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Photogeneration of Quinone Methides as Latent Electrophiles for Lysine Targeting

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Photogeneration of Quinone Methides as Latent Electrophiles for Lysine Targeting

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dc.contributor.author Pérez Ruiz, Raul es_ES
dc.contributor.author Molins-Molina, Oscar es_ES
dc.contributor.author Lence, Emilio es_ES
dc.contributor.author González-Bello, Concepción es_ES
dc.contributor.author Miranda Alonso, Miguel Ángel es_ES
dc.contributor.author Jiménez Molero, María Consuelo es_ES
dc.date.accessioned 2020-06-10T03:32:21Z
dc.date.available 2020-06-10T03:32:21Z
dc.date.issued 2018-11-02 es_ES
dc.identifier.issn 0022-3263 es_ES
dc.identifier.uri http://hdl.handle.net/10251/145864
dc.description.abstract [EN] Latent electrophiles are nowadays very attractive chemical entities for drug discovery, as they are unreactive unless activated upon binding with the specific target. In this work, the utility of 4-trifluoromethyl phenols as precursors of latent electrophiles, quinone methides (QM), for lysine-targeting is demonstrated. These Michael acceptors were photogenerated for specific covalent modification of lysine residues using human serum albumin (HSA) as a model target. The reactive QM-type intermediates I or II, generated upon irradiation of 4-trifluoromethyl-1-naphthol (1)@HSA or 4-(4-trifluorometylphenyl)phenol (2)@HSA complexes, exhibited chemoselective reactivity toward lysine residues leading to amide adducts, which was confirmed by proteomic analysis. For ligand 1, the covalent modification of residues Lys106 and Lys414 (located in subdomains IA and IIIA, respectively) was observed, whereas for ligand 2, the modification of Lys195 (in subdomain IIA) took place. Docking and molecular dynamics simulation studies provided an insight into the molecular basis of the selectivity of 1 and 2 for these HSA subdomains and the covalent modification mechanism. These studies open the opportunity of performing protein silencing by generating reactive ligands under very mild conditions (irradiation) for specific covalent modification of hidden lysine residues. es_ES
dc.description.sponsorship Financial support from the Spanish Ministry of Economy and Competiveness [CTQ2016-78875-P, SAF2016-75638-R and BES-2014-069404 (predoctoral fellowship to O.M.-M.)], the Generalitat Valenciana (PROMETEO/2017/075), the Community of Madrid (2016-T1/AMB-1275), the Xunta de Galicia (Centro Singular de Investigacion de Galicia accreditation 2016-2019, ED431G/09 and postdoctoral fellowship to E.L.), and the European Union (European Regional Development Fund, ERDF) is gratefully acknowledged. The proteomic analysis was performed in the proteomics facility of SCSIE University of Valencia that belongs to ProteoRed PRB2-ISCIII and is supported by grant PT13/0001, of the PE I+D+i 2013-2016, funded by ISCIII and FEDER. We are grateful to the Centro de Supercomputacion de Galicia (CESGA) for use of the Finis Terrae computer. es_ES
dc.language Inglés es_ES
dc.publisher American Chemical Society es_ES
dc.relation.ispartof The Journal of Organic Chemistry es_ES
dc.rights Reserva de todos los derechos es_ES
dc.subject Quinone methide es_ES
dc.subject Photochemistry es_ES
dc.subject Lysine targeting es_ES
dc.subject.classification QUIMICA ORGANICA es_ES
dc.title Photogeneration of Quinone Methides as Latent Electrophiles for Lysine Targeting es_ES
dc.type Artículo es_ES
dc.identifier.doi 10.1021/acs.joc.8b01559 es_ES
dc.relation.projectID info:eu-repo/grantAgreement/MINECO//CTQ2016-78875-P/ES/CONTROL SUPRAMOLECULAR DE LA FOTORREACTIVIDAD EN MEDIOS MICROHETEROGENOS BASADOS EN AMINOACIDOS: GELES MOLECULARES Y PROTEINAS TRANSPORTADORAS COMO NANORREACTORES./ es_ES
dc.relation.projectID info:eu-repo/grantAgreement/MINECO//SAF2016-75638-R/ES/DESARROLLO DE NUEVOS FARMACOS PARA EL TRATAMIENTO DE LAS INFECCIONES BACTERIANAS MULTIRESISTENTES: APROXIMACIONES QUE INCIDEN SOBRE VIABILIDAD, RESISTENCIA Y VIRULENCIA/ es_ES
dc.relation.projectID info:eu-repo/grantAgreement/Xunta de Galicia//ED431G%2F09/ es_ES
dc.relation.projectID info:eu-repo/grantAgreement/UV//PT13%2F0001/ es_ES
dc.relation.projectID info:eu-repo/grantAgreement/ISCIII//PT13%2F0001/ es_ES
dc.relation.projectID info:eu-repo/grantAgreement/MINECO//PT13%2F0001/ es_ES
dc.relation.projectID info:eu-repo/grantAgreement/MINECO//CTQ2013-47872-C2-1-P/ES/METABOLITOS FOTOACTIVOS/ es_ES
dc.relation.projectID info:eu-repo/grantAgreement/MINECO//BES-2014-069404/ES/BES-2014-069404/ es_ES
dc.relation.projectID info:eu-repo/grantAgreement/GVA//PROMETEO%2F2017%2F075/ES/Reacciones fotoquímicas de biomoléculas/ es_ES
dc.rights.accessRights Abierto es_ES
dc.contributor.affiliation Universitat Politècnica de València. Departamento de Química - Departament de Química es_ES
dc.description.bibliographicCitation Pérez Ruiz, R.; Molins-Molina, O.; Lence, E.; González-Bello, C.; Miranda Alonso, MÁ.; Jiménez Molero, MC. (2018). Photogeneration of Quinone Methides as Latent Electrophiles for Lysine Targeting. The Journal of Organic Chemistry. 83(21):13019-13029. https://doi.org/10.1021/acs.joc.8b01559 es_ES
dc.description.accrualMethod S es_ES
dc.relation.publisherversion https://doi.org/10.1021/acs.joc.8b01559 es_ES
dc.description.upvformatpinicio 13019 es_ES
dc.description.upvformatpfin 13029 es_ES
dc.type.version info:eu-repo/semantics/publishedVersion es_ES
dc.description.volume 83 es_ES
dc.description.issue 21 es_ES
dc.identifier.pmid 30274513 es_ES
dc.relation.pasarela S\372717 es_ES
dc.contributor.funder Xunta de Galicia es_ES
dc.contributor.funder Generalitat Valenciana es_ES
dc.contributor.funder Universitat de València es_ES
dc.contributor.funder Instituto de Salud Carlos III es_ES
dc.contributor.funder European Regional Development Fund es_ES
dc.contributor.funder Ministerio de Economía y Competitividad es_ES


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