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dc.creatorRoldán Peña, Jesús Migueles
dc.creatorAlejandre Ramos, Danieles
dc.creatorLópez López, Óscares
dc.creatorMaya Castilla, Inéses
dc.creatorLagunes, Irenees
dc.creatorPadrón, José M.es
dc.creatorPeña Altamira, Luis Emilianoes
dc.creatorBartolini, Manuelaes
dc.creatorMonti, Barbaraes
dc.creatorBolognesi, Maria L.es
dc.creatorFernández-Bolaños Guzmán, José Maríaes
dc.date.accessioned2023-05-26T17:37:51Z
dc.date.available2023-05-26T17:37:51Z
dc.date.issued2017
dc.identifier.citationRoldán Peña, J.M., Alejandre Ramos, D., López López, Ó., Maya Castilla, I., Lagunes, I., Padrón, J.M.,...,Fernández-Bolaños Guzmán, J.M. (2017). New tacrine dimers with antioxidant linkers as dual drugs: Anti-Alzheimer's and antiproliferative agents. European Journal of Medicinal Chemistry, 138, 761-773. https://doi.org/10.1016/j.ejmech.2017.06.048.
dc.identifier.issn0223-5234es
dc.identifier.issn1768-3254es
dc.identifier.urihttps://hdl.handle.net/11441/146702
dc.description.abstractWe have designed a series of tacrine-based homo- and heterodimers that incorporate an antioxidant tether (selenoureido, chalcogenide) as new dual compounds: for the treatment of Alzheimer's disease and as antiproliferative agents. Symmetrical homodimers bearing a dichalcogenide or selenide-based tether, the best compounds in the series, were found to be strong and highly selective electric eel AChE inhibitors, with inhibition constants within the low nanomolar range. This high inhibitory activity was confirmed on recombinant human AChE for the most interesting derivatives. The three most promising homodimers also showed a good inhibitory activity towards amyloid-β self aggregation. The symmetric disulfide derivative bis[5-(1′,2′,3′,4’-tetrahydroacridin-9′-ylamino)pentyl]disulfide (19) showed the best multipotent profile and was not neurotoxic on immortalized mouse cortical neurons even at 50 μM concentration. These results represent an improvement in activity and selectivity compared to parent tacrine, the first marketed drug against Alzheimer's disease. Title compounds also exhibited excellent in vitro antiproliferative activities against a panel of 6 human tumor cell lines, with GI50 values within the submicromolar range for the most potent derivatives (0.12–0.95 μM); such values represent a spectacular increase compared to currently-used chemotherapeutic agents, such as 5-FU (up to 306−fold) and cisplatin (up to 162−fold). Cell cycle experiments indicated the accumulation of cells in the G1 phase of the cycle, a different mechanism than the reported for cisplatin. The breast cancer cell lines turned out to be the most sensitive one of the panel tested.es
dc.description.sponsorshipDirección General de Investigación CTQ2016-78703-P, CTQ2011-28417-C02-01, CEI10/00018es
dc.description.sponsorshipJunta de Andalucía FQM134es
dc.description.sponsorshipFondo Europeo de Desarrollo Regional 501100008530es
dc.description.sponsorshipEU Research Potential FP7-REGPOT-2012-CT2012-31637-IMBRAINes
dc.formatapplication/pdfes
dc.format.extent67 p.es
dc.language.isoenges
dc.publisherElsevieres
dc.relation.ispartofEuropean Journal of Medicinal Chemistry, 138, 761-773.
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectAChE inhibitiones
dc.subjectAnti-Alzheimeres
dc.subjectAntioxidantes
dc.subjectAntiproliferative agentes
dc.subjectTacrine dimerses
dc.titleNew tacrine dimers with antioxidant linkers as dual drugs: Anti-Alzheimer's and antiproliferative agentses
dc.typeinfo:eu-repo/semantics/articlees
dcterms.identifierhttps://ror.org/03yxnpp24
dc.type.versioninfo:eu-repo/semantics/acceptedVersiones
dc.rights.accessRightsinfo:eu-repo/semantics/openAccesses
dc.contributor.affiliationUniversidad de Sevilla. Departamento de Química orgánicaes
dc.relation.projectIDCTQ2016-78703-Pes
dc.relation.projectIDCTQ2011-28417-C02-01es
dc.relation.projectIDCEI10/00018es
dc.relation.projectIDFQM134es
dc.relation.projectID501100008530es
dc.relation.projectIDFP7-REGPOT-2012-CT2012-31637-IMBRAINes
dc.relation.publisherversionhttps://doi.org/10.1016/j.ejmech.2017.06.048es
dc.identifier.doi10.1016/j.ejmech.2017.06.048es
dc.journaltitleEuropean Journal of Medicinal Chemistryes
dc.publication.volumen138es
dc.publication.initialPage761es
dc.publication.endPage773es
dc.contributor.funderDirección General de Investigación (DGI). Españaes
dc.contributor.funderJunta de Andalucíaes
dc.contributor.funderEuropean Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)es
dc.contributor.funderEU Research Potentiales
dc.description.awardwinningPremio Mensual Publicación Científica Destacada de la US. Escuela Politécnica Superior

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