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Article

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

by
Mónica Martínez-Montiel
1,2,†,
Giulia Arrighi
1,3,†,
Paloma Begines
1,3,
Aday González-Bakker
4,
Adrián Puerta
4,
Miguel X. Fernandes
4,
Penélope Merino-Montiel
2,
Sara Montiel-Smith
2,
Alessio Nocentini
3,
Claudiu T. Supuran
3,
José M. Padrón
4,
José G. Fernández-Bolaños
1 and
Óscar López
1,*
1
Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, E-41071 Seville, Spain
2
Facultad de Ciencias Químicas, Ciudad Universitaria, Benemérita Universidad Autónoma de Puebla, Puebla 72570, PUE, Mexico
3
NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, University of Florence, 50019 Florence, Italy
4
BioLab, Instituto Universitario de Bio-Orgánica “Antonio González” (IUBO-AG), Universidad de La Laguna, c/Astrofísico Francisco Sánchez 2, E-38206 La Laguna, Spain
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2025, 26(3), 1225; https://doi.org/10.3390/ijms26031225
Submission received: 7 December 2024 / Revised: 24 January 2025 / Accepted: 24 January 2025 / Published: 30 January 2025
(This article belongs to the Section Biochemistry)
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Abstract

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.
Keywords: carbonic anhydrases; sulfonamides; thiosemicarbazones; docking simulations; metal chelation; antiproliferative activity carbonic anhydrases; sulfonamides; thiosemicarbazones; docking simulations; metal chelation; antiproliferative activity

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MDPI and ACS Style

Martínez-Montiel, M.; Arrighi, G.; Begines, P.; González-Bakker, A.; Puerta, A.; Fernandes, M.X.; Merino-Montiel, P.; Montiel-Smith, S.; Nocentini, A.; Supuran, C.T.; et al. Multifaceted Sulfonamide-Derived Thiosemicarbazones: Combining Metal Chelation and Carbonic Anhydrases Inhibition in Anticancer Therapy. Int. J. Mol. Sci. 2025, 26, 1225. https://doi.org/10.3390/ijms26031225

AMA Style

Martínez-Montiel M, Arrighi G, Begines P, González-Bakker A, Puerta A, Fernandes MX, Merino-Montiel P, Montiel-Smith S, Nocentini A, Supuran CT, et al. Multifaceted Sulfonamide-Derived Thiosemicarbazones: Combining Metal Chelation and Carbonic Anhydrases Inhibition in Anticancer Therapy. International Journal of Molecular Sciences. 2025; 26(3):1225. https://doi.org/10.3390/ijms26031225

Chicago/Turabian Style

Martínez-Montiel, Mónica, Giulia Arrighi, Paloma Begines, Aday González-Bakker, Adrián Puerta, Miguel X. Fernandes, Penélope Merino-Montiel, Sara Montiel-Smith, Alessio Nocentini, Claudiu T. Supuran, and et al. 2025. "Multifaceted Sulfonamide-Derived Thiosemicarbazones: Combining Metal Chelation and Carbonic Anhydrases Inhibition in Anticancer Therapy" International Journal of Molecular Sciences 26, no. 3: 1225. https://doi.org/10.3390/ijms26031225

APA Style

Martínez-Montiel, M., Arrighi, G., Begines, P., González-Bakker, A., Puerta, A., Fernandes, M. X., Merino-Montiel, P., Montiel-Smith, S., Nocentini, A., Supuran, C. T., Padrón, J. M., Fernández-Bolaños, J. G., & López, Ó. (2025). Multifaceted Sulfonamide-Derived Thiosemicarbazones: Combining Metal Chelation and Carbonic Anhydrases Inhibition in Anticancer Therapy. International Journal of Molecular Sciences, 26(3), 1225. https://doi.org/10.3390/ijms26031225

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