Novel betulin derivatives as multidrug reversal agents targeting P-glycoprotein

Autores
Laiolo, Jerónimo; Graikioti, Dafni G.; Barbieri, Cecilia Luján; Joray, Mariana Belén; Antoniou, Antonia I.; Vera, Domingo Mariano Adolfo; Athanassopoulos, Constantinos M.; Carpinella, Maria Cecilia
Año de publicación
2024
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Chemotherapy is a powerful means of cancer treatment but its efficacy is compromised by theemergence of multidrug resistance (MDR), mainly linked to the efflux transporter BCB1/Pglycoprotein (P-gp). Based on the chemical structure of betulin, identified in our previous work as an effective modulator of the P-gp function, a series of analogs were designed, synthesized and evaluated as a source of novel inhibitors. Compounds 6g and 6i inhibited rhodamine 123 efflux in the P-gp overexpressed leukemia cells, K562/Dox, at concentrations of 0.19 μM and 0.39 μM, respectively, and increased the intracellular accumulation of doxorubicin at the submicromolar concentration of 0.098 μM. Compounds 6g and 6i were able to restore the sensitivity of K562/Dox to Dox at 0.024 μM and 0.19 μM, respectively. Structure–activity relationship analysis and molecular modeling revealed important information about the structural features conferring activity. All the active compounds fitted in a specific region involving mainly transmembrane helices (TMH) 4–6 from one homologous half and TMH 7 and 12 from the other, also showing close contacts with TMH 6 and 12. Compounds that bound preferentially to another region were inactive, regardless of their free energy of binding. It should be noted that compounds 6g and 6i were devoid of toxic effects against peripheral blood mononuclear normal cells and erythrocytes. The data obtained indicates that both compounds might be proposed as scaffolds for obtaining promising P-gp inhibitors for overcoming MDR.
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: Graikioti, Dafni G.. University Of Patras (university Of Patras);
Fil: Barbieri, Cecilia Luján. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Química; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones En Biodiversidad y Biotecnología. Grupo de Investigación en Química Analítica y Modelado Molecular; Argentina
Fil: Joray, Mariana Belén. 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: Antoniou, Antonia I.. University Of Patras (university Of Patras);
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. Grupo de Investigación en Química Analítica y Modelado Molecular; Argentina
Fil: Athanassopoulos, Constantinos M.. University Of Patras (university Of Patras);
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
INHIBIRES DE P-GP
DERIVADOS DE BETULINA
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/240402
Acceder
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network_name_str CONICET Digital (CONICET)
spelling Novel betulin derivatives as multidrug reversal agents targeting P-glycoproteinLaiolo, JerónimoGraikioti, Dafni G.Barbieri, Cecilia LujánJoray, Mariana BelénAntoniou, Antonia I.Vera, Domingo Mariano AdolfoAthanassopoulos, Constantinos M.Carpinella, Maria CeciliaINHIBIRES DE P-GPDERIVADOS DE BETULINAhttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1Chemotherapy is a powerful means of cancer treatment but its efficacy is compromised by theemergence of multidrug resistance (MDR), mainly linked to the efflux transporter BCB1/Pglycoprotein (P-gp). Based on the chemical structure of betulin, identified in our previous work as an effective modulator of the P-gp function, a series of analogs were designed, synthesized and evaluated as a source of novel inhibitors. Compounds 6g and 6i inhibited rhodamine 123 efflux in the P-gp overexpressed leukemia cells, K562/Dox, at concentrations of 0.19 μM and 0.39 μM, respectively, and