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

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

  • Eur J Med Chem. 2017 Jul 7:134:97-109. doi: 10.1016/j.ejmech.2017.03.078.
Raoni Pais Siqueira 1,  Marcus Vinícius de Andrade Barros 2,  Éverton de Almeida Alves Barbosa 1,  Thiago Souza Onofre 1,  Victor Hugo Sousa Gonçalves 1,  Higor Sette Pereira 1,  Abelardo Silva Júnior 3,  Leandro Licursi de Oliveira 4,  Márcia Rogéria Almeida 1,  Juliana Lopes Rangel Fietto 1,  Róbson Ricardo Teixeira 5,  Gustavo Costa Bressan 6
Affiliations

Affiliations

  • 1 Universidade Federal de Viçosa, Departamento de Bioquímica e Biologia Molecular, Viçosa, MG, Brazil.
  • 2 Universidade Federal de Viçosa, Departamento de Química, Viçosa, MG, Brazil.
  • 3 Universidade Federal de Viçosa, Departamento de Veterinária, Viçosa, MG, Brazil.
  • 4 Universidade Federal de Viçosa, Departamento de Biologia Geral, Viçosa, MG, Brazil.
  • 5 Universidade Federal de Viçosa, Departamento de Química, Viçosa, MG, Brazil. Electronic address: robsonr.teixeira@ufv.br.
  • 6 Universidade Federal de Viçosa, Departamento de Bioquímica e Biologia Molecular, Viçosa, MG, Brazil. Electronic address: gustavo.bressan@ufv.br.
PMID: 28407594 DOI: 10.1016/j.ejmech.2017.03.078
Abstract

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.

Keywords

Leukemia; Pre-mRNA splicing; SRPIN340; SRPK; Serine/arginine-rich protein kinase; Trifluoromethyl arylamides.

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