Harnessing coumarin-thio(seleno)cyanate conjugates: potent In vivo antiproliferative agents targeting carbonic anhydrasesHarnessing coumarin-thio(seleno)cyanate conjugates: potent In vivo antiproliferative agents targeting carbonic anhydrases

We synthesised coumarin-based derivatives bearing thio- and selenocyanates to selectively inhibit tumour-associated carbonic anhydrases (CAs) IX and XII and to exert antiproliferative effects on tumour cells. Structural variations included chalcogen atom type (S, Se), substitutions at C-3/C-4, and t...

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Bibliographic Details
Authors: Meza-Ireta, Silvia Alejandra, Romero-Hernández, Laura L., Begines, Paloma, Giouvannuzi, Simone, Puerta, Adrián, González-Bakker, Aday, Romero-Franco, Amador, Huertas, Pablo, Nocentini, Alessio, Vega-Báez, José Luis, Montiel-Smith, Sara, Fernández-Bolaños, José G., Castellano-Pozo, Maikel, Padrón, José M., Supuran, Claudiu T., Merino-Montiel, Penélope, López, Óscar
Format: conjunto de datos
Publication Date:2025
Country:España
Institution:Consejo Superior de Investigaciones Científicas (CSIC)
Repository:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/412307
Online Access:http://hdl.handle.net/10261/412307
https://digital.csic.es/handle/10261/412199
Access Level:Open access
Keyword:C. elegans
Antiproliferative agents
Carbonic anhydrases
Coumarins
Organoselenium
Description
Summary:We synthesised coumarin-based derivatives bearing thio- and selenocyanates to selectively inhibit tumour-associated carbonic anhydrases (CAs) IX and XII and to exert antiproliferative effects on tumour cells. Structural variations included chalcogen atom type (S, Se), substitutions at C-3/C-4, and tether length at C-7 of the coumarin core. Thiocyanates 4 and 7b showed potent CA IX/XII inhibition (Ki = 17.9-27.4 nM) with >5000-fold selectivity over off-target isoforms (CAs I and II). Selenocyanate 8a exhibited strong antiproliferative activity (GI50 = 0.78-2.6 µM) across six human solid tumour cell lines. Mechanistic studies revealed a cytostatic effect via cell cycle arrest and reduced mitotic progression. In vivo assays in Caenorhabditis elegans confirmed selective cytostatic action of selenocyanate 8c, reducing tumorous germline size without affecting healthy tissues at therapeutic doses.

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