The Masked Polar Group Incorporation (MPGI) Strategy in Drug Design: Effects of Nitrogen Substitutions on Combretastatin and Isocombretastatin Tubulin Inhibitors

Colchicine site ligands suffer from low aqueous solubility due to the highly hydrophobic nature of the binding site. A new strategy for increasing molecular polarity without exposing polar groups—termed masked polar group incorporation (MPGI)—was devised and applied to nitrogenated combretastatin an...

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Autores: González Díaz, Myriam, Ellahioui, Younes, Álvarez Lozano, Raquel, Gallego-Yerga, Laura, Caballero Salvador, Esther, Vicente-Blázquez, Alba, Ramudo González, Laura, Marín, Miguel, Sanz, Cristina, Medarde Agustín, Manuel, Peláez Lamamie de C. Arroyo, Rafael
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Universidad de Salamanca (USAL)
Repositorio:GREDOS. Repositorio Institucional de la Universidad de Salamanca
OAI Identifier:oai:gredos.usal.es:10366/148389
Acceso en línea:http://hdl.handle.net/10366/148389
Access Level:acceso abierto
Palabra clave:Tubulin
Colchicine-site
Combretastatins
Isocombretastatins
Phenstatins
Nitrogenated
Masked polar group introduction
Solubility
Cytotoxicity
Docking
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spelling The Masked Polar Group Incorporation (MPGI) Strategy in Drug Design: Effects of Nitrogen Substitutions on Combretastatin and Isocombretastatin Tubulin InhibitorsGonzález Díaz, MyriamEllahioui, YounesÁlvarez Lozano, RaquelGallego-Yerga, LauraCaballero Salvador, EstherVicente-Blázquez, AlbaRamudo González, LauraMarín, MiguelSanz, CristinaMedarde Agustín, ManuelPeláez Lamamie de C. Arroyo, RafaelTubulinColchicine-siteCombretastatinsIsocombretastatinsPhenstatinsNitrogenatedMasked polar group introductionSolubilityCytotoxicityDockingColchicine site ligands suffer from low aqueous solubility due to the highly hydrophobic nature of the binding site. A new strategy for increasing molecular polarity without exposing polar groups—termed masked polar group incorporation (MPGI)—was devised and applied to nitrogenated combretastatin analogues. Bulky ortho substituents to the pyridine nitrogen hinder it from the hydrophobic pocket while increasing molecular polarity. The resulting analogues show improved aqueous solubilities and highly potent antiproliferative activity against several cancer cell lines of different origin. The more potent compounds showed moderate tubulin polymerization inhibitory activity, arrested the cell cycle of treated cells at the G2/M phase, and subsequently caused apoptotic cell death represented by the cells gathered at the subG0/G1 population after 48 h of treatment. Annexin V/Propidium Iodide (PI) double-positive cells observed after 72 h confirmed the induction of apoptosis. Docking studies suggest binding at the colchicine site of tubulin in a similar way as combretastatin A4, with the polar groups masked by the vicinal substituents. These results validate the proposed strategy for the design of colchicine site ligands and open a new road to increasing the aqueous solubility of ligands binding in apolar environments.This research was funded by Consejería de Educación de la Junta de Castilla y León and FEDER Funds (SA030U16 and SA262P18) and Ministerio de Ciencia, Innovación y Universidades, Proyectos I + D + i «Retos de Investigación» del Programa Estatal de I + D + i Orientada a los Retos de la Sociedad RTI2018-099474-B-I00. M.G. acknowledges a predoctoral fellowship from the Consejería de Educación de la Junta de Castilla y León (EDU/602/2016). Y.E. acknowledges a predoctoral fellowship from the AECID. A.V.B. acknowledges a predoctoral fellowship from the Ministerio de Educación, Cultura y Deporte (FPU15/02457). We acknowledge the NMR and MS facilities of the Nucleus Platform of the University of Salamanca for the spectra.202220222019info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10366/148389reponame:GREDOS. Repositorio Institucional de la Universidad de Salamancainstname:Universidad de Salamanca (USAL)InglésSA030U16SA262P18RTI2018-099474-B-I00Attribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:gredos.usal.es:10366/1483892026-06-07T06:28:51Z
dc.title.none.fl_str_mv The Masked Polar Group Incorporation (MPGI) Strategy in Drug Design: Effects of Nitrogen Substitutions on Combretastatin and Isocombretastatin Tubulin Inhibitors
title The Masked Polar Group Incorporation (MPGI) Strategy in Drug Design: Effects of Nitrogen Substitutions on Combretastatin and Isocombretastatin Tubulin Inhibitors
