Harnessing 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 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.