Synthesis, computational studies and assessment of <i>in vitro</i> inhibitory activity of umbelliferon-based compounds against tumour-associated carbonic anhydrase isoforms IX and XII
Francesca Mancuso, Laura De Luca, Andrea Angeli, Sonia Del Prete, Clemente Capasso, Claudiu T. Supuran, Rosaria Gitto
Abstract
Coumarins are widely diffused secondary metabolites possessing a plethora of biological activities. It has been established that coumarins represent a peculiar class of human carbonic anhydrase (hCA) inhibitors having a distinct mechanism of action involving a non-classical binding with amino acid residues paving the entrance of hCA catalytic site. Herein, we report the synthesis of a small series of new coumarin derivatives 7-11, 15, 17 prepared via classical Pechmann condensation starting from resorcinol derivatives and suitable β-ketoesters. The evaluation of inhibitory activity revealed that these compounds possessed nanomolar affinity and high selectivity towards tumour-associated hCA IX and XII over cytosolic hCA I and hCA II isoforms. To investigate the binding mode of these new coumarin-inspired inhibitors, the most active compounds 10 and 17 were docked within hCA XII catalytic cleft.