Multifaceted Sulfonamide-Derived Thiosemicarbazones: Combining Metal Chelation and Carbonic Anhydrases Inhibition in Anticancer Therapy

The selective inhibition of key enzymes, such as carbonic anhydrases (CAs IX and XII), which are overexpressed in cancer tissues, has emerged as a promising strategy in cancer research. However, a multitarget approach is often preferred to achieve enhanced therapeutic outcomes. In this study, aryl s...

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Autores: Martínez Montiel, Mónica, Arrighi, Giulia, Begines Aguilar, Paloma, González-Bakker, Aday, Puerta, Adrián, Fernandes, Miguel X., Merino-Montiel, Penélope, Montiel-Smith, Sara, Nocentini, Alessio, Supuran, Claudiu T., Padrón, José M., Fernández-Bolaños Guzmán, José María
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2025
País:España
Recursos:Universidad de Sevilla (US)
Repositório:idUS. Depósito de Investigación de la Universidad de Sevilla
OAI Identifier:oai:idus.us.es:11441/169537
Acesso em linha:https://hdl.handle.net/11441/169537
https://doi.org/10.3390/ijms26031225
Access Level:Acceso aberto
Palavra-chave:Antiproliferative activity
Carbonic anhydrases
Docking simulations
Metal chelation
Sulfonamides
Thiosemicarbazones
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spelling Multifaceted Sulfonamide-Derived Thiosemicarbazones: Combining Metal Chelation and Carbonic Anhydrases Inhibition in Anticancer TherapyMartínez Montiel, MónicaArrighi, GiuliaBegines Aguilar, PalomaGonzález-Bakker, AdayPuerta, AdriánFernandes, Miguel X.Merino-Montiel, PenélopeMontiel-Smith, SaraNocentini, AlessioSupuran, Claudiu T.Padrón, José M.Fernández-Bolaños Guzmán, José MaríaAntiproliferative activityCarbonic anhydrasesDocking simulationsMetal chelationSulfonamidesThiosemicarbazonesThe selective inhibition of key enzymes, such as carbonic anhydrases (CAs IX and XII), which are overexpressed in cancer tissues, has emerged as a promising strategy in cancer research. However, a multitarget approach is often preferred to achieve enhanced therapeutic outcomes. In this study, aryl sulfonamides were conjugated with a thiosemicarbazone moiety to enable dual functionality: the inhibition of CAs and the chelation of metal cations. Several structural factors were systematically modified, including the position of the sulfonamido group, the length of the linker, the nature of the aromatic residue, and the type of substituents. Tumor-associated CAs IX and XII inhibition was evaluated using the stopped-flow CO2 hydrase assay, and the inhibition constants (Ki) were determined. The most promising compounds were further analyzed through molecular docking simulations. Metal chelation capabilities were evaluated using UV–Vis spectroscopy, while antiproliferative activities were measured using the sulforhodamine B (SBR) assay. Additionally, holotomographic 3D microscopy was employed to investigate the mechanisms of cell death. Sulfonamido-derived Schiff bases were synthesized through a three-step procedure that did not require column chromatography purification: (1) isothiocyanation of amino-sulfonamides, (2) nucleophilic addition of hydrazine, and (3) acid-promoted condensation with different aldehydes (benzaldehydes or pyridine-2-carboxaldehyde). The synthesized compounds exhibited inhibition of CAs in the low nanomolar to submicromolar range, with selectivity largely influenced by structural features. Notably, the m-sulfonamide derivative 5b, bearing a pyridin-2-yl residue, demonstrated potent and selective inhibition of CA IX (Ki = 4.9 nM) and XII (Ki = 5.6 nM). Additionally, it efficiently chelated Fe2+, Fe3+, and Cu2+ and showed promising antiproliferative activity (GI50 4.5–10 µM). Mechanistic studies revealed that apoptosis was involved in its mode of action. Therefore, the synergistic integration of sulfonamides and thiosemicarbazones represents an effective strategy for the development of multimodal anticancer agents.Ministerio de Ciencia e Innovación PID2020- 116460RB-I00, PID2021-123059OB-I00Junta de Andalucía FQM134Universidad de Sevilla 100521265-VIEP2024Multidisciplinary Digital Publishing Institute (MDPI)Química OrgánicaMinisterio de Ciencia e Innovación (MICIN). EspañaJunta de AndalucíaUniversidad de Sevilla2025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/11441/169537https://doi.org/10.3390/ijms26031225reponame:idUS. Depósito de Investigación de la Universidad de Sevillainstname:Universidad de Sevilla (US)InglésInternational Journal of Molecular Sciences, 26 (3), 1225.PID2020- 116460RB-I00PID2021-123059OB-I00FQM134100521265-VIEP2024https://doi.org/10.3390/ijms26031225info:eu-repo/semantics/openAccessoai:idus.us.es:11441/1695372026-06-17T12:51:07Z
dc.title.none.fl_str_mv Multifaceted Sulfonamide-Derived Thiosemicarbazones: Combining Metal Chelation and Carbonic Anhydrases Inhibition in Anticancer Therapy
title Multifaceted Sulfonamide-Derived Thiosemicarbazones: Combining Metal Chelation and Carbonic Anhydrases Inhibition in Anticancer Therapy
spellingShingle Multifaceted Sulfonamide-Derived Thiosemicarbazones: Combining Metal Chelation and Carbonic Anhydrases Inhibition in Anticancer Therapy
Martínez Montiel, Mónica
Antiproliferative activity
Carbonic anhydrases
Docking simulations
Metal chelation
Sulfonamides
Thiosemicarbazones
title_short Multifaceted Sulfonamide-Derived Thiosemicarbazones: Combining Metal Chelation and Carbonic Anhydrases Inhibition in Anticancer Therapy
title_full Multifaceted Sulfonamide-Derived Thiosemicarbazones: Combining Metal Chelation and Carbonic Anhydrases Inhibition in Anticancer Therapy
title_fullStr Multifaceted Sulfonamide-Derived Thiosemicarbazones: Combining Metal Chelation and Carbonic Anhydrases Inhibition in Anticancer Therapy
title_full_unstemmed Multifaceted Sulfonamide-Derived Thiosemicarbazones: Combining Metal Chelation and Carbonic Anhydrases Inhibition in Anticancer Therapy
title_sort Multifaceted Sulfonamide-Derived Thiosemicarbazones: Combining Metal Chelation and Carbonic Anhydrases Inhibition in Anticancer Therapy
dc.creator.none.fl_str_mv Martínez Montiel, Mónica
Arrighi, Giulia
Begines Aguilar, Paloma
González-Bakker, Aday
Puerta, Adrián
Fernandes, Miguel X.
