Cytotoxic Cyclolignans Obtained by the Enlargement of the Cyclolignan Skeleton of Podophyllic Aldehyde, a Selective Podophyllotoxin-Derived Cyclolignan

Podophyllotoxin, a cyclolignan natural product, has been the object of extensive chemomodulation to obtain better chemotherapeutic agents. Among the obtained podophyllotoxin derivatives, podophyllic aldehyde showed very interesting potency and selectivity against several tumoral cell lines, so it be...

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Autores: García, Pablo A., Hernández, Ángela-Patricia, Gómez-Zurita, Mª Antonia, Miguel del Corral, José M., Gordaliza, Marina, Francesch, Andrés, San Feliciano, Arturo, Castro, M. Ángeles
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/367115
Acceso en línea:http://hdl.handle.net/10261/367115
Access Level:acceso abierto
Palabra clave:Natural products
Podophyllotoxin
Podophyllic aldehyde
Nucleophilic addition reactions
Anticancer
Cytotoxicity
Selectivity
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spelling Cytotoxic Cyclolignans Obtained by the Enlargement of the Cyclolignan Skeleton of Podophyllic Aldehyde, a Selective Podophyllotoxin-Derived CyclolignanGarcía, Pablo A.Hernández, Ángela-PatriciaGómez-Zurita, Mª AntoniaMiguel del Corral, José M.Gordaliza, MarinaFrancesch, AndrésSan Feliciano, ArturoCastro, M. ÁngelesNatural productsPodophyllotoxinPodophyllic aldehydeNucleophilic addition reactionsAnticancerCytotoxicitySelectivityPodophyllotoxin, a cyclolignan natural product, has been the object of extensive chemomodulation to obtain better chemotherapeutic agents. Among the obtained podophyllotoxin derivatives, podophyllic aldehyde showed very interesting potency and selectivity against several tumoral cell lines, so it became our lead compound for further modifications, as described in this work, oriented toward the enlargement of the cyclolignan skeleton. Thus, modifications performed at the aldehyde function included nucleophilic addition reactions and the incorporation of the aldehyde carbon into several five-membered rings, such as thiazolidinones and benzo-fused azoles. The synthesized derivatives were evaluated against several types of cancer cells, and although some compounds were cytotoxic at the nanomolar range, most of them were less potent and less selective than the parent compound podophyllic aldehyde, with the most potent being those having the lactone ring of podophyllotoxin. In silico ADME evaluation predicted good druggability for most of them. The results indicate that the γ-lactone ring is important for potency, while the α,β-unsaturated aldehyde is necessary to induce selectivity in these cyclolignans.This research was funded by Spanish MCIN/AEI/10.13039/501100011033 (Project PID2020-118303G-I00) and by the Junta de Castilla y León, co-funded by the European Social Fund (Project SA076P20).Peer reviewedMultidisciplinary Digital Publishing InstituteMinisterio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)Junta de Castilla y LeónConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202420242024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/367115reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-118303GB-I00The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.3390/molecules29071442https://doi.org/10.3390/molecules29071442Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3671152026-05-22T06:33:51Z
dc.title.none.fl_str_mv Cytotoxic Cyclolignans Obtained by the Enlargement of the Cyclolignan Skeleton of Podophyllic Aldehyde, a Selective Podophyllotoxin-Derived Cyclolignan
title Cytotoxic Cyclolignans Obtained by the Enlargement of the Cyclolignan Skeleton of Podophyllic Aldehyde, a Selective Podophyllotoxin-Derived Cyclolignan
spellingShingle Cytotoxic Cyclolignans Obtained by the Enlargement of the Cyclolignan Skeleton of Podophyllic Aldehyde, a Selective Podophyllotoxin-Derived Cyclolignan
García, Pablo A.
Natural products
Podophyllotoxin
Podophyllic aldehyde
Nucleophilic addition reactions
Anticancer
Cytotoxicity
Selectivity
title_short Cytotoxic Cyclolignans Obtained by the Enlargement of the Cyclolignan Skeleton of Podophyllic Aldehyde, a Selective Podophyllotoxin-Derived Cyclolignan
title_full Cytotoxic Cyclolignans Obtained by the Enlargement of the Cyclolignan Skeleton of Podophyllic Aldehyde, a Selective Podophyllotoxin-Derived Cyclolignan
title_fullStr Cytotoxic Cyclolignans Obtained by the Enlargement of the Cyclolignan Skeleton of Podophyllic Aldehyde, a Selective Podophyllotoxin-Derived Cyclolignan
title_full_unstemmed Cytotoxic Cyclolignans Obtained by the Enlargement of the Cyclolignan Skeleton of Podophyllic Aldehyde, a Selective Podophyllotoxin-Derived Cyclolignan
title_sort Cytotoxic Cyclolignans Obtained by the Enlargement of the Cyclolignan Skeleton of Podophyllic Aldehyde, a Selective Podophyllotoxin-Derived Cyclolignan
dc.creator.none.fl_str_mv García, Pablo A.
Hernández, Ángela-Patricia
Gómez-Zurita, Mª Antonia
Miguel del Corral, José M.
Gordaliza, Marina
Francesch, Andrés
San Feliciano, Arturo
Castro, M. Ángeles
author García, Pablo A.
author_facet García, Pablo A.
Hernández, Ángela-Patricia
Gómez-Zurita, Mª Antonia
Miguel del Corral, José M.
Gordaliza, Marina
Francesch, Andrés
San Feliciano, Arturo
Castro, M. Ángeles
author_role author
author2 Hernández, Ángela-Patricia
Gómez-Zurita, Mª Antonia
Miguel del Corral, José M.
Gordaliza, Marina
Francesch, Andrés
San Feliciano, Arturo
Castro, M. Ángeles
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
Junta de Castilla y León
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Natural products
Podophyllotoxin
Podophyllic aldehyde
Nucleophilic addition reactions
Anticancer
Cytotoxicity
Selectivity
topic Natural products
Podophyllotoxin
Podophyllic aldehyde
Nucleophilic addition reactions
Anticancer
Cytotoxicity
Selectivity
description Podophyllotoxin, a cyclolignan natural product, has been the object of extensive chemomodulation to obtain better chemotherapeutic agents. Among the obtained podophyllotoxin derivatives, podophyllic aldehyde showed very interesting potency and selectivity against several tumoral cell lines, so it became our lead compound for further modifications, as described in this work, oriented toward the enlargement of the cyclolignan skeleton. Thus, modifications performed at the aldehyde function included nucleophilic addition reactions and the incorporation of the aldehyde carbon into several five-membered rings, such as thiazolidinones and benzo-fused azoles. The synthesized derivatives were evaluated against several types of cancer cells, and although some compounds were cytotoxic at the nanomolar range, most of them were less potent and less selective than the parent compound podophyllic aldehyde, with the most potent being those having the lactone ring of podophyllotoxin. In silico ADME evaluation predicted good druggability for most of them. The results indicate that the γ-lactone ring is important for potency, while the α,β-unsaturated aldehyde is necessary to induce selectivity in these cyclolignans.
publishDate 2024
dc.date.none.fl_str_mv 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/10261/367115
url http://hdl.handle.net/10261/367115
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-118303GB-I00
The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.3390/molecules29071442
https://doi.org/10.3390/molecules29071442
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
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
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repository.mail.fl_str_mv
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