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

Autor: Siqueira RP; Universidade Federal de Viçosa, Departamento de Bioquímica e Biologia Molecular, Viçosa, MG, Brazil., Barros MVA; Universidade Federal de Viçosa, Departamento de Química, Viçosa, MG, Brazil., Barbosa ÉAA; Universidade Federal de Viçosa, Departamento de Bioquímica e Biologia Molecular, Viçosa, MG, Brazil., Onofre TS; Universidade Federal de Viçosa, Departamento de Bioquímica e Biologia Molecular, Viçosa, MG, Brazil., Gonçalves VHS; Universidade Federal de Viçosa, Departamento de Bioquímica e Biologia Molecular, Viçosa, MG, Brazil., Pereira HS; Universidade Federal de Viçosa, Departamento de Bioquímica e Biologia Molecular, Viçosa, MG, Brazil., Silva Júnior A; Universidade Federal de Viçosa, Departamento de Veterinária, Viçosa, MG, Brazil., de Oliveira LL; Universidade Federal de Viçosa, Departamento de Biologia Geral, Viçosa, MG, Brazil., Almeida MR; Universidade Federal de Viçosa, Departamento de Bioquímica e Biologia Molecular, Viçosa, MG, Brazil., Fietto JLR; Universidade Federal de Viçosa, Departamento de Bioquímica e Biologia Molecular, Viçosa, MG, Brazil., Teixeira RR; Universidade Federal de Viçosa, Departamento de Química, Viçosa, MG, Brazil. Electronic address: robsonr.teixeira@ufv.br., Bressan GC; Universidade Federal de Viçosa, Departamento de Bioquímica e Biologia Molecular, Viçosa, MG, Brazil. Electronic address: gustavo.bressan@ufv.br.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2017 Jul 07; Vol. 134, pp. 97-109. Date of Electronic Publication: 2017 Mar 31.
DOI: 10.1016/j.ejmech.2017.03.078
Abstrakt: 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 IC 50 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.
(Copyright © 2017 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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