increased the intracellular accumulation of doxorubicin at the submicromolar concentration of 0.098 μM. Compounds 6g and 6i were able to restore the sensitivity of K562/Dox to Dox at 0.024 μM and 0.19 μM, respectively. Structure–activity relationship analysis and molecular modeling revealed important information about the structural features conferring activity. All the active compounds fitted in a specific region involving mainly transmembrane helices (TMH) 4–6 from one homologous half and TMH 7 and 12 from the other, also showing close contacts with TMH 6 and 12. Compounds that bound preferentially to another region were inactive, regardless of their free energy of binding. It should be noted that compounds 6g and 6i were devoid of toxic effects against peripheral blood mononuclear normal cells and erythrocytes. The data obtained indicates that both compounds might be proposed as scaffolds for obtaining promising P-gp inhibitors for overcoming MDR.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: Graikioti, Dafni G.. University Of Patras (university Of Patras);Fil: Barbieri, Cecilia Luján. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Química; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones En Biodiversidad y Biotecnología. Grupo de Investigación en Química Analítica y Modelado Molecular; ArgentinaFil: Joray, Mariana Belén. 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: Antoniou, Antonia I.. University Of Patras (university Of Patras);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. Grupo de Investigación en Química Analítica y Modelado Molecular; ArgentinaFil: Athanassopoulos, Constantinos M.. University Of Patras (university Of Patras);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.; ArgentinaNature2024-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/240402Laiolo, Jerónimo; Graikioti, Dafni G.; Barbieri, Cecilia Luján; Joray, Mariana Belén; Antoniou, Antonia I.; et al.; Novel betulin derivatives as multidrug reversal agents targeting P-glycoprotein; Nature; Scientific Reports; 14; 1; 1-2024; 1-232045-2322CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41598-023-49939-9info:eu-repo/semantics/altIdentifier/doi/10.1038/s41598-023-49939-9info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:34:55Zoai:ri.conicet.gov.ar:11336/240402instacron: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 11:34:55.308CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Novel betulin derivatives as multidrug reversal agents targeting P-glycoprotein
title Novel betulin derivatives as multidrug reversal agents targeting P-glycoprotein
spellingShingle Novel betulin derivatives as multidrug reversal agents targeting P-glycoprotein
Laiolo, Jerónimo
INHIBIRES DE P-GP
DERIVADOS DE BETULINA
title_short Novel betulin derivatives as multidrug reversal agents targeting P-glycoprotein
title_full Novel betulin derivatives as multidrug reversal agents targeting P-glycoprotein
title_fullStr Novel betulin derivatives as multidrug reversal agents targeting P-glycoprotein
title_full_unstemmed Novel betulin derivatives as multidrug reversal agents targeting P-glycoprotein
title_sort Novel betulin derivatives as multidrug reversal agents targeting P-glycoprotein
dc.creator.none.fl_str_mv Laiolo, Jerónimo
Graikioti, Dafni G.
Barbieri, Cecilia Luján
Joray, Mariana Belén
Antoniou, Antonia I.
Vera, Domingo Mariano Adolfo
Athanassopoulos, Constantinos M.
Carpinella, Maria Cecilia
author Laiolo, Jerónimo
author_facet Laiolo, Jerónimo
Graikioti, Dafni G.
Barbieri, Cecilia Luján
Joray, Mariana Belén
Antoniou, Antonia I.
Vera, Domingo Mariano Adolfo
Athanassopoulos, Constantinos M.
Carpinella, Maria Cecilia
author_role author
author2 Graikioti, Dafni G.
Barbieri, Cecilia Luján
Joray, Mariana Belén
Antoniou, Antonia I.
Vera, Domingo Mariano Adolfo
Athanassopoulos, Constantinos M.
