Analogues of the Lignan Pinoresinol as Novel Lead Compounds for P-glycoprotein (P-gp) Inhibitors

Autores
Laiolo, Jerónimo; Tomasič, Tihomir; Vera, Domingo Mariano Adolfo; González, María L.; Lanza Castronuovo, Priscila Ailin; Gancedo, Samanta Nerea; Hodnik, Žiga; Peterlin Masic, Lucija; Kikelj, Danijel; Carpinella, Maria Cecilia
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
To find novel P-gp-inhibitors, a library of pregnane X receptor (PXR) ligands and the ZINC DrugsNow library were superimposed on the P-gp inhibitor (+)-pinoresinol (1) used as a query for a three-dimensional similarity search. After determining the TanimotoCombo index of similarity with 1, eight compounds from the PXR library and two ZINC compounds were selected for biological evaluation. The P-gp inhibition study showed that compounds 7, 8, and 9 successfully increased intracellular doxorubicin (DOX) accumulation in the P-gp overexpressed Lucena 1 cells from 25, 12.5, and 6.25 μM, respectively. Among a series of analogues of 9, compounds 26–30 were shown to be active, with 26 and 27 causing a significant increase in DOX accumulation from 1.56 μM and rendering Lucena 1 sensitive to DOX from 1.56 and 0.78 μM, respectively. Molecular modeling studies showed that both compounds bind to the P-gp at transmembrane helices (TMH) 4, 5, and 6, with 27 also showing contacts with TMH 3.
Fil: Laiolo, Jerónimo. Universidad Católica de Córdoba. Instituto de Investigaciones en Recursos Naturales y Sustentabilidad José Sanchez Labrador S. J. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Recursos Naturales y Sustentabilidad José Sanchez Labrador S. J.; Argentina
Fil: Tomasič, Tihomir. University of Ljubljana; Eslovenia
Fil: Vera, Domingo Mariano Adolfo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Biodiversidad y Biotecnología; Argentina
Fil: González, María L.. Universidad Católica de Córdoba. Instituto de Investigaciones en Recursos Naturales y Sustentabilidad José Sanchez Labrador S. J. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Recursos Naturales y Sustentabilidad José Sanchez Labrador S. J.; Argentina
Fil: Lanza Castronuovo, Priscila Ailin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Biodiversidad y Biotecnología; Argentina
Fil: Gancedo, Samanta Nerea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Biodiversidad y Biotecnología; Argentina
Fil: Hodnik, Žiga. University of Ljubljana; Eslovenia
Fil: Peterlin Masic, Lucija. University of Ljubljana; Eslovenia
Fil: Kikelj, Danijel. University of Ljubljana; Eslovenia
Fil: Carpinella, Maria Cecilia. Universidad Católica de Córdoba. Instituto de Investigaciones en Recursos Naturales y Sustentabilidad José Sanchez Labrador S. J. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Recursos Naturales y Sustentabilidad José Sanchez Labrador S. J.; Argentina
Materia
DIETHYLSTILBESTROL DERIVATIVES
MDR REVERSING AGENTS
MOLECULAR DOCKING
P-GLYCOPROTEIN
PINORESINOL
STRUCTURE-ACTIVITY RELATIONSHIP
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/95224
Acceder
id CONICETDig_ccb5b57a2dbbe3972b16ea9622c99cb0
oai_identifier_str oai:ri.conicet.gov.ar:11336/95224
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Analogues of the Lignan Pinoresinol as Novel Lead Compounds for P-glycoprotein (P-gp) InhibitorsLaiolo, JerónimoTomasič, TihomirVera, Domingo Mariano AdolfoGonzález, María L.Lanza Castronuovo, Priscila AilinGancedo, Samanta NereaHodnik, ŽigaPeterlin Masic, LucijaKikelj, DanijelCarpinella, Maria CeciliaDIETHYLSTILBESTROL DERIVATIVESMDR REVERSING AGENTSMOLECULAR DOCKINGP-GLYCOPROTEINPINORESINOLSTRUCTURE-ACTIVITY RELATIONSHIPhttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1To find novel P-gp-inhibitors, a library of pregnane X receptor (PXR) ligands and the ZINC DrugsNow library were superimposed on the P-gp inhibitor (+)-pinoresinol (1) used as a query for a three-dimensional similarity search. After determining the TanimotoCombo index of similarity with 1, eight compounds from the PXR library and two ZINC compounds were selected for biological evaluation. The P-gp inhibition study showed that compounds 7, 8, and 9 successfully increased intracellular doxorubicin (DOX) accumulation in the P-gp overexpressed Lucena 1 cells from 25, 12.5, and 6.25 μM, respectively. Among a series of analogues of 9, compounds 26–30 were shown to be active, with 26 and 27 causing a significant increase in DOX accumulation from 1.56 μM and rendering Lucena 1 sensitive to DOX from 1.56 and 0.78 μM, respectively. Molecular modeling studies showed that both compounds bind to the P-gp at transmembrane helices (TMH) 4, 5, and 6, with 27 also showing contacts with TMH 3.Fil: Laiolo, Jerónimo. Universidad Católica de Córdoba. Instituto de Investigaciones en Recursos Naturales y Sustentabilidad José Sanchez Labrador S. J. