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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/240402
Ver los metadatos del registro completo
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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 Técnicas2025-09-29T10:05:13Zoai: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:34982025-09-29 10:05:13.876CONICET 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 |
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CONICET Digital (CONICET) |
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CONICET Digital (CONICET) |
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Consejo Nacional de Investigaciones Científicas y Técnicas |
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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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1844613886232231936 |
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13.070432 |