Structure-activity relationship studies on divalent naphthalene diimide G quadruplex ligands with anticancer and antiparasitic activity.

Naphthalene diimide (NDI) is a central scaffold that has been commonly used in the design of G-quadruplex (G4) ligands. Previous work revealed notable anticancer activity of a disubstituted N-methylpiperazine propyl NDI G4 ligand. Here, we explored structure–activity relationship studies around liga...

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Autores: Pérez Soto, Manuel, Peñalver, Pablo, Street, Steven T. G., Weenink, Dora, O'Hagan, M.P., Ramos-Soriano, Javier, Jiang, Y. Jennifer, Hollingworth, Gregory J., Galán, M. Carmen, Morales, Juan Carlos
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/360877
Acceso en línea:http://hdl.handle.net/10261/360877
Access Level:acceso abierto
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spelling Structure-activity relationship studies on divalent naphthalene diimide G quadruplex ligands with anticancer and antiparasitic activity.Pérez Soto, ManuelPeñalver, PabloStreet, Steven T. G.Weenink, DoraO'Hagan, M.P.Ramos-Soriano, JavierJiang, Y. JenniferHollingworth, Gregory J.Galán, M. CarmenMorales, Juan CarlosNaphthalene diimide (NDI) is a central scaffold that has been commonly used in the design of G-quadruplex (G4) ligands. Previous work revealed notable anticancer activity of a disubstituted N-methylpiperazine propyl NDI G4 ligand. Here, we explored structure–activity relationship studies around ligand bis-N,Ń-2,7-(3-(4-methylpiperazin-1-yl)propyl)-1,4,5,8-naphthalenetetracarboxylic diimide, maintaining the central NDI core whilst modifying the spacer and the nature of the cationic groups. We prepared new disubstituted NDI derivatives of the original compound and examined their in vitro antiproliferative and antiparasitic activity. Several N-methylpiperazine propyl NDIs showed sub-micromolar activity against Trypanosoma brucei and Leishmania major parasites with up to 30 fold selectivity versus MRC-5 cells. The best compound was a dimorpholino NDI with an IC50 of 0.17 μM against T.brucei and 40 fold selectivity versus MRC-5 cells. However, no clear correlation between G4 binding of the new NDI derivatives and antiproliferative or antiparasitic activity was observed, indicating that other mechanisms of action may be responsible for the observed biological activity.This work was funded by the Spanish Ministerio de Economía y Competitividad (RTI2018-099036-B-I00; EUIN2017-88791). We thank the Bristol Chemical Synthesis Centre for Doctoral Training for PhD scholarships for STGS (EPSRC EP/G036764/1 and EP/N509619/1), MPO (EPSRC EP/L015366/1) and JJ (EPSRC EP/L015366/1 and EP/S026215/1). MCG thanks the European Research Council (ERC-COG: 648239). JRS acknowledges a MSCA fellowship (project 843720-BioNanoProbes).Pergamon PressMinisterio de Economía y Competitividad (España)European Research CouncilUniversity of BristolConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2024202420222024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/360877reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://dx.doi.org/10.1016/j.bmc.2022.116946Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3608772026-05-22T06:33:51Z
dc.title.none.fl_str_mv Structure-activity relationship studies on divalent naphthalene diimide G quadruplex ligands with anticancer and antiparasitic activity.
title Structure-activity relationship studies on divalent naphthalene diimide G quadruplex ligands with anticancer and antiparasitic activity.
spellingShingle Structure-activity relationship studies on divalent naphthalene diimide G quadruplex ligands with anticancer and antiparasitic activity.
Pérez Soto, Manuel
title_short Structure-activity relationship studies on divalent naphthalene diimide G quadruplex ligands with anticancer and antiparasitic activity.
title_full Structure-activity relationship studies on divalent naphthalene diimide G quadruplex ligands with anticancer and antiparasitic activity.
title_fullStr Structure-activity relationship studies on divalent naphthalene diimide G quadruplex ligands with anticancer and antiparasitic activity.
title_full_unstemmed Structure-activity relationship studies on divalent naphthalene diimide G quadruplex ligands with anticancer and antiparasitic activity.
title_sort Structure-activity relationship studies on divalent naphthalene diimide G quadruplex ligands with anticancer and antiparasitic activity.
dc.creator.none.fl_str_mv Pérez Soto, Manuel
Peñalver, Pablo
Street, Steven T. G.
Weenink, Dora
O'Hagan, M.P.
Ramos-Soriano, Javier
Jiang, Y. Jennifer
Hollingworth, Gregory J.
Galán, M. Carmen
Morales, Juan Carlos
author Pérez Soto, Manuel
author_facet Pérez Soto, Manuel
Peñalver, Pablo
Street, Steven T. G.
Weenink, Dora
O'Hagan, M.P.
Ramos-Soriano, Javier
Jiang, Y. Jennifer
Hollingworth, Gregory J.
Galán, M. Carmen
Morales, Juan Carlos
author_role author
author2 Peñalver, Pablo
Street, Steven T. G.
Weenink, Dora
O'Hagan, M.P.
Ramos-Soriano, Javier
Jiang, Y. Jennifer
Hollingworth, Gregory J.
Galán, M. Carmen
Morales, Juan Carlos
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
European Research Council
University of Bristol
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
description Naphthalene diimide (NDI) is a central scaffold that has been commonly used in the design of G-quadruplex (G4) ligands. Previous work revealed notable anticancer activity of a disubstituted N-methylpiperazine propyl NDI G4 ligand. Here, we explored structure–activity relationship studies around ligand bis-N,Ń-2,7-(3-(4-methylpiperazin-1-yl)propyl)-1,4,5,8-naphthalenetetracarboxylic diimide, maintaining the central NDI core whilst modifying the spacer and the nature of the cationic groups. We prepared new disubstituted NDI derivatives of the original compound and examined their in vitro antiproliferative and antiparasitic activity. Several N-methylpiperazine propyl NDIs showed sub-micromolar activity against Trypanosoma brucei and Leishmania major parasites with up to 30 fold selectivity versus MRC-5 cells. The best compound was a dimorpholino NDI with an IC50 of 0.17 μM against T.brucei and 40 fold selectivity versus MRC-5 cells. However, no clear correlation between G4 binding of the new NDI derivatives and antiproliferative or antiparasitic activity was observed, indicating that other mechanisms of action may be responsible for the observed biological activity.
publishDate 2022
dc.date.none.fl_str_mv 2022
2024
2024
2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/360877
url http://hdl.handle.net/10261/360877
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://dx.doi.org/10.1016/j.bmc.2022.116946
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Pergamon Press
publisher.none.fl_str_mv Pergamon Press
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.811543

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