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(Phenylamino)pyrimidine-1,2,3-triazole derivatives as analogs of imatinib: searching for novel compounds against chronic myeloid leukemia

The enzyme tyrosine kinase BCR-Abl-1 is the main molecular target in the treatment of chronic myeloid leukemia and can be competitively inhibited by tyrosine kinase inhibitors such as imatinib. New potential competitive inhibitors were synthesized using the (phenylamino)pyrimidine-pyridine (PAPP) gr...

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Autores principales: Pimentel, Luiz Claudio Ferreira, Hoelz, Lucas Villas Boas, Canzian, Henayle Fernandes, Branco, Frederico Silva Castelo, de Oliveira, Andressa Paula, Campos, Vinicius Rangel, Júnior, Floriano Paes Silva, Dantas, Rafael Ferreira, Resende, Jackson Antônio Lamounier Camargos, Cunha, Anna Claudia, Boechat, Nubia, Bastos, Mônica Macedo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Beilstein-Institut 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450943/
https://www.ncbi.nlm.nih.gov/pubmed/34621389
http://dx.doi.org/10.3762/bjoc.17.144
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author Pimentel, Luiz Claudio Ferreira
Hoelz, Lucas Villas Boas
Canzian, Henayle Fernandes
Branco, Frederico Silva Castelo
de Oliveira, Andressa Paula
Campos, Vinicius Rangel
Júnior, Floriano Paes Silva
Dantas, Rafael Ferreira
Resende, Jackson Antônio Lamounier Camargos
Cunha, Anna Claudia
Boechat, Nubia
Bastos, Mônica Macedo
author_facet Pimentel, Luiz Claudio Ferreira
Hoelz, Lucas Villas Boas
Canzian, Henayle Fernandes
Branco, Frederico Silva Castelo
de Oliveira, Andressa Paula
Campos, Vinicius Rangel
Júnior, Floriano Paes Silva
Dantas, Rafael Ferreira
Resende, Jackson Antônio Lamounier Camargos
Cunha, Anna Claudia
Boechat, Nubia
Bastos, Mônica Macedo
author_sort Pimentel, Luiz Claudio Ferreira
collection PubMed
description The enzyme tyrosine kinase BCR-Abl-1 is the main molecular target in the treatment of chronic myeloid leukemia and can be competitively inhibited by tyrosine kinase inhibitors such as imatinib. New potential competitive inhibitors were synthesized using the (phenylamino)pyrimidine-pyridine (PAPP) group as a pharmacophoric fragment, and these compounds were biologically evaluated. The synthesis of twelve new compounds was performed in three steps and assisted by microwave irradiation in a 1,3-dipolar cycloaddition to obtain 1,2,3-triazole derivatives substituted on carbon C-4 of the triazole nucleus. All compounds were evaluated for their inhibitory activities against a chronic myeloid leukemia cell line (K562) that expresses the enzyme tyrosine kinase BCR-Abl-1 and against healthy cells (WSS-1) to observe their selectivity. Three compounds showed promising results, with IC(50) values between 1.0 and 7.3 μM, and were subjected to molecular docking studies. The results suggest that such compounds can interact at the same binding site as imatinib, probably sharing a competitive inhibition mechanism. One compound showed the greatest interaction affinity for BCR-Abl-1 in the docking studies.
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spelling pubmed-84509432021-10-06 (Phenylamino)pyrimidine-1,2,3-triazole derivatives as analogs of imatinib: searching for novel compounds against chronic myeloid leukemia Pimentel, Luiz Claudio Ferreira Hoelz, Lucas Villas Boas Canzian, Henayle Fernandes Branco, Frederico Silva Castelo de Oliveira, Andressa Paula Campos, Vinicius Rangel Júnior, Floriano Paes Silva Dantas, Rafael Ferreira Resende, Jackson Antônio Lamounier Camargos Cunha, Anna Claudia Boechat, Nubia Bastos, Mônica Macedo Beilstein J Org Chem Full Research Paper The enzyme tyrosine kinase BCR-Abl-1 is the main molecular target in the treatment of chronic myeloid leukemia and can be competitively inhibited by tyrosine kinase inhibitors such as imatinib. New potential competitive inhibitors were synthesized using the (phenylamino)pyrimidine-pyridine (PAPP) group as a pharmacophoric fragment, and these compounds were biologically evaluated. The synthesis of twelve new compounds was performed in three steps and assisted by microwave irradiation in a 1,3-dipolar cycloaddition to obtain 1,2,3-triazole derivatives substituted on carbon C-4 of the triazole nucleus. All compounds were evaluated for their inhibitory activities against a chronic myeloid leukemia cell line (K562) that expresses the enzyme tyrosine kinase BCR-Abl-1 and against healthy cells (WSS-1) to observe their selectivity. Three compounds showed promising results, with IC(50) values between 1.0 and 7.3 μM, and were subjected to molecular docking studies. The results suggest that such compounds can interact at the same binding site as imatinib, probably sharing a competitive inhibition mechanism. One compound showed the greatest interaction affinity for BCR-Abl-1 in the docking studies. Beilstein-Institut 2021-09-01 /pmc/articles/PMC8450943/ /pubmed/34621389 http://dx.doi.org/10.3762/bjoc.17.144 Text en Copyright © 2021, Pimentel et al. https://creativecommons.org/licenses/by/4.0/https://www.beilstein-journals.org/bjoc/terms/termsThis is an Open Access article under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0 (https://creativecommons.org/licenses/by/4.0/) ). Please note that the reuse, redistribution and reproduction in particular requires that the author(s) and source are credited and that individual graphics may be subject to special legal provisions. The license is subject to the Beilstein Journal of Organic Chemistry terms and conditions: (https://www.beilstein-journals.org/bjoc/terms/terms)
spellingShingle Full Research Paper
Pimentel, Luiz Claudio Ferreira
Hoelz, Lucas Villas Boas
Canzian, Henayle Fernandes
Branco, Frederico Silva Castelo
de Oliveira, Andressa Paula
Campos, Vinicius Rangel
Júnior, Floriano Paes Silva
Dantas, Rafael Ferreira
Resende, Jackson Antônio Lamounier Camargos
Cunha, Anna Claudia
Boechat, Nubia
Bastos, Mônica Macedo
(Phenylamino)pyrimidine-1,2,3-triazole derivatives as analogs of imatinib: searching for novel compounds against chronic myeloid leukemia
title (Phenylamino)pyrimidine-1,2,3-triazole derivatives as analogs of imatinib: searching for novel compounds against chronic myeloid leukemia
title_full (Phenylamino)pyrimidine-1,2,3-triazole derivatives as analogs of imatinib: searching for novel compounds against chronic myeloid leukemia
title_fullStr (Phenylamino)pyrimidine-1,2,3-triazole derivatives as analogs of imatinib: searching for novel compounds against chronic myeloid leukemia
title_full_unstemmed (Phenylamino)pyrimidine-1,2,3-triazole derivatives as analogs of imatinib: searching for novel compounds against chronic myeloid leukemia
title_short (Phenylamino)pyrimidine-1,2,3-triazole derivatives as analogs of imatinib: searching for novel compounds against chronic myeloid leukemia
title_sort (phenylamino)pyrimidine-1,2,3-triazole derivatives as analogs of imatinib: searching for novel compounds against chronic myeloid leukemia
topic Full Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450943/
https://www.ncbi.nlm.nih.gov/pubmed/34621389
http://dx.doi.org/10.3762/bjoc.17.144
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