Harnessing coumarin-thio(seleno)cyanate conjugates: potent <i>In vivo</i> 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 tether length at C-7 of the coumarin core. Thiocyanates <b>4</b> and <b>7b</b> showed potent CA IX/XII inhibition (<i>K</i><sub>i</sub> = 17.9-27.4 nM) with >5000-fold selectivity over off-target isoforms (CAs I and II). Selenocyanate <b>8a</b> exhibited strong antiproliferative activity (GI<sub>50</sub> = 0.78-2.6 µM) across six human solid tumour cell lines. Mechanistic studies revealed a cytostatic effect <i>via</i> cell cycle arrest and reduced mitotic progression. <i>In vivo</i> assays in <i>Caenorhabditis elegans</i> confirmed selective cytostatic action of selenocyanate <b>8c</b>, reducing tumorous germline size without affecting healthy tissues at therapeutic doses.
Authors
- Maikel Castellano‐Pozo (ORCID: https://orcid.org/0000-0003-4134-9025)
- Óscar López (ORCID: https://orcid.org/0000-0003-2896-6993)
- Paloma Begines (ORCID: https://orcid.org/0000-0001-5188-2005)
- Alessio Nocentini (ORCID: https://orcid.org/0000-0003-3342-702X)
- Sara Montiel‐Smith (ORCID: https://orcid.org/0000-0002-3080-9252)
- José Manuel Padrón (ORCID: https://orcid.org/0000-0001-6268-6552)
- Laura L. Romero-Hernández (ORCID: https://orcid.org/0000-0001-9658-532X)
- Aday González‐Bakker (ORCID: https://orcid.org/0000-0002-9792-5194)
- Penélope Merino‐Montiel (ORCID: https://orcid.org/0000-0003-1376-9671)
- Amador Romero-Franco (ORCID: https://orcid.org/0000-0003-3212-1643)
- Pablo Huertas (ORCID: https://orcid.org/0000-0002-1756-4449)
- José G. Fernández‐Bolaños (ORCID: https://orcid.org/0000-0003-1499-0650)
- Adrián Puerta
- Silvia Alejandra Meza-Ireta
- José Luis Vega-Báez
- Simone Giouvannuzi
Institutions
- Hospital Universitario Dr José Eleuterio Gonzalez (MX)
- Istituto Nazionale di Fisica Nucleare, Sezione di Firenze (IT)
- Centro Andaluz de Biología Molecular y Medicina Regenerativa (ES)
- University of Florence (IT)
- Benemérita Universidad Autónoma de Puebla (MX)
- Universidad de Sevilla (ES)
- Universidad Pablo de Olavide (ES)
Publication Details
- Journal
- Journal of Enzyme Inhibition and Medicinal Chemistry
- Published
- 2025-11-10
- DOI
- https://doi.org/10.1080/14756366.2025.2578183
- Primary Topic
- Enzyme function and inhibition
- Type
- article
- Field-Weighted Citation Impact
- 0.00