posted on 2020-06-10, 12:12authored byEmanuela Berrino, Andrea Angeli, Dmitry D. Zhdanov, Anna P. Kiryukhina, Andrea Milaneschi, Alessandro De Luca, Murat Bozdag, Simone Carradori, Silvia Selleri, Gianluca Bartolucci, Thomas S. Peat, Marta Ferraroni, Claudiu T. Supuran, Fabrizio Carta
Cancer cells rely on the enzyme telomerase
(EC 2.7.7.49) to promote
cellular immortality. Telomerase inhibitors (i.e., azidothymidine)
can represent promising antitumor agents, although showing high toxicity
when administered alone. Better outcomes were observed within a multipharmacological
approach instead. In this context, we exploited the validated antitumor
targets carbonic anhydrases (CAs; EC 4.2.1.1) IX and XII to attain
the first proof of concept on CA–telomerase dual-hybrid inhibitors.
Compounds 1b, 7b, 8b, and 11b showed good in vitro
inhibition potency against the CAs IX and XII, with KI values in the low nanomolar range, and strong antitelomerase
activity in PC-3 and HT-29 cells (IC50 values ranging from
5.2 to 9.1 μM). High-resolution X-ray crystallography on selected
derivatives in the adduct with hCA II as a model study allowed to
determine their binding modes and thus to set the structural determinants
necessary for further development of compounds selectively targeting
the tumoral cells.