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Recursos Naturales y Sustentabilidad José Sanchez Labrador S. J.; ArgentinaFil: Tomasič, Tihomir. University of Ljubljana; EsloveniaFil: Vera, Domingo Mariano Adolfo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Biodiversidad y Biotecnología; ArgentinaFil: González, María L.. Universidad Católica de Córdoba. Instituto de Investigaciones en Recursos Naturales y Sustentabilidad José Sanchez Labrador S. J. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Recursos Naturales y Sustentabilidad José Sanchez Labrador S. J.; ArgentinaFil: Lanza Castronuovo, Priscila Ailin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Biodiversidad y Biotecnología; ArgentinaFil: Gancedo, Samanta Nerea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Biodiversidad y Biotecnología; ArgentinaFil: Hodnik, Žiga. University of Ljubljana; EsloveniaFil: Peterlin Masic, Lucija. University of Ljubljana; EsloveniaFil: Kikelj, Danijel. University of Ljubljana; EsloveniaFil: Carpinella, Maria Cecilia. Universidad Católica de Córdoba. Instituto de Investigaciones en Recursos Naturales y Sustentabilidad José Sanchez Labrador S. J. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Recursos Naturales y Sustentabilidad José Sanchez Labrador S. J.; ArgentinaAmerican Chemical Society2018-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/95224Laiolo, Jerónimo; Tomasič, Tihomir; Vera, Domingo Mariano Adolfo; González, María L.; Lanza Castronuovo, Priscila Ailin; et al.; Analogues of the Lignan Pinoresinol as Novel Lead Compounds for P-glycoprotein (P-gp) Inhibitors; American Chemical Society; ACS Medicinal Chemistry Letters; 9; 12; 11-2018; 1186-11921948-5875CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00324info:eu-repo/semantics/altIdentifier/doi/10.1021/acsmedchemlett.8b00324info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:14:04Zoai:ri.conicet.gov.ar:11336/95224instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 11:14:04.846CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Analogues of the Lignan Pinoresinol as Novel Lead Compounds for P-glycoprotein (P-gp) Inhibitors
title Analogues of the Lignan Pinoresinol as Novel Lead Compounds for P-glycoprotein (P-gp) Inhibitors
spellingShingle Analogues of the Lignan Pinoresinol as Novel Lead Compounds for P-glycoprotein (P-gp) Inhibitors
Laiolo, Jerónimo
DIETHYLSTILBESTROL DERIVATIVES
MDR REVERSING AGENTS
MOLECULAR DOCKING
P-GLYCOPROTEIN
PINORESINOL
STRUCTURE-ACTIVITY RELATIONSHIP
title_short Analogues of the Lignan Pinoresinol as Novel Lead Compounds for P-glycoprotein (P-gp) Inhibitors
title_full Analogues of the Lignan Pinoresinol as Novel Lead Compounds for P-glycoprotein (P-gp) Inhibitors
title_fullStr Analogues of the Lignan Pinoresinol as Novel Lead Compounds for P-glycoprotein (P-gp) Inhibitors
title_full_unstemmed Analogues of the Lignan Pinoresinol as Novel Lead Compounds for P-glycoprotein (P-gp) Inhibitors
title_sort Analogues of the Lignan Pinoresinol as Novel Lead Compounds for P-glycoprotein (P-gp) Inhibitors
dc.creator.none.fl_str_mv Laiolo, Jerónimo
Tomasič, Tihomir
Vera, Domingo Mariano Adolfo
González, María L.
Lanza Castronuovo, Priscila Ailin
Gancedo, Samanta Nerea
Hodnik, Žiga
Peterlin Masic, Lucija
Kikelj, Danijel
Carpinella, Maria Cecilia
author Laiolo, Jerónimo
author_facet Laiolo, Jerónimo
Tomasič, Tihomir
Vera, Domingo Mariano Adolfo
González, María L.
Lanza Castronuovo, Priscila Ailin
Gancedo, Samanta Nerea
Hodnik, Žiga
Peterlin Masic, Lucija
Kikelj, Danijel
Carpinella, Maria Cecilia
author_role author
author2 Tomasič, Tihomir
Vera, Domingo Mariano Adolfo
González, María L.