Carpinella, Maria Cecilia
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv INHIBIRES DE P-GP
DERIVADOS DE BETULINA
topic INHIBIRES DE P-GP
DERIVADOS DE BETULINA
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Chemotherapy is a powerful means of cancer treatment but its efficacy is compromised by theemergence of multidrug resistance (MDR), mainly linked to the efflux transporter BCB1/Pglycoprotein (P-gp). Based on the chemical structure of betulin, identified in our previous work as an effective modulator of the P-gp function, a series of analogs were designed, synthesized and evaluated as a source of novel inhibitors. Compounds 6g and 6i inhibited rhodamine 123 efflux in the P-gp overexpressed leukemia cells, K562/Dox, at concentrations of 0.19 μM and 0.39 μM, respectively, and increased the intracellular accumulation of doxorubicin at the submicromolar concentration of 0.098 μM. Compounds 6g and 6i were able to restore the sensitivity of K562/Dox to Dox at 0.024 μM and 0.19 μM, respectively. Structure–activity relationship analysis and molecular modeling revealed important information about the structural features conferring activity. All the active compounds fitted in a specific region involving mainly transmembrane helices (TMH) 4–6 from one homologous half and TMH 7 and 12 from the other, also showing close contacts with TMH 6 and 12. Compounds that bound preferentially to another region were inactive, regardless of their free energy of binding. It should be noted that compounds 6g and 6i were devoid of toxic effects against peripheral blood mononuclear normal cells and erythrocytes. The data obtained indicates that both compounds might be proposed as scaffolds for obtaining promising P-gp inhibitors for overcoming MDR.
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: Graikioti, Dafni G.. University Of Patras (university Of Patras);
Fil: Barbieri, Cecilia Luján. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Química; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones En Biodiversidad y Biotecnología. Grupo de Investigación en Química Analítica y Modelado Molecular; Argentina
Fil: Joray, Mariana Belén. 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: Antoniou, Antonia I.. University Of Patras (university Of Patras);
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. Grupo de Investigación en Química Analítica y Modelado Molecular; Argentina
Fil: Athanassopoulos, Constantinos M.. University Of Patras (university Of Patras);
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 Chemotherapy is a powerful means of cancer treatment but its efficacy is compromised by theemergence of multidrug resistance (MDR), mainly linked to the efflux transporter BCB1/Pglycoprotein (P-gp). Based on the chemical structure of betulin, identified in our previous work as an effective modulator of the P-gp function, a series of analogs were designed, synthesized and evaluated as a source of novel inhibitors. Compounds 6g and 6i inhibited rhodamine 123 efflux in the P-gp overexpressed leukemia cells, K562/Dox, at concentrations of 0.19 μM and 0.39 μM, respectively, and increased the intracellular accumulation of doxorubicin at the submicromolar concentration of 0.098 μM. Compounds 6g and 6i were able to restore the sensitivity of K562/Dox to Dox at 0.024 μM and 0.19 μM, respectively. Structure–activity relationship analysis and molecular modeling revealed important information about the structural features conferring activity. All the active compounds fitted in a specific region involving mainly transmembrane helices (TMH) 4–6 from one homologous half and TMH 7 and 12 from the other, also showing close contacts with TMH 6 and 12. Compounds that bound preferentially to another region were inactive, regardless of their free energy of binding. It should be noted that compounds 6g and 6i were devoid of toxic effects against peripheral blood mononuclear normal cells and erythrocytes. The data obtained indicates that both compounds might be proposed as scaffolds for obtaining promising P-gp inhibitors for overcoming MDR.
publishDate 2024
dc.date.none.fl_str_mv 2024-01
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/11336/240402
Laiolo, Jerónimo; Graikioti, Dafni G.; Barbieri, Cecilia Luján; Joray, Mariana Belén; Antoniou, Antonia I.; et al.; Novel betulin derivatives as multidrug reversal agents targeting P-glycoprotein; Nature; Scientific Reports; 14; 1; 1-2024; 1-23
2045-2322
CONICET Digital
CONICET
url http://hdl.handle.net/11336/240402
identifier_str_mv Laiolo, Jerónimo; Graikioti, Dafni G.; Barbieri, Cecilia Luján; Joray, Mariana Belén; Antoniou, Antonia I.; et al.; Novel betulin derivatives as multidrug reversal agents targeting P-glycoprotein; Nature; Scientific Reports; 14; 1; 1-2024; 1-23
2045-2322
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://www.nature.com/articles/s41598-023-49939-9
info:eu-repo/semantics/altIdentifier/doi/10.1038/s41598-023-49939-9
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature
publisher.none.fl_str_mv Nature
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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