Synthesis and Biological Evaluation of New cis-Restricted Triazole Analogues of Combretastatin A-4

The natural products combretastatins A-1 and A-4 are potent antimitotic and vascular-disrupting agents through their binding at the colchicine site in tubulin. However, these compounds suffer from a low water solubility and a tendency to isomerize to the inactive trans stilbenes. In this study, we h...

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Autores: Prieto, L, Gaviña, D, Escolano, M, Cánovas-Belchí, M, Sánchez-Roselló, M, del Pozo, C, Falomir, E, Díaz-Oltra, S
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)
Repositorio:r-FISABIO. Repositorio Institucional de Producción Científica
OAI Identifier:oai:dnet:r-fisabio___::8235d19064ed9ce2d6ebe9f34a5b26ef
Acceso en línea:https://fisabio.portalinvestigacion.com/publicaciones/21024
Access Level:acceso abierto
Palabra clave:cancer
tubulin
antimitotics
combretastatin A-4
triazoles
cytotoxicity
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spelling Synthesis and Biological Evaluation of New cis-Restricted Triazole Analogues of Combretastatin A-4Prieto, LGaviña, DEscolano, MCánovas-Belchí, MSánchez-Roselló, Mdel Pozo, CFalomir, EDíaz-Oltra, Scancertubulinantimitoticscombretastatin A-4triazolescytotoxicityThe natural products combretastatins A-1 and A-4 are potent antimitotic and vascular-disrupting agents through their binding at the colchicine site in tubulin. However, these compounds suffer from a low water solubility and a tendency to isomerize to the inactive trans stilbenes. In this study, we have prepared a series of 18 cis-restricted triazole analogues of combretastatin A-4 (CA-4), maintaining, in all cases, the 3,4,5-trimethoxy phenyl ring A, with the aim of investigating the substitution pattern on the B-ring in a systematic way. To this end, cytotoxic activities of the cis-restricted analogues of CA-4 prepared were determined in two tumor cell lines, namely, HT-29 and A-549, as well as in the non-tumor cell line HEK-293, to pre-evaluate the selectivity profile of the compounds for the tumor cell lines. The main conclusion was the essential presence of methoxyl or ethoxyl groups at the para position of the B-ring in order to obtain good antitumor activities. Thus, the more active compounds in our study displayed IC50 values in the nanomolar range for the tumor cell lines but not for the normal cells. Consequently, these triazole analogues of CA-4 could serve as promising alternatives to the natural product, although further studies about their biological activity are essential in order to fully determine their viability as therapeutic agents in the treatment of cancer.MDPI2025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://fisabio.portalinvestigacion.com/publicaciones/21024MOLECULESISSN: 14203049reponame:r-FISABIO. Repositorio Institucional de Producción Científicainstname:Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)Inglésinfo:eu-repo/semantics/openAccessoai:dnet:r-fisabio___::8235d19064ed9ce2d6ebe9f34a5b26ef2026-06-11T12:45:17Z
dc.title.none.fl_str_mv Synthesis and Biological Evaluation of New cis-Restricted Triazole Analogues of Combretastatin A-4
title Synthesis and Biological Evaluation of New cis-Restricted Triazole Analogues of Combretastatin A-4
spellingShingle Synthesis and Biological Evaluation of New cis-Restricted Triazole Analogues of Combretastatin A-4
Prieto, L
cancer
tubulin
antimitotics
combretastatin A-4
triazoles
cytotoxicity
title_short Synthesis and Biological Evaluation of New cis-Restricted Triazole Analogues of Combretastatin A-4
title_full Synthesis and Biological Evaluation of New cis-Restricted Triazole Analogues of Combretastatin A-4
title_fullStr Synthesis and Biological Evaluation of New cis-Restricted Triazole Analogues of Combretastatin A-4
title_full_unstemmed Synthesis and Biological Evaluation of New cis-Restricted Triazole Analogues of Combretastatin A-4
title_sort Synthesis and Biological Evaluation of New cis-Restricted Triazole Analogues of Combretastatin A-4
dc.creator.none.fl_str_mv Prieto, L
Gaviña, D
Escolano, M
Cánovas-Belchí, M
Sánchez-Roselló, M
del Pozo, C
Falomir, E
Díaz-Oltra, S
author Prieto, L
author_facet Prieto, L
Gaviña, D
Escolano, M
Cánovas-Belchí, M
Sánchez-Roselló, M
del Pozo, C
Falomir, E
Díaz-Oltra, S
author_role author
author2 Gaviña, D
Escolano, M
Cánovas-Belchí, M
Sánchez-Roselló, M
del Pozo, C
Falomir, E
Díaz-Oltra, S
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv cancer
tubulin
antimitotics
combretastatin A-4
triazoles
cytotoxicity
topic cancer
tubulin
antimitotics
combretastatin A-4
triazoles
cytotoxicity
description The natural products combretastatins A-1 and A-4 are potent antimitotic and vascular-disrupting agents through their binding at the colchicine site in tubulin. However, these compounds suffer from a low water solubility and a tendency to isomerize to the inactive trans stilbenes. In this study, we have prepared a series of 18 cis-restricted triazole analogues of combretastatin A-4 (CA-4), maintaining, in all cases, the 3,4,5-trimethoxy phenyl ring A, with the aim of investigating the substitution pattern on the B-ring in a systematic way. To this end, cytotoxic activities of the cis-restricted analogues of CA-4 prepared were determined in two tumor cell lines, namely, HT-29 and A-549, as well as in the non-tumor cell line HEK-293, to pre-evaluate the selectivity profile of the compounds for the tumor cell lines. The main conclusion was the essential presence of methoxyl or ethoxyl groups at the para position of the B-ring in order to obtain good antitumor activities. Thus, the more active compounds in our study displayed IC50 values in the nanomolar range for the tumor cell lines but not for the normal cells. Consequently, these triazole analogues of CA-4 could serve as promising alternatives to the natural product, although further studies about their biological activity are essential in order to fully determine their viability as therapeutic agents in the treatment of cancer.
publishDate 2025
dc.date.none.fl_str_mv 2025
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 https://fisabio.portalinvestigacion.com/publicaciones/21024
url https://fisabio.portalinvestigacion.com/publicaciones/21024
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv MOLECULES
ISSN: 14203049
reponame:r-FISABIO. Repositorio Institucional de Producción Científica
instname:Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)
instname_str Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)
reponame_str r-FISABIO. Repositorio Institucional de Producción Científica
collection r-FISABIO. Repositorio Institucional de Producción Científica
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repository.mail.fl_str_mv
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