Azidothymidine "Clicked" into 1,2,3-Triazoles: First Report on Carbonic Anhydrase-Telomerase Dual-Hybrid Inhibitors

J Med Chem. 2020 Jul 9;63(13):7392-7409. doi: 10.1021/acs.jmedchem.0c00636. Epub 2020 Jun 10.


Cancer cells rely on the enzyme telomerase (EC 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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Carbonic Anhydrase II / antagonists & inhibitors
  • Carbonic Anhydrase II / chemistry
  • Carbonic Anhydrase II / metabolism
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / metabolism
  • Carbonic Anhydrase Inhibitors / pharmacology
  • Catalytic Domain
  • Crystallography, X-Ray
  • Cycloaddition Reaction
  • Drug Design
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • HT29 Cells
  • Humans
  • PC-3 Cells
  • Structure-Activity Relationship
  • Telomerase / antagonists & inhibitors*
  • Telomerase / genetics
  • Telomerase / metabolism
  • Triazoles / chemistry
  • Zidovudine / chemistry*


  • Antineoplastic Agents
  • Carbonic Anhydrase Inhibitors
  • Enzyme Inhibitors
  • Triazoles
  • Zidovudine
  • TERT protein, human
  • Telomerase
  • Carbonic Anhydrase II