Lanza Castronuovo, Priscila Ailin
Gancedo, Samanta Nerea
Hodnik, Žiga
Peterlin Masic, Lucija
Kikelj, Danijel
Carpinella, Maria Cecilia
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv DIETHYLSTILBESTROL DERIVATIVES
MDR REVERSING AGENTS
MOLECULAR DOCKING
P-GLYCOPROTEIN
PINORESINOL
STRUCTURE-ACTIVITY RELATIONSHIP
topic DIETHYLSTILBESTROL DERIVATIVES
MDR REVERSING AGENTS
MOLECULAR DOCKING
P-GLYCOPROTEIN
PINORESINOL
STRUCTURE-ACTIVITY RELATIONSHIP
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv To find novel P-gp-inhibitors, a library of pregnane X receptor (PXR) ligands and the ZINC DrugsNow library were superimposed on the P-gp inhibitor (+)-pinoresinol (1) used as a query for a three-dimensional similarity search. After determining the TanimotoCombo index of similarity with 1, eight compounds from the PXR library and two ZINC compounds were selected for biological evaluation. The P-gp inhibition study showed that compounds 7, 8, and 9 successfully increased intracellular doxorubicin (DOX) accumulation in the P-gp overexpressed Lucena 1 cells from 25, 12.5, and 6.25 μM, respectively. Among a series of analogues of 9, compounds 26–30 were shown to be active, with 26 and 27 causing a significant increase in DOX accumulation from 1.56 μM and rendering Lucena 1 sensitive to DOX from 1.56 and 0.78 μM, respectively. Molecular modeling studies showed that both compounds bind to the P-gp at transmembrane helices (TMH) 4, 5, and 6, with 27 also showing contacts with TMH 3.
Fil: Laiolo, Jerónimo. Universidad Católica de Córdoba. Instituto de Investigaciones en Recursos Naturales y Sustentabilidad José Sanchez Labrador S. J. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Recursos Naturales y Sustentabilidad José Sanchez Labrador S. J.; Argentina
Fil: Tomasič, Tihomir. University of Ljubljana; Eslovenia
Fil: Vera, Domingo Mariano Adolfo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Biodiversidad y Biotecnología; Argentina
Fil: González, María L.. Universidad Católica de Córdoba. Instituto de Investigaciones en Recursos Naturales y Sustentabilidad José Sanchez Labrador S. J. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Recursos Naturales y Sustentabilidad José Sanchez Labrador S. J.; Argentina
Fil: Lanza Castronuovo, Priscila Ailin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Biodiversidad y Biotecnología; Argentina
Fil: Gancedo, Samanta Nerea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Biodiversidad y Biotecnología; Argentina
Fil: Hodnik, Žiga. University of Ljubljana; Eslovenia
Fil: Peterlin Masic, Lucija. University of Ljubljana; Eslovenia
Fil: Kikelj, Danijel. University of Ljubljana; Eslovenia
Fil: Carpinella, Maria Cecilia. Universidad Católica de Córdoba. Instituto de Investigaciones en Recursos Naturales y Sustentabilidad José Sanchez Labrador S. J. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Recursos Naturales y Sustentabilidad José Sanchez Labrador S. J.; Argentina
description To find novel P-gp-inhibitors, a library of pregnane X receptor (PXR) ligands and the ZINC DrugsNow library were superimposed on the P-gp inhibitor (+)-pinoresinol (1) used as a query for a three-dimensional similarity search. After determining the TanimotoCombo index of similarity with 1, eight compounds from the PXR library and two ZINC compounds were selected for biological evaluation. The P-gp inhibition study showed that compounds 7, 8, and 9 successfully increased intracellular doxorubicin (DOX) accumulation in the P-gp overexpressed Lucena 1 cells from 25, 12.5, and 6.25 μM, respectively. Among a series of analogues of 9, compounds 26–30 were shown to be active, with 26 and 27 causing a significant increase in DOX accumulation from 1.56 μM and rendering Lucena 1 sensitive to DOX from 1.56 and 0.78 μM, respectively. Molecular modeling studies showed that both compounds bind to the P-gp at transmembrane helices (TMH) 4, 5, and 6, with 27 also showing contacts with TMH 3.
publishDate 2018
dc.date.none.fl_str_mv 2018-11
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 http://hdl.handle.net/11336/95224
Laiolo, Jerónimo; Tomasič, Tihomir; Vera, Domingo Mariano Adolfo; González, María L.; Lanza Castronuovo, Priscila Ailin; et al.; Analogues of the Lignan Pinoresinol as Novel Lead Compounds for P-glycoprotein (P-gp) Inhibitors; American Chemical Society; ACS Medicinal Chemistry Letters; 9; 12; 11-2018; 1186-1192
1948-5875
CONICET Digital
CONICET
url http://hdl.handle.net/11336/95224
identifier_str_mv Laiolo, Jerónimo; Tomasič, Tihomir; Vera, Domingo Mariano Adolfo; González, María L.; Lanza Castronuovo, Priscila Ailin; et al.; Analogues of the Lignan Pinoresinol as Novel Lead Compounds for P-glycoprotein (P-gp) Inhibitors; American Chemical Society; ACS Medicinal Chemistry Letters; 9; 12; 11-2018; 1186-1192
1948-5875
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00324
info:eu-repo/semantics/altIdentifier/doi/10.1021/acsmedchemlett.8b00324
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Chemical Society
publisher.none.fl_str_mv American Chemical Society
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.982451

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