Mechanisms of the Antiproliferative and Antitumor Activity of Novel Telomerase-Carbonic Anhydrase Dual-Hybrid Inhibitors

Human (h) telomerase (TL; EC plays a key role in sustaining cancer cells by means of elongating telomeric repeats at the 3′ ends of chromosomes. Since TL-inhibitor (TI) stand-alone cancer therapy has been proven to be remarkably challenging, a polypharmacological approach represents a valid alternative. Here we consider a series of compounds able to inhibit both hTL and the tumor-associated carbonic anhydrases (CAs; EC IX and XII. Compounds 7 and 9 suppressed hTL activity in both cell lysates and human colon cancer cell lines, and prolonged incubation with either 7 or 9 resulted in telomere shortening, cell cycle arrest, replicative senescence, and apoptosis. Enzyme kinetics showed that 7 and 9 are mixed-type inhibitors of the binding of DNA primers and deoxynucleoside triphosphate (dNTP) to the TL catalytic subunit hTERT, which is in agreement with docking experiments. Compound 9 showed antitumor activity in Colo-205 mouse xenografts and suppressed telomerase activity by telomere reduction. