Trifluoromethyl arylamides with antileukemia effect and intracellular inhibitory activity over serine/arginine-rich protein kinases (SRPKs)

• Autor(a) principal: Siqueira, Raoni Pais
• Data de Publicação: 2017
• Outros Autores: Barros, Marcus Vinícius de Andrade, Barbosa, Éverton de Almeida Alves, Onofre, Thiago Souza, Gonçalves, Victor Hugo Sousa, Pereira, Higor Sette, Silva Júnior, Abelardo, Oliveira, Leandro Licursi de, Almeida, Márcia Rogéria, Fietto, Juliana Lopes Rangel, Teixeira, Róbson Ricardo, Bressan, Gustavo Costa
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: LOCUS Repositório Institucional da UFV
• Texto Completo: https://doi.org/10.1016/j.ejmech.2017.03.078; http://www.locus.ufv.br/handle/123456789/19944
• topic: Trifluoromethyl arylamides; SRPK; SRPIN340; Serine/arginine-rich protein kinase; Leukemia; Pre-mRNA splicing

The serine/arginine-rich protein kinases (SRPKs) have frequently been found with altered activity in a number of cancers, suggesting they could serve as potential therapeutic targets in oncology. Here we describe the synthesis of a series of twenty-two trifluoromethyl arylamides based on the known SRPKs inhibitor N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide (SRPIN340) and the evaluation of their antileukemia effects. Some derivatives presented superior cytotoxic effects against myeloid and lymphoid leukemia cell lines compared to SRPIN340. In particular, compounds 24, 30, and 36 presented IC50 values ranging between 6.0 and 35.7 μM. In addition, these three compounds were able to trigger apoptosis and autophagy, and to exhibit synergistic effects with the chemotherapeutic agent vincristine. Furthermore, compound 30 was more efficient than SRPIN340 in impairing the intracellular phosphorylation status of SR proteins as well as the expression of MAP2K1, MAP2K2, VEGF, and RON oncogenic isoforms. Therefore, novel compounds with increased intracellular effects against SRPK activity were obtained, contributing to medicinal chemistry efforts towards the development of new anticancer agents.