Merino-Montiel, Penélope
Montiel-Smith, Sara
Nocentini, Alessio
Supuran, Claudiu T.
Padrón, José M.
Fernández-Bolaños Guzmán, José María
author Martínez Montiel, Mónica
author_facet Martínez Montiel, Mónica
Arrighi, Giulia
Begines Aguilar, Paloma
González-Bakker, Aday
Puerta, Adrián
Fernandes, Miguel X.
Merino-Montiel, Penélope
Montiel-Smith, Sara
Nocentini, Alessio
Supuran, Claudiu T.
Padrón, José M.
Fernández-Bolaños Guzmán, José María
author_role author
author2 Arrighi, Giulia
Begines Aguilar, Paloma
González-Bakker, Aday
Puerta, Adrián
Fernandes, Miguel X.
Merino-Montiel, Penélope
Montiel-Smith, Sara
Nocentini, Alessio
Supuran, Claudiu T.
Padrón, José M.
Fernández-Bolaños Guzmán, José María
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Química Orgánica
Ministerio de Ciencia e Innovación (MICIN). España
Junta de Andalucía
Universidad de Sevilla
dc.subject.none.fl_str_mv Antiproliferative activity
Carbonic anhydrases
Docking simulations
Metal chelation
Sulfonamides
Thiosemicarbazones
topic Antiproliferative activity
Carbonic anhydrases
Docking simulations
Metal chelation
Sulfonamides
Thiosemicarbazones
description The selective inhibition of key enzymes, such as carbonic anhydrases (CAs IX and XII), which are overexpressed in cancer tissues, has emerged as a promising strategy in cancer research. However, a multitarget approach is often preferred to achieve enhanced therapeutic outcomes. In this study, aryl sulfonamides were conjugated with a thiosemicarbazone moiety to enable dual functionality: the inhibition of CAs and the chelation of metal cations. Several structural factors were systematically modified, including the position of the sulfonamido group, the length of the linker, the nature of the aromatic residue, and the type of substituents. Tumor-associated CAs IX and XII inhibition was evaluated using the stopped-flow CO2 hydrase assay, and the inhibition constants (Ki) were determined. The most promising compounds were further analyzed through molecular docking simulations. Metal chelation capabilities were evaluated using UV–Vis spectroscopy, while antiproliferative activities were measured using the sulforhodamine B (SBR) assay. Additionally, holotomographic 3D microscopy was employed to investigate the mechanisms of cell death. Sulfonamido-derived Schiff bases were synthesized through a three-step procedure that did not require column chromatography purification: (1) isothiocyanation of amino-sulfonamides, (2) nucleophilic addition of hydrazine, and (3) acid-promoted condensation with different aldehydes (benzaldehydes or pyridine-2-carboxaldehyde). The synthesized compounds exhibited inhibition of CAs in the low nanomolar to submicromolar range, with selectivity largely influenced by structural features. Notably, the m-sulfonamide derivative 5b, bearing a pyridin-2-yl residue, demonstrated potent and selective inhibition of CA IX (Ki = 4.9 nM) and XII (Ki = 5.6 nM). Additionally, it efficiently chelated Fe2+, Fe3+, and Cu2+ and showed promising antiproliferative activity (GI50 4.5–10 µM). Mechanistic studies revealed that apoptosis was involved in its mode of action. Therefore, the synergistic integration of sulfonamides and thiosemicarbazones represents an effective strategy for the development of multimodal anticancer agents.
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://hdl.handle.net/11441/169537
https://doi.org/10.3390/ijms26031225
url https://hdl.handle.net/11441/169537
https://doi.org/10.3390/ijms26031225
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv International Journal of Molecular Sciences, 26 (3), 1225.
PID2020- 116460RB-I00
PID2021-123059OB-I00
FQM134
100521265-VIEP2024
https://doi.org/10.3390/ijms26031225
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute (MDPI)
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute (MDPI)
dc.source.none.fl_str_mv reponame:idUS. Depósito de Investigación de la Universidad de Sevilla
instname:Universidad de Sevilla (US)
instname_str Universidad de Sevilla (US)
reponame_str idUS. Depósito de Investigación de la Universidad de Sevilla
collection idUS. Depósito de Investigación de la Universidad de Sevilla
repository.name.fl_str_mv
repository.mail.fl_str_mv
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