C9‐Functionalized Doxycycline Analogs as Drug Candidates to Prevent Pathological α‐Synuclein Aggregation and Neuroinflammation in Parkinson's Disease Degeneration

Autores
Rose, Clémence; Tomas Grau, Rodrigo Hernán; Zabala, Brenda Adriana; Michel, Patrick Pierre; Brunel, Jean Michel; Chehin, Rosana Nieves; Raisman Vozari, Rita; Ferrié, Laurent; Figadère, Bruno
Año de publicación
2024
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Doxycycline, a semi-synthetic tetracycline, is a widely used antibiotic for treating mild-to-moderate infections, including skin problems. However, its anti-inflammatory and antioxidant properties, combined with its ability to interfere with α-synuclein aggregation, make it an attractive candidate for repositioning in Parkinson's disease. Nevertheless, the antibiotic activity of doxycycline restricts its potential use for long-term treatment of Parkinsonian patients. In the search for non-antibiotic tetracyclines that could operate against Parkinson's disease pathomechanisms, eighteen novel doxycycline derivatives were designed. Specifically, the dimethyl-amino group at C4 was reduced, resulting in limited antimicrobial activity, and several coupling reactions were performed at position C9 of the aromatic D ring, this position being one of the most reactive for introducing substituents. Using the Thioflavin-T assay, we found seven compounds were more effective than doxycycline in inhibiting α-synuclein aggregation. Furthermore, two of these derivatives exhibited better anti-inflammatory effects than doxycycline in a culture system of microglial cells used to model Parkinson's disease neuroinflammatory processes. Overall, through structure-activity relationship studies, we identified two newly designed tetracyclines as promising drug candidates for Parkinson's disease treatment.
Fil: Rose, Clémence. Universite Paris-Saclay ;
Fil: Tomas Grau, Rodrigo Hernán. Universidad Nacional de Tucumán. Instituto de Investigaciones En Medicina Molecular y Celular Aplicada del Bicentenario. - Gobierno de la Provincia de Tucumán. Ministerio de Salud. Sistema Provincial de Salud. Instituto de Investigaciones en Medicina Molecular y Celular Aplicada del Bicentenario. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet Noa Sur. Instituto de Investigaciones en Medicina Molecular y Celular Aplicada del Bicentenario; Argentina
Fil: Zabala, Brenda Adriana. Sorbonne University; Francia. Inserm; Francia
Fil: Michel, Patrick Pierre. Sorbonne University; Francia. Inserm; Francia
Fil: Brunel, Jean Michel. Inserm; Francia. Aix-Marseille Université; Francia
Fil: Chehin, Rosana Nieves. Universidad Nacional de Tucumán. Instituto de Investigaciones En Medicina Molecular y Celular Aplicada del Bicentenario. - Gobierno de la Provincia de Tucumán. Ministerio de Salud. Sistema Provincial de Salud. Instituto de Investigaciones en Medicina Molecular y Celular Aplicada del Bicentenario. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet Noa Sur. Instituto de Investigaciones en Medicina Molecular y Celular Aplicada del Bicentenario; Argentina
Fil: Raisman Vozari, Rita. Inserm; Francia. Sorbonne University; Francia
Fil: Ferrié, Laurent. Universite Paris-Saclay ; . Centre National de la Recherche Scientifique; Francia
Fil: Figadère, Bruno. Centre National de la Recherche Scientifique; Francia. Universite Paris-Saclay ;
Materia
Parkinson’s Disease
Drug Candidates
Doxycycline Analogs
α-Synuclein Aggregation
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/263002
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/263002
