Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study
- Autores
- Camposa, Ludmila E.; Garibotto, Francisco; Angelina, Emilio Luis; Kos, Jiri; Gonec, Tomas; Marvanova, Pavlina; Vettorazzi, Marcela Cristina; Oravece, Michal; Jendrzejewska, Izabela; Jampilekc, Josef; Alvareza, Sergio E.; Enriz, Ricardo D.
- Año de publicación
- 2020
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Fil: Camposa, Ludmila E. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto Multidisciplinario de Investigaciones Biológicas; Argentina.
Fil: Garibotto, Francisco. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto Multidisciplinario de Investigaciones Biológicas; Argentina.
Fil: Angelina, Emilio Luis. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas y Naturales y Agrimensura; Argentina.
Fil: Kos, Jiri. Palacky University. Faculty of Science; Chequia.
Fil: Gonec, Tomas. Universidad de Ciencias Veterinarias y Farmacéuticas Brno. Facultad de Farmacia; Chequia.
Fil: Marvanova, Pavlina. Universidad de Ciencias Veterinarias y Farmacéuticas Brno. Facultad de Farmacia; Chequia.
Fil: Vettorazzi, Marcela Cristina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto Multidisciplinario de Investigaciones Biológicas; Argentina.
Fil: Oravece, Michal. Global Change Research Institute CAS; Chequia.
Fil: Jendrzejewska, Izabela. University of Silesia. Institute of Chemistry; Polonia.
Fil: Jampilekc, Josef. Palacky University. Faculty of Science; Chequia.
Fil: Alvareza, Sergio E. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto Multidisciplinario de Investigaciones Biológicas; Argentina.
Fil: Enriza, Ricardo D. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto Multidisciplinario de Investigaciones Biológicas; Argentina.
The oncogenic mutated kinase BRAFV600E is an attractive molecular target because it is expressed in several human cancers, including melanoma. To present, only three BRAF small inhibitors are approved by the FDA for the treatment of patients with metastatic melanoma: Vemurafenib, Dabrafenib and Encorafenib. Although many protocol treatments have been probed in clinical trials, BRAF inhibition has a limited effectiveness because patients invariably develop resistance and secondary toxic effects associated with the therapy. These limitations highlight the importance of designing new and better inhibitors with different structures that could establish different interactions in the active site of the enzyme and therefore decrease resistance progress. Considering the data from our previous report, here we studied two series of derivatives of structural scaffolds as potential BRAF inhibitors: hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols. Our results indicate that structural analogues of substituted piperazinylpropandiols do not show significantly better activities to that previously reported. In contrast, the hydroxynaphthalenecarboxamides derivatives significantly inhibited cell viability and ERK phosphorylation, a measure of BRAF activity, in Lu1205 BRAFV600E melanoma cells. In order to better understand these experimental results, we carried out a molecular modeling study using different combined techniques: docking, MD simulations and quantum theory of atoms in molecules (QTAIM) calculations. Thus, by using this approach we determined that the molecular interactions that stabilize the different molecular complexes are closely related to Vemurafenib, a well-documented BRAF inhibitor. Furthermore, we found that bi-substituted compounds may interact more strongly respect to the mono-substituted analogues, by establishing additional interactions with the DFG-loop at the BRAF-active site. On the bases of these results we synthesized and tested a new series of hydroxynaphthalenecarboxamides bi-substituted. Remarkably, all these compounds displayed significant inhibitory effects on the bioassays performed. Thus, the structural information reported here is important for the design of new BRAFV600E inhibitors possessing this type of structural scaffold. - Fuente
- Bioorganic Chemistry, 2020, vol. 103, p. 1-13.
