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New Imatinib Derivatives with Antiproliferative Activity against A549 and K562 Cancer Cells
Tyrosine kinase enzymes are among the primary molecular targets for the treatment of some human neoplasms, such as those in lung cancer and chronic myeloid leukemia. Mutations in the enzyme domain can cause resistance and new inhibitors capable of circumventing these mutations are highly desired. Th...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8838532/ https://www.ncbi.nlm.nih.gov/pubmed/35164014 http://dx.doi.org/10.3390/molecules27030750 |
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author | Oliveira, Andressa Moura, Stefany Pimentel, Luiz Neto, João Dantas, Rafael Silva-Jr, Floriano Bastos, Monica Boechat, Nubia |
author_facet | Oliveira, Andressa Moura, Stefany Pimentel, Luiz Neto, João Dantas, Rafael Silva-Jr, Floriano Bastos, Monica Boechat, Nubia |
author_sort | Oliveira, Andressa |
collection | PubMed |
description | Tyrosine kinase enzymes are among the primary molecular targets for the treatment of some human neoplasms, such as those in lung cancer and chronic myeloid leukemia. Mutations in the enzyme domain can cause resistance and new inhibitors capable of circumventing these mutations are highly desired. The objective of this work was to synthesize and evaluate the antiproliferative ability of ten new analogs that contain isatins and the phenylamino-pyrimidine pyridine (PAPP) skeleton, the main pharmacophore group of imatinib. The 1,2,3-triazole core was used as a spacer in the derivatives through a click chemistry reaction and gave good yields. All the analogs were tested against A549 and K562 cells, lung cancer and chronic myeloid leukemia (CML) cell lines, respectively. In A549 cells, the 3,3-difluorinated compound (3a), the 5-chloro-3,3-difluorinated compound (3c) and the 5-bromo-3,3-difluorinated compound (3d) showed IC(50) values of 7.2, 6.4, and 7.3 μM, respectively, and were all more potent than imatinib (IC(50) of 65.4 μM). In K562 cells, the 3,3-difluoro-5-methylated compound (3b) decreased cell viability to 57.5% and, at 10 µM, showed an IC(50) value of 35.8 μM (imatinib, IC(50) = 0.08 μM). The results suggest that 3a, 3c, and 3d can be used as prototypes for the development of more potent and selective derivatives against lung cancer. |
format | Online Article Text |
id | pubmed-8838532 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-88385322022-02-13 New Imatinib Derivatives with Antiproliferative Activity against A549 and K562 Cancer Cells Oliveira, Andressa Moura, Stefany Pimentel, Luiz Neto, João Dantas, Rafael Silva-Jr, Floriano Bastos, Monica Boechat, Nubia Molecules Article Tyrosine kinase enzymes are among the primary molecular targets for the treatment of some human neoplasms, such as those in lung cancer and chronic myeloid leukemia. Mutations in the enzyme domain can cause resistance and new inhibitors capable of circumventing these mutations are highly desired. The objective of this work was to synthesize and evaluate the antiproliferative ability of ten new analogs that contain isatins and the phenylamino-pyrimidine pyridine (PAPP) skeleton, the main pharmacophore group of imatinib. The 1,2,3-triazole core was used as a spacer in the derivatives through a click chemistry reaction and gave good yields. All the analogs were tested against A549 and K562 cells, lung cancer and chronic myeloid leukemia (CML) cell lines, respectively. In A549 cells, the 3,3-difluorinated compound (3a), the 5-chloro-3,3-difluorinated compound (3c) and the 5-bromo-3,3-difluorinated compound (3d) showed IC(50) values of 7.2, 6.4, and 7.3 μM, respectively, and were all more potent than imatinib (IC(50) of 65.4 μM). In K562 cells, the 3,3-difluoro-5-methylated compound (3b) decreased cell viability to 57.5% and, at 10 µM, showed an IC(50) value of 35.8 μM (imatinib, IC(50) = 0.08 μM). The results suggest that 3a, 3c, and 3d can be used as prototypes for the development of more potent and selective derivatives against lung cancer. MDPI 2022-01-24 /pmc/articles/PMC8838532/ /pubmed/35164014 http://dx.doi.org/10.3390/molecules27030750 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Oliveira, Andressa Moura, Stefany Pimentel, Luiz Neto, João Dantas, Rafael Silva-Jr, Floriano Bastos, Monica Boechat, Nubia New Imatinib Derivatives with Antiproliferative Activity against A549 and K562 Cancer Cells |
title | New Imatinib Derivatives with Antiproliferative Activity against A549 and K562 Cancer Cells |
title_full | New Imatinib Derivatives with Antiproliferative Activity against A549 and K562 Cancer Cells |
title_fullStr | New Imatinib Derivatives with Antiproliferative Activity against A549 and K562 Cancer Cells |
title_full_unstemmed | New Imatinib Derivatives with Antiproliferative Activity against A549 and K562 Cancer Cells |
title_short | New Imatinib Derivatives with Antiproliferative Activity against A549 and K562 Cancer Cells |
title_sort | new imatinib derivatives with antiproliferative activity against a549 and k562 cancer cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8838532/ https://www.ncbi.nlm.nih.gov/pubmed/35164014 http://dx.doi.org/10.3390/molecules27030750 |
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