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling C9‐Functionalized Doxycycline Analogs as Drug Candidates to Prevent Pathological α‐Synuclein Aggregation and Neuroinflammation in Parkinson's Disease DegenerationRose, ClémenceTomas Grau, Rodrigo HernánZabala, Brenda AdrianaMichel, Patrick PierreBrunel, Jean MichelChehin, Rosana NievesRaisman Vozari, RitaFerrié, LaurentFigadère, BrunoParkinson’s DiseaseDrug CandidatesDoxycycline Analogsα-Synuclein Aggregationhttps://purl.org/becyt/ford/3.4https://purl.org/becyt/ford/3Doxycycline, a semi-synthetic tetracycline, is a widely used antibiotic for treating mild-to-moderate infections, including skin problems. However, its anti-inflammatory and antioxidant properties, combined with its ability to interfere with α-synuclein aggregation, make it an attractive candidate for repositioning in Parkinson's disease. Nevertheless, the antibiotic activity of doxycycline restricts its potential use for long-term treatment of Parkinsonian patients. In the search for non-antibiotic tetracyclines that could operate against Parkinson's disease pathomechanisms, eighteen novel doxycycline derivatives were designed. Specifically, the dimethyl-amino group at C4 was reduced, resulting in limited antimicrobial activity, and several coupling reactions were performed at position C9 of the aromatic D ring, this position being one of the most reactive for introducing substituents. Using the Thioflavin-T assay, we found seven compounds were more effective than doxycycline in inhibiting α-synuclein aggregation. Furthermore, two of these derivatives exhibited better anti-inflammatory effects than doxycycline in a culture system of microglial cells used to model Parkinson's disease neuroinflammatory processes. Overall, through structure-activity relationship studies, we identified two newly designed tetracyclines as promising drug candidates for Parkinson's disease treatment.Fil: Rose, Clémence. Universite Paris-Saclay ;Fil: Tomas Grau, Rodrigo Hernán. Universidad Nacional de Tucumán. Instituto de Investigaciones En Medicina Molecular y Celular Aplicada del Bicentenario. - Gobierno de la Provincia de Tucumán. Ministerio de Salud. Sistema Provincial de Salud. Instituto de Investigaciones en Medicina Molecular y Celular Aplicada del Bicentenario. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet Noa Sur. Instituto de Investigaciones en Medicina Molecular y Celular Aplicada del Bicentenario; ArgentinaFil: Zabala, Brenda Adriana. Sorbonne University; Francia. Inserm; FranciaFil: Michel, Patrick Pierre. Sorbonne University; Francia. Inserm; FranciaFil: Brunel, Jean Michel. Inserm; Francia. Aix-Marseille Université; FranciaFil: Chehin, Rosana Nieves. Universidad Nacional de Tucumán. Instituto de Investigaciones En Medicina Molecular y Celular Aplicada del Bicentenario. - Gobierno de la Provincia de Tucumán. Ministerio de Salud. Sistema Provincial de Salud. Instituto de Investigaciones en Medicina Molecular y Celular Aplicada del Bicentenario. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet Noa Sur. Instituto de Investigaciones en Medicina Molecular y Celular Aplicada del Bicentenario; ArgentinaFil: Raisman Vozari, Rita. Inserm; Francia. Sorbonne University; FranciaFil: Ferrié, Laurent. Universite Paris-Saclay ; . Centre National de la Recherche Scientifique; FranciaFil: Figadère, Bruno. Centre National de la Recherche Scientifique; Francia. Universite Paris-Saclay ;Wiley VCH Verlag2024-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/263002Rose, Clémence; Tomas Grau, Rodrigo Hernán; Zabala, Brenda Adriana; Michel, Patrick Pierre; Brunel, Jean Michel; et al.; C9‐Functionalized Doxycycline Analogs as Drug Candidates to Prevent Pathological α‐Synuclein Aggregation and Neuroinflammation in Parkinson's Disease Degeneration; Wiley VCH Verlag; Chemmedchem; 19; 12; 4-2024; 1-131860-7179CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.202300597info:eu-repo/semantics/altIdentifier/doi/10.1002/cmdc.202300597info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:56:22Zoai:ri.conicet.gov.ar:11336/263002instacron: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:34982025-09-03 09:56:24.102CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv C9‐Functionalized Doxycycline Analogs as Drug Candidates to Prevent Pathological α‐Synuclein Aggregation and Neuroinflammation in Parkinson's Disease Degeneration
title C9‐Functionalized Doxycycline Analogs as Drug Candidates to Prevent Pathological α‐Synuclein Aggregation and Neuroinflammation in Parkinson's Disease Degeneration
spellingShingle C9‐Functionalized Doxycycline Analogs as Drug Candidates to Prevent Pathological α‐Synuclein Aggregation and Neuroinflammation in Parkinson's Disease Degeneration
Rose, Clémence
Parkinson’s Disease
Drug Candidates
Doxycycline Analogs
α-Synuclein Aggregation
title_short C9‐Functionalized Doxycycline Analogs as Drug Candidates to Prevent Pathological α‐Synuclein Aggregation and Neuroinflammation in Parkinson's Disease Degeneration
title_full C9‐Functionalized Doxycycline Analogs as Drug Candidates to Prevent Pathological α‐Synuclein Aggregation and Neuroinflammation in Parkinson's Disease Degeneration
title_fullStr C9‐Functionalized Doxycycline Analogs as Drug Candidates to Prevent Pathological α‐Synuclein Aggregation and Neuroinflammation in Parkinson's Disease Degeneration
title_full_unstemmed C9‐Functionalized Doxycycline Analogs as Drug Candidates to Prevent Pathological α‐Synuclein Aggregation and Neuroinflammation in Parkinson's Disease Degeneration
title_sort C9‐Functionalized Doxycycline Analogs as Drug Candidates to Prevent Pathological α‐Synuclein Aggregation and Neuroinflammation in Parkinson's Disease Degeneration
dc.creator.none.fl_str_mv Rose, Clémence
Tomas Grau, Rodrigo Hernán
Zabala, Brenda Adriana
Michel, Patrick Pierre
Brunel, Jean Michel
Chehin, Rosana Nieves
Raisman Vozari, Rita
Ferrié, Laurent
Figadère, Bruno
author Rose, Clémence
author_facet Rose, Clémence
Tomas Grau, Rodrigo Hernán
Zabala, Brenda Adriana
Michel, Patrick Pierre
Brunel, Jean Michel
Chehin, Rosana Nieves
Raisman Vozari, Rita
Ferrié, Laurent
Figadère, Bruno
author_role author
author2 Tomas Grau, Rodrigo Hernán
Zabala, Brenda Adriana
Michel, Patrick Pierre
Brunel, Jean Michel
Chehin, Rosana Nieves
Raisman Vozari, Rita
Ferrié, Laurent
Figadère, Bruno
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Parkinson’s Disease
Drug Candidates
Doxycycline Analogs
α-Synuclein Aggregation
topic Parkinson’s Disease
Drug Candidates
Doxycycline Analogs
α-Synuclein Aggregation
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.4
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Doxycycline, a semi-synthetic tetracycline, is a widely used antibiotic for treating mild-to-moderate infections, including skin problems. However, its anti-inflammatory and antioxidant properties, combined with its ability to interfere with α-synuclein aggregation, make it an attractive candidate for repositioning in Parkinson's disease. Nevertheless, the antibiotic activity of doxycycline restricts its potential use for long-term treatment of Parkinsonian patients. In the search for non-antibiotic tetracyclines that could operate against Parkinson's disease pathomechanisms, eighteen novel doxycycline derivatives were designed. Specifically, the dimethyl-amino group at C4 was reduced, resulting in limited antimicrobial activity, and several coupling reactions were performed at position C9 of the aromatic D ring, this position being one of the most reactive for introducing substituents. Using the Thioflavin-T assay, we found seven compounds were more effective than doxycycline in inhibiting α-synuclein aggregation. Furthermore, two of these derivatives exhibited better anti-inflammatory effects than doxycycline in a culture system of microglial cells used to model Parkinson's disease neuroinflammatory processes. Overall, through structure-activity relationship studies, we identified two newly designed tetracyclines as promising drug candidates for Parkinson's disease treatment.
Fil: Rose, Clémence. Universite Paris-Saclay ;
Fil: Tomas Grau, Rodrigo Hernán. Universidad Nacional de Tucumán. Instituto de Investigaciones En Medicina Molecular y Celular Aplicada del Bicentenario. - Gobierno de la Provincia de Tucumán. Ministerio de Salud. Sistema Provincial de Salud. Instituto de Investigaciones en Medicina Molecular y Celular Aplicada del Bicentenario. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet Noa Sur. Instituto de Investigaciones en Medicina Molecular y Celular Aplicada del Bicentenario; Argentina
Fil: Zabala, Brenda Adriana. Sorbonne University; Francia. Inserm; Francia
Fil: Michel, Patrick Pierre. Sorbonne University; Francia. Inserm; Francia
Fil: Brunel, Jean Michel. Inserm; Francia. Aix-Marseille Université; Francia
Fil: Chehin, Rosana Nieves. Universidad Nacional de Tucumán. Instituto de Investigaciones En Medicina Molecular y Celular Aplicada del Bicentenario. - Gobierno de la Provincia de Tucumán. Ministerio de Salud. Sistema Provincial de Salud. Instituto de Investigaciones en Medicina Molecular y Celular Aplicada del Bicentenario. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet Noa Sur. Instituto de Investigaciones en Medicina Molecular y Celular Aplicada del Bicentenario; Argentina
Fil: Raisman Vozari, Rita. Inserm; Francia. Sorbonne University; Francia
Fil: Ferrié, Laurent. Universite Paris-Saclay ; . Centre National de la Recherche Scientifique; Francia
Fil: Figadère, Bruno. Centre National de la Recherche Scientifique; Francia. Universite Paris-Saclay ;
description Doxycycline, a semi-synthetic tetracycline, is a widely used antibiotic for treating mild-to-moderate infections, including skin problems. However, its anti-inflammatory and antioxidant properties, combined with its ability to interfere with α-synuclein aggregation, make it an attractive candidate for repositioning in Parkinson's disease. Nevertheless, the antibiotic activity of doxycycline restricts its potential use for long-term treatment of Parkinsonian patients. In the search for non-antibiotic tetracyclines that could operate against Parkinson's disease pathomechanisms, eighteen novel doxycycline derivatives were designed. Specifically, the dimethyl-amino group at C4 was reduced, resulting in limited antimicrobial activity, and several coupling reactions were performed at position C9 of the aromatic D ring, this position being one of the most reactive for introducing substituents. Using the Thioflavin-T assay, we found seven compounds were more effective than doxycycline in inhibiting α-synuclein aggregation. Furthermore, two of these derivatives exhibited better anti-inflammatory effects than doxycycline in a culture system of microglial cells used to model Parkinson's disease neuroinflammatory processes. Overall, through structure-activity relationship studies, we identified two newly designed tetracyclines as promising drug candidates for Parkinson's disease treatment.
publishDate 2024
dc.date.none.fl_str_mv 2024-04
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/11336/263002
Rose, Clémence; Tomas Grau, Rodrigo Hernán; Zabala, Brenda Adriana; Michel, Patrick Pierre; Brunel, Jean Michel; et al.; C9‐Functionalized Doxycycline Analogs as Drug Candidates to Prevent Pathological α‐Synuclein Aggregation and Neuroinflammation in Parkinson's Disease Degeneration; Wiley VCH Verlag; Chemmedchem; 19; 12; 4-2024; 1-13
1860-7179
CONICET Digital
CONICET
url http://hdl.handle.net/11336/263002
identifier_str_mv Rose, Clémence; Tomas Grau, Rodrigo Hernán; Zabala, Brenda Adriana; Michel, Patrick Pierre; Brunel, Jean Michel; et al.; C9‐Functionalized Doxycycline Analogs as Drug Candidates to Prevent Pathological α‐Synuclein Aggregation and Neuroinflammation in Parkinson's Disease Degeneration; Wiley VCH Verlag; Chemmedchem; 19; 12; 4-2024; 1-13
1860-7179
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://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.202300597
info:eu-repo/semantics/altIdentifier/doi/10.1002/cmdc.202300597
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Wiley VCH Verlag
publisher.none.fl_str_mv Wiley VCH Verlag
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 13.13397

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