Azidothymidine 'clicked' into 1,2,3-Triazoles: First Report on Carbonic Anhydrase-Telomerase Dual-Hybrid Inhibitors
| Autor: | Emanuela Berrino, Thomas S. Peat, Silvia Selleri, Gianluca Bartolucci, Claudiu T. Supuran, Murat Bozdag, D. D. Zhdanov, Andrea Milaneschi, Fabrizio Carta, Alessandro De Luca, Simone Carradori, Andrea Angeli, Anna Pavlovna Kiryukhina, Marta Ferraroni |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Telomerase
carbonic anhydrase Antineoplastic Agents Context (language use) Crystallography X-Ray Carbonic Anhydrase II 01 natural sciences Article Adduct Structure-Activity Relationship 03 medical and health sciences Catalytic Domain Carbonic anhydrase Drug Discovery Humans Structure–activity relationship sulphonamide Enzyme Inhibitors Carbonic Anhydrase Inhibitors 030304 developmental biology chemistry.chemical_classification 0303 health sciences Cycloaddition Reaction biology Chemistry Triazoles In vitro 0104 chemical sciences inhibitor 010404 medicinal & biomolecular chemistry Enzyme Biochemistry Drug Design PC-3 Cells Cancer cell biology.protein Molecular Medicine HT29 Cells Zidovudine |
| Zdroj: | Journal of Medicinal Chemistry |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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