spellingShingle The Masked Polar Group Incorporation (MPGI) Strategy in Drug Design: Effects of Nitrogen Substitutions on Combretastatin and Isocombretastatin Tubulin Inhibitors
González Díaz, Myriam
Tubulin
Colchicine-site
Combretastatins
Isocombretastatins
Phenstatins
Nitrogenated
Masked polar group introduction
Solubility
Cytotoxicity
Docking
title_short The Masked Polar Group Incorporation (MPGI) Strategy in Drug Design: Effects of Nitrogen Substitutions on Combretastatin and Isocombretastatin Tubulin Inhibitors
title_full The Masked Polar Group Incorporation (MPGI) Strategy in Drug Design: Effects of Nitrogen Substitutions on Combretastatin and Isocombretastatin Tubulin Inhibitors
title_fullStr The Masked Polar Group Incorporation (MPGI) Strategy in Drug Design: Effects of Nitrogen Substitutions on Combretastatin and Isocombretastatin Tubulin Inhibitors
title_full_unstemmed The Masked Polar Group Incorporation (MPGI) Strategy in Drug Design: Effects of Nitrogen Substitutions on Combretastatin and Isocombretastatin Tubulin Inhibitors
title_sort The Masked Polar Group Incorporation (MPGI) Strategy in Drug Design: Effects of Nitrogen Substitutions on Combretastatin and Isocombretastatin Tubulin Inhibitors
dc.creator.none.fl_str_mv González Díaz, Myriam
Ellahioui, Younes
Álvarez Lozano, Raquel
Gallego-Yerga, Laura
Caballero Salvador, Esther
Vicente-Blázquez, Alba
Ramudo González, Laura
Marín, Miguel
Sanz, Cristina
Medarde Agustín, Manuel
Peláez Lamamie de C. Arroyo, Rafael
author González Díaz, Myriam
author_facet González Díaz, Myriam
Ellahioui, Younes
Álvarez Lozano, Raquel
Gallego-Yerga, Laura
Caballero Salvador, Esther
Vicente-Blázquez, Alba
Ramudo González, Laura
Marín, Miguel
Sanz, Cristina
Medarde Agustín, Manuel
Peláez Lamamie de C. Arroyo, Rafael
author_role author
author2 Ellahioui, Younes
Álvarez Lozano, Raquel
Gallego-Yerga, Laura
Caballero Salvador, Esther
Vicente-Blázquez, Alba
Ramudo González, Laura
Marín, Miguel
Sanz, Cristina
Medarde Agustín, Manuel
Peláez Lamamie de C. Arroyo, Rafael
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Tubulin
Colchicine-site
Combretastatins
Isocombretastatins
Phenstatins
Nitrogenated
Masked polar group introduction
Solubility
Cytotoxicity
Docking
topic Tubulin
Colchicine-site
Combretastatins
Isocombretastatins
Phenstatins
Nitrogenated
Masked polar group introduction
Solubility
Cytotoxicity
Docking
description Colchicine site ligands suffer from low aqueous solubility due to the highly hydrophobic nature of the binding site. A new strategy for increasing molecular polarity without exposing polar groups—termed masked polar group incorporation (MPGI)—was devised and applied to nitrogenated combretastatin analogues. Bulky ortho substituents to the pyridine nitrogen hinder it from the hydrophobic pocket while increasing molecular polarity. The resulting analogues show improved aqueous solubilities and highly potent antiproliferative activity against several cancer cell lines of different origin. The more potent compounds showed moderate tubulin polymerization inhibitory activity, arrested the cell cycle of treated cells at the G2/M phase, and subsequently caused apoptotic cell death represented by the cells gathered at the subG0/G1 population after 48 h of treatment. Annexin V/Propidium Iodide (PI) double-positive cells observed after 72 h confirmed the induction of apoptosis. Docking studies suggest binding at the colchicine site of tubulin in a similar way as combretastatin A4, with the polar groups masked by the vicinal substituents. These results validate the proposed strategy for the design of colchicine site ligands and open a new road to increasing the aqueous solubility of ligands binding in apolar environments.
publishDate 2019
dc.date.none.fl_str_mv 2019
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10366/148389
url http://hdl.handle.net/10366/148389
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv SA030U16
SA262P18
RTI2018-099474-B-I00
dc.rights.none.fl_str_mv Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:GREDOS. Repositorio Institucional de la Universidad de Salamanca
instname:Universidad de Salamanca (USAL)
instname_str Universidad de Salamanca (USAL)
reponame_str GREDOS. Repositorio Institucional de la Universidad de Salamanca
collection GREDOS. Repositorio Institucional de la Universidad de Salamanca
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,301603

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