- Materia
-
BRAF inhibitors
Melanoma
Molecular modeling
Cell viability
ERK phosphorylation - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- http://creativecommons.org/licenses/by-nc-nd/2.5/ar/
- Repositorio
- Institución
- Universidad Nacional del Nordeste
- OAI Identificador
- oai:repositorio.unne.edu.ar:123456789/56480
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Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental studyCamposa, Ludmila E.Garibotto, FranciscoAngelina, Emilio LuisKos, JiriGonec, TomasMarvanova, PavlinaVettorazzi, Marcela CristinaOravece, MichalJendrzejewska, IzabelaJampilekc, JosefAlvareza, Sergio E.Enriz, Ricardo D.BRAF inhibitorsMelanomaMolecular modelingCell viabilityERK phosphorylationFil: Camposa, Ludmila E. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto Multidisciplinario de Investigaciones Biológicas; Argentina.Fil: Garibotto, Francisco. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto Multidisciplinario de Investigaciones Biológicas; Argentina.Fil: Angelina, Emilio Luis. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas y Naturales y Agrimensura; Argentina.Fil: Kos, Jiri. Palacky University. Faculty of Science; Chequia.Fil: Gonec, Tomas. Universidad de Ciencias Veterinarias y Farmacéuticas Brno. Facultad de Farmacia; Chequia.Fil: Marvanova, Pavlina. Universidad de Ciencias Veterinarias y Farmacéuticas Brno. Facultad de Farmacia; Chequia.Fil: Vettorazzi, Marcela Cristina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto Multidisciplinario de Investigaciones Biológicas; Argentina.Fil: Oravece, Michal. Global Change Research Institute CAS; Chequia.Fil: Jendrzejewska, Izabela. University of Silesia. Institute of Chemistry; Polonia.Fil: Jampilekc, Josef. Palacky University. Faculty of Science; Chequia.Fil: Alvareza, Sergio E. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto Multidisciplinario de Investigaciones Biológicas; Argentina.Fil: Enriza, Ricardo D. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto Multidisciplinario de Investigaciones Biológicas; Argentina.The oncogenic mutated kinase BRAFV600E is an attractive molecular target because it is expressed in several human cancers, including melanoma. To present, only three BRAF small inhibitors are approved by the FDA for the treatment of patients with metastatic melanoma: Vemurafenib, Dabrafenib and Encorafenib. Although many protocol treatments have been probed in clinical trials, BRAF inhibition has a limited effectiveness because patients invariably develop resistance and secondary toxic effects associated with the therapy. These limitations highlight the importance of designing new and better inhibitors with different structures that could establish different interactions in the active site of the enzyme and therefore decrease resistance progress. Considering the data from our previous report, here we studied two series of derivatives of structural scaffolds as potential BRAF inhibitors: hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols. Our results indicate that structural analogues of substituted piperazinylpropandiols do not show significantly better activities to that previously reported. In contrast, the hydroxynaphthalenecarboxamides derivatives significantly inhibited cell viability and ERK phosphorylation, a measure of BRAF activity, in Lu1205 BRAFV600E melanoma cells. In order to better understand these experimental results, we carried out a molecular modeling study using different combined techniques: docking, MD simulations and quantum theory of atoms in molecules (QTAIM) calculations. Thus, by using this approach we determined that the molecular interactions that stabilize the different molecular complexes are closely related to Vemurafenib, a well-documented BRAF inhibitor. Furthermore, we found that bi-substituted compounds may interact more strongly respect to the mono-substituted analogues, by establishing additional interactions with the DFG-loop at the BRAF-active site. On the bases of these results we synthesized and tested a new series of hydroxynaphthalenecarboxamides bi-substituted. Remarkably, all these compounds displayed significant inhibitory effects on the bioassays performed. Thus, the structural information reported here is important for the design of new BRAFV600E inhibitors possessing this type of structural scaffold.Elsevier2020-07-24info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfp. 1-13application/pdfCamposa, Ludmila E., et al., 2020. Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study. Bioorganic Chemistry. Estados Unidos: Elsevier, vol. 103, p. 1-13. ISSN 0045-2068.0045-2068http://repositorio.unne.edu.ar/handle/123456789/56480Bioorganic Chemistry, 2020, vol. 103, p. 1-13.reponame:Repositorio Institucional de la Universidad Nacional del Nordeste (UNNE)instname:Universidad Nacional del Nordesteenghttps://doi.org/10.1016/j.bioorg.2020.104145info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by-nc-nd/2.5/ar/Atribución-NoComercial-SinDerivadas 2.5 Argentina2025-09-29T14:30:21Zoai:repositorio.unne.edu.ar:123456789/56480instacron:UNNEInstitucionalhttp://repositorio.unne.edu.ar/Universidad públicaNo correspondehttp://repositorio.unne.edu.ar/oaiososa@bib.unne.edu.ar;sergio.alegria@unne.edu.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:48712025-09-29 14:30:22.321Repositorio Institucional de la Universidad Nacional del Nordeste (UNNE) - Universidad Nacional del Nordestefalse |
dc.title.none.fl_str_mv |
Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study |
title |
Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study |
spellingShingle |
Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study Camposa, Ludmila E. BRAF inhibitors Melanoma Molecular modeling Cell viability ERK phosphorylation |
title_short |
Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study |
title_full |
Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study |
title_fullStr |
Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study |
title_full_unstemmed |
Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study |
title_sort |
Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study |
dc.creator.none.fl_str_mv |
Camposa, Ludmila E. Garibotto, Francisco Angelina, Emilio Luis Kos, Jiri Gonec, Tomas Marvanova, Pavlina Vettorazzi, Marcela Cristina Oravece, Michal Jendrzejewska, Izabela Jampilekc, Josef Alvareza, Sergio E. Enriz, Ricardo D. |
author |
Camposa, Ludmila E. |
author_facet |
Camposa, Ludmila E. Garibotto, Francisco Angelina, Emilio Luis Kos, Jiri Gonec, Tomas Marvanova, Pavlina Vettorazzi, Marcela Cristina Oravece, Michal Jendrzejewska, Izabela Jampilekc, Josef Alvareza, Sergio E. Enriz, Ricardo D. |
author_role |
author |
author2 |
Garibotto, Francisco Angelina, Emilio Luis Kos, Jiri Gonec, Tomas Marvanova, Pavlina Vettorazzi, Marcela Cristina Oravece, Michal Jendrzejewska, Izabela Jampilekc, Josef Alvareza, Sergio E. Enriz, Ricardo D. |
author2_role |
author author author author author author author author author author author |
dc.subject.none.fl_str_mv |
BRAF inhibitors Melanoma Molecular modeling Cell viability ERK phosphorylation |
topic |
BRAF inhibitors Melanoma Molecular modeling Cell viability ERK phosphorylation |
dc.description.none.fl_txt_mv |
Fil: Camposa, Ludmila E. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto Multidisciplinario de Investigaciones Biológicas; Argentina. Fil: Garibotto, Francisco. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto Multidisciplinario de Investigaciones Biológicas; Argentina. Fil: Angelina, Emilio Luis. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas y Naturales y Agrimensura; Argentina. Fil: Kos, Jiri. Palacky University. Faculty of Science; Chequia. Fil: Gonec, Tomas. Universidad de Ciencias Veterinarias y Farmacéuticas Brno. Facultad de Farmacia; Chequia. Fil: Marvanova, Pavlina. Universidad de Ciencias Veterinarias y Farmacéuticas Brno. Facultad de Farmacia; Chequia. Fil: Vettorazzi, Marcela Cristina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto Multidisciplinario de Investigaciones Biológicas; Argentina. Fil: Oravece, Michal. Global Change Research Institute CAS; Chequia. Fil: Jendrzejewska, Izabela. University of Silesia. Institute of Chemistry; Polonia. Fil: Jampilekc, Josef. Palacky University. Faculty of Science; Chequia. Fil: Alvareza, Sergio E. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto Multidisciplinario de Investigaciones Biológicas; Argentina. Fil: Enriza, Ricardo D. