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

Detalhes bibliográficos
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
Resumo: 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.
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spelling Siqueira, Raoni PaisBarros, Marcus Vinícius de AndradeBarbosa, Éverton de Almeida AlvesOnofre, Thiago SouzaGonçalves, Victor Hugo SousaPereira, Higor SetteSilva Júnior, AbelardoOliveira, Leandro Licursi deAlmeida, Márcia RogériaFietto, Juliana Lopes RangelTeixeira, Róbson RicardoBressan, Gustavo Costa2018-06-05T14:51:22Z2018-06-05T14:51:22Z2017-03-3102235234https://doi.org/10.1016/j.ejmech.2017.03.078http://www.locus.ufv.br/handle/123456789/19944The 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.engEuropean Journal of Medicinal Chemistryv. 134, p. 97-109, July 2017Elsevier Masson SAS.info:eu-repo/semantics/openAccessTrifluoromethyl arylamidesSRPKSRPIN340Serine/arginine-rich protein kinaseLeukemiaPre-mRNA splicingTrifluoromethyl arylamides with antileukemia effect and intracellular inhibitory activity over serine/arginine-rich protein kinases (SRPKs)info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfreponame:LOCUS Repositório Institucional da UFVinstname:Universidade Federal de Viçosa (UFV)instacron:UFVORIGINALartigo.pdfartigo.pdfTexto completoapplication/pdf2637155https://locus.ufv.br//bitstream/123456789/19944/1/artigo.pdf6b5b2f7245d287477cad2e993639a1e5MD51LICENSElicense.txtlicense.txttext/plain; charset=utf-81748https://locus.ufv.br//bitstream/123456789/19944/2/license.txt8a4605be74aa9ea9d79846c1fba20a33MD52THUMBNAILartigo.pdf.jpgartigo.pdf.jpgIM Thumbnailimage/jpeg6463https://locus.ufv.br//bitstream/123456789/19944/3/artigo.pdf.jpg5f3155c121b3459551aa187211efbc75MD53123456789/199442018-06-05 23:00:34.239oai:locus.ufv.br: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Repositório InstitucionalPUBhttps://www.locus.ufv.br/oai/requestfabiojreis@ufv.bropendoar:21452018-06-06T02:00:34LOCUS Repositório Institucional da UFV - Universidade Federal de Viçosa (UFV)false
dc.title.en.fl_str_mv Trifluoromethyl arylamides with antileukemia effect and intracellular inhibitory activity over serine/arginine-rich protein kinases (SRPKs)
title Trifluoromethyl arylamides with antileukemia effect and intracellular inhibitory activity over serine/arginine-rich protein kinases (SRPKs)
spellingShingle Trifluoromethyl arylamides with antileukemia effect and intracellular inhibitory activity over serine/arginine-rich protein kinases (SRPKs)
Siqueira, Raoni Pais
Trifluoromethyl arylamides
SRPK
SRPIN340
Serine/arginine-rich protein kinase
Leukemia
Pre-mRNA splicing
title_short Trifluoromethyl arylamides with antileukemia effect and intracellular inhibitory activity over serine/arginine-rich protein kinases (SRPKs)
title_full Trifluoromethyl arylamides with antileukemia effect and intracellular inhibitory activity over serine/arginine-rich protein kinases (SRPKs)
title_fullStr Trifluoromethyl arylamides with antileukemia effect and intracellular inhibitory activity over serine/arginine-rich protein kinases (SRPKs)
title_full_unstemmed Trifluoromethyl arylamides with antileukemia effect and intracellular inhibitory activity over serine/arginine-rich protein kinases (SRPKs)
title_sort Trifluoromethyl arylamides with antileukemia effect and intracellular inhibitory activity over serine/arginine-rich protein kinases (SRPKs)
author Siqueira, Raoni Pais
author_facet Siqueira, Raoni Pais
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
author_role author
author2 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
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.author.fl_str_mv Siqueira, Raoni Pais
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
dc.subject.pt-BR.fl_str_mv Trifluoromethyl arylamides
SRPK
SRPIN340
Serine/arginine-rich protein kinase
Leukemia
Pre-mRNA splicing
topic Trifluoromethyl arylamides
SRPK
SRPIN340
Serine/arginine-rich protein kinase
Leukemia
Pre-mRNA splicing
description 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.
publishDate 2017
dc.date.issued.fl_str_mv 2017-03-31
dc.date.accessioned.fl_str_mv 2018-06-05T14:51:22Z
dc.date.available.fl_str_mv 2018-06-05T14:51:22Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
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dc.identifier.uri.fl_str_mv https://doi.org/10.1016/j.ejmech.2017.03.078
http://www.locus.ufv.br/handle/123456789/19944
dc.identifier.issn.none.fl_str_mv 02235234
identifier_str_mv 02235234
url https://doi.org/10.1016/j.ejmech.2017.03.078
http://www.locus.ufv.br/handle/123456789/19944
dc.language.iso.fl_str_mv eng
language eng
dc.relation.ispartofseries.pt-BR.fl_str_mv v. 134, p. 97-109, July 2017
dc.rights.driver.fl_str_mv Elsevier Masson SAS.
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publisher.none.fl_str_mv European Journal of Medicinal Chemistry
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