Computational studies, design and synthesis of Pd(II)-based complexes: Allosteric inhibitors of the Human Topoisomerase-IIα
Autor(a) principal: | |
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Data de Publicação: | 2019 |
Outros Autores: | , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1016/j.jinorgbio.2019.110725 http://hdl.handle.net/11449/189466 |
Resumo: | Herein, a robust docking protocol was developed by using a low-cost workflow to highlight the modulation at ATPase domain from Human Topoisomerase-IIα (TOP2A) towards four novel Pd(II)-complexes bearing N,S-donor ligands. In vitro TOP2A inhibition assay confirmed the ability of them to prevent the enzyme functions into concentration ranging at 6.25–25 μM. These results exhibited more effectivity than anticancer agent etoposide (35 μM) and merbarone (40–50 μM). The compounds were screened via Resazurin assay against MCF-7, MDA-MB-231 (Human breast), DU-145 (Human prostate), A549 (Human lung) and Cal27 (Human tongue) tumor cell lines revealing great cytotoxic effects, primarily to MCF-7 (IC50 = 1.81–4.46 μM). As well, 1–4 exhibited their selectivity index (SI) higher than cisplatin against HEK-293 (human kidney) normal cells, at least 11.6-fold (SI1–4 = 1.4–5.0; SIcis = 0.12). Further, Red Blood Cell hemolytic test suggested in vitro non-toxic character for compound 4, previously evaluated as the most effective TOP2A inhibitor. |
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Computational studies, design and synthesis of Pd(II)-based complexes: Allosteric inhibitors of the Human Topoisomerase-IIαHerein, a robust docking protocol was developed by using a low-cost workflow to highlight the modulation at ATPase domain from Human Topoisomerase-IIα (TOP2A) towards four novel Pd(II)-complexes bearing N,S-donor ligands. In vitro TOP2A inhibition assay confirmed the ability of them to prevent the enzyme functions into concentration ranging at 6.25–25 μM. These results exhibited more effectivity than anticancer agent etoposide (35 μM) and merbarone (40–50 μM). The compounds were screened via Resazurin assay against MCF-7, MDA-MB-231 (Human breast), DU-145 (Human prostate), A549 (Human lung) and Cal27 (Human tongue) tumor cell lines revealing great cytotoxic effects, primarily to MCF-7 (IC50 = 1.81–4.46 μM). As well, 1–4 exhibited their selectivity index (SI) higher than cisplatin against HEK-293 (human kidney) normal cells, at least 11.6-fold (SI1–4 = 1.4–5.0; SIcis = 0.12). Further, Red Blood Cell hemolytic test suggested in vitro non-toxic character for compound 4, previously evaluated as the most effective TOP2A inhibitor.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Universidade Estadual PaulistaFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)UFSCar – Univ Federal de São Carlos Departamento de QuímicaUNESP – Univ Estadual Paulista Instituto de Química Departamento de Química Geral e InorgânicaUNESP – Univ Estadual Paulista Instituto de Química Departamento de Química OrgânicaUNESP – Univ Estadual Paulista Instituto de Química Departamento de Bioquímica e Tecnologia QuímicaUSP – Univ de São Paulo Department of Clinical Analyses Toxicology and Food SciencesUFS – Univ Federal de Sergipe Departamento de QuímicaRheinische Friedrich-Wilhelms-Universität Bonn Institut für Anorganische ChemieUNESP – Univ Estadual Paulista Instituto de Química Departamento de Química Geral e InorgânicaUNESP – Univ Estadual Paulista Instituto de Química Departamento de Química OrgânicaUNESP – Univ Estadual Paulista Instituto de Química Departamento de Bioquímica e Tecnologia QuímicaCAPES: 001Universidade Estadual Paulista: 1.185.001FAPESP: 2012/15486-3FAPESP: 2013/20156-5FAPESP: 2016/04201-9FAPESP: 2016/17711-5CNPq: 573.564/2008-6FAPERJ: E-26/170.020/2008Universidade Federal de São Carlos (UFSCar)Universidade Estadual Paulista (Unesp)Universidade de São Paulo (USP)Universidade Federal de Sergipe (UFS)Institut für Anorganische ChemieRocha, Fillipe V.Farias, Renan L. [UNESP]Lima, Mauro A.Batista, Victor S. [UNESP]Nascimento-Júnior, Nailton M. [UNESP]Garrido, Saulo S. [UNESP]Leopoldino, Andréia M.Goto, Renata N.Oliveira, Adriano B.Beck, JohannesLandvogt, ChristianMauro, Antônio E. [UNESP]Netto, Adelino V.G. [UNESP]2019-10-06T16:41:40Z2019-10-06T16:41:40Z2019-10-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1016/j.jinorgbio.2019.110725Journal of Inorganic Biochemistry, v. 199.1873-33440162-0134http://hdl.handle.net/11449/18946610.1016/j.jinorgbio.2019.1107252-s2.0-85069861401Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengJournal of Inorganic Biochemistryinfo:eu-repo/semantics/openAccess2021-10-22T19:03:19Zoai:repositorio.unesp.br:11449/189466Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T15:33:42.897786Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Computational studies, design and synthesis of Pd(II)-based complexes: Allosteric inhibitors of the Human Topoisomerase-IIα |
