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
Repositorio Institucional de la Universidad Nacional del Nordeste (UNNE)
Institución
Universidad Nacional del Nordeste
OAI Identificador
oai:repositorio.unne.edu.ar:123456789/56480

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network_acronym_str RIUNNE
repository_id_str 4871
network_name_str Repositorio Institucional de la Universidad Nacional del Nordeste (UNNE)
spelling 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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