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto Multidisciplinario de Investigaciones Biológicas; Argentina. The oncogenic mutated kinase BRAFV600E is an attractive molecular target because it is expressed in several human cancers, including melanoma. To present, only three BRAF small inhibitors are approved by the FDA for the treatment of patients with metastatic melanoma: Vemurafenib, Dabrafenib and Encorafenib. Although many protocol treatments have been probed in clinical trials, BRAF inhibition has a limited effectiveness because patients invariably develop resistance and secondary toxic effects associated with the therapy. These limitations highlight the importance of designing new and better inhibitors with different structures that could establish different interactions in the active site of the enzyme and therefore decrease resistance progress. Considering the data from our previous report, here we studied two series of derivatives of structural scaffolds as potential BRAF inhibitors: hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols. Our results indicate that structural analogues of substituted piperazinylpropandiols do not show significantly better activities to that previously reported. In contrast, the hydroxynaphthalenecarboxamides derivatives significantly inhibited cell viability and ERK phosphorylation, a measure of BRAF activity, in Lu1205 BRAFV600E melanoma cells. In order to better understand these experimental results, we carried out a molecular modeling study using different combined techniques: docking, MD simulations and quantum theory of atoms in molecules (QTAIM) calculations. Thus, by using this approach we determined that the molecular interactions that stabilize the different molecular complexes are closely related to Vemurafenib, a well-documented BRAF inhibitor. Furthermore, we found that bi-substituted compounds may interact more strongly respect to the mono-substituted analogues, by establishing additional interactions with the DFG-loop at the BRAF-active site. On the bases of these results we synthesized and tested a new series of hydroxynaphthalenecarboxamides bi-substituted. Remarkably, all these compounds displayed significant inhibitory effects on the bioassays performed. Thus, the structural information reported here is important for the design of new BRAFV600E inhibitors possessing this type of structural scaffold. |
description |
Fil: Camposa, Ludmila E. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto Multidisciplinario de Investigaciones Biológicas; Argentina. |
publishDate |
2020 |
dc.date.none.fl_str_mv |
2020-07-24 |
dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
format |
article |
status_str |
publishedVersion |
dc.identifier.none.fl_str_mv |
Camposa, Ludmila E., et al., 2020. Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study. Bioorganic Chemistry. Estados Unidos: Elsevier, vol. 103, p. 1-13. ISSN 0045-2068. 0045-2068 http://repositorio.unne.edu.ar/handle/123456789/56480 |
identifier_str_mv |
Camposa, Ludmila E., et al., 2020. Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study. Bioorganic Chemistry. Estados Unidos: Elsevier, vol. 103, p. 1-13. ISSN 0045-2068. 0045-2068 |
url |
http://repositorio.unne.edu.ar/handle/123456789/56480 |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
https://doi.org/10.1016/j.bioorg.2020.104145 |
dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by-nc-nd/2.5/ar/ Atribución-NoComercial-SinDerivadas 2.5 Argentina |
eu_rights_str_mv |
openAccess |
rights_invalid_str_mv |
http://creativecommons.org/licenses/by-nc-nd/2.5/ar/ Atribución-NoComercial-SinDerivadas 2.5 Argentina |
dc.format.none.fl_str_mv |
application/pdf p. 1-13 application/pdf |
dc.publisher.none.fl_str_mv |
Elsevier |
publisher.none.fl_str_mv |
Elsevier |
dc.source.none.fl_str_mv |
Bioorganic Chemistry, 2020, vol. 103, p. 1-13. reponame:Repositorio Institucional de la Universidad Nacional del Nordeste (UNNE) instname:Universidad Nacional del Nordeste |
reponame_str |
Repositorio Institucional de la Universidad Nacional del Nordeste (UNNE) |
collection |
Repositorio Institucional de la Universidad Nacional del Nordeste (UNNE) |
instname_str |
Universidad Nacional del Nordeste |
repository.name.fl_str_mv |
Repositorio Institucional de la Universidad Nacional del Nordeste (UNNE) - Universidad Nacional del Nordeste |
repository.mail.fl_str_mv |
ososa@bib.unne.edu.ar;sergio.alegria@unne.edu.ar |
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1844621688326586368 |
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12.559606 |