NO donor. Compounds were synthesized in yields ranging from 13 to 30%. The compounds demonstrated ability to release NO at levels ranging from 1 to 30%. In CD34+ cellular cultures, compound 4b at 2.5 μM concentration was able to induce γ-globin, while HU was active only at 4-fold higher concentrations (10 μM). Preliminary studies of the mechanism of action have shown that compound 4b does not interfere with transcription factors such as BCL11A, IKAROS, LRF and histone H3 acetylation levels. Our results indicate that, the mechanism of action of this compound differs from the parental drug pomalidomide. Compound 4b also increased cGMP levels in HUVEC and CD34 + cells. For CD34 + cells, cGMP levels were comparable to that of HU. These results sugest that compound 4b is a promising lead candidate for the development of drug candidates for treatment of SCA.
Sickle cell anemia (SCA) is a inherited hemolitical anemia characterized by a mutation in the β-globin gene. In addition to the vaso-occlusive condition, there is a chronic inflammatory process in the patients characterized by the increase of several pro-inflammatory cytokines, such as TNF-α. Currently, hydroxyurea (HU) is the only drug available for treatment and its beneficial effects are associated with nitric oxide (NO), generated after biotransformation. NO has beneficial effects on the disease such as vasodilatation, inhibition of platelet aggregation and fetal hemoglobin (HbF) production. In this context, the compounds 3 (a-b), 4(a-b) and 5(a-b) were synthesized using molecular hybridization approach of the pomalidomide TNF-α inhibitor subunit with the furoxan ring (1,2,5-oxadiazol-2-N-oxide) as NO donor. Compounds were synthesized in yields ranging from 13 to 30%. The compounds demonstrated ability to release NO at levels ranging from 1 to 30%. In CD34+ cellular cultures, compound 4b at 2.5 μM concentration was able to induce γ-globin, while HU was active only at 4-fold higher concentrations (10 μM). Preliminary studies of the mechanism of action have shown that compound 4b does not interfere with transcription factors such as BCL11A, IKAROS, LRF and histone H3 acetylation levels. Our results indicate that, the mechanism of action of this compound differs from the parental drug pomalidomide. Compound 4b also increased cGMP levels in HUVEC and CD34 + cells. For CD34 + cells, cGMP levels were comparable to that of HU. These results sugest that compound 4b is a promising lead candidate for the development of drug candidates for treatment of SCA.
Descrição
Palavras-chave
Anemia Falciforme, pomalidomida, Sickle cell anemia, pomalidomide, nitric oxide donors, doadores de óxido nítrico