title |
Computational studies, design and synthesis of Pd(II)-based complexes: Allosteric inhibitors of the Human Topoisomerase-IIα |
spellingShingle |
Computational studies, design and synthesis of Pd(II)-based complexes: Allosteric inhibitors of the Human Topoisomerase-IIα Rocha, Fillipe V. |
title_short |
Computational studies, design and synthesis of Pd(II)-based complexes: Allosteric inhibitors of the Human Topoisomerase-IIα |
title_full |
Computational studies, design and synthesis of Pd(II)-based complexes: Allosteric inhibitors of the Human Topoisomerase-IIα |
title_fullStr |
Computational studies, design and synthesis of Pd(II)-based complexes: Allosteric inhibitors of the Human Topoisomerase-IIα |
title_full_unstemmed |
Computational studies, design and synthesis of Pd(II)-based complexes: Allosteric inhibitors of the Human Topoisomerase-IIα |
title_sort |
Computational studies, design and synthesis of Pd(II)-based complexes: Allosteric inhibitors of the Human Topoisomerase-IIα |
author |
Rocha, Fillipe V. |
author_facet |
Rocha, Fillipe V. Farias, Renan L. [UNESP] Lima, Mauro A. Batista, Victor S. [UNESP] Nascimento-Júnior, Nailton M. [UNESP] Garrido, Saulo S. [UNESP] Leopoldino, Andréia M. Goto, Renata N. Oliveira, Adriano B. Beck, Johannes Landvogt, Christian Mauro, Antônio E. [UNESP] Netto, Adelino V.G. [UNESP] |
author_role |
author |
author2 |
Farias, Renan L. [UNESP] Lima, Mauro A. Batista, Victor S. [UNESP] Nascimento-Júnior, Nailton M. [UNESP] Garrido, Saulo S. [UNESP] Leopoldino, Andréia M. Goto, Renata N. Oliveira, Adriano B. Beck, Johannes Landvogt, Christian Mauro, Antônio E. [UNESP] Netto, Adelino V.G. [UNESP] |
author2_role |
author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade Federal de São Carlos (UFSCar) Universidade Estadual Paulista (Unesp) Universidade de São Paulo (USP) Universidade Federal de Sergipe (UFS) Institut für Anorganische Chemie |
dc.contributor.author.fl_str_mv |
Rocha, Fillipe V. Farias, Renan L. [UNESP] Lima, Mauro A. Batista, Victor S. [UNESP] Nascimento-Júnior, Nailton M. [UNESP] Garrido, Saulo S. [UNESP] Leopoldino, Andréia M. Goto, Renata N. Oliveira, Adriano B. Beck, Johannes Landvogt, Christian Mauro, Antônio E. [UNESP] Netto, Adelino V.G. [UNESP] |
description |
Herein, a robust docking protocol was developed by using a low-cost workflow to highlight the modulation at ATPase domain from Human Topoisomerase-IIα (TOP2A) towards four novel Pd(II)-complexes bearing N,S-donor ligands. In vitro TOP2A inhibition assay confirmed the ability of them to prevent the enzyme functions into concentration ranging at 6.25–25 μM. These results exhibited more effectivity than anticancer agent etoposide (35 μM) and merbarone (40–50 μM). The compounds were screened via Resazurin assay against MCF-7, MDA-MB-231 (Human breast), DU-145 (Human prostate), A549 (Human lung) and Cal27 (Human tongue) tumor cell lines revealing great cytotoxic effects, primarily to MCF-7 (IC50 = 1.81–4.46 μM). As well, 1–4 exhibited their selectivity index (SI) higher than cisplatin against HEK-293 (human kidney) normal cells, at least 11.6-fold (SI1–4 = 1.4–5.0; SIcis = 0.12). Further, Red Blood Cell hemolytic test suggested in vitro non-toxic character for compound 4, previously evaluated as the most effective TOP2A inhibitor. |
publishDate |
2019 |
dc.date.none.fl_str_mv |
2019-10-06T16:41:40Z 2019-10-06T16:41:40Z 2019-10-01 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1016/j.jinorgbio.2019.110725 Journal of Inorganic Biochemistry, v. 199. 1873-3344 0162-0134 http://hdl.handle.net/11449/189466 10.1016/j.jinorgbio.2019.110725 2-s2.0-85069861401 |
url |
http://dx.doi.org/10.1016/j.jinorgbio.2019.110725 http://hdl.handle.net/11449/189466 |
identifier_str_mv |
Journal of Inorganic Biochemistry, v. 199. 1873-3344 0162-0134 10.1016/j.jinorgbio.2019.110725 2-s2.0-85069861401 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Journal of Inorganic Biochemistry |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
|
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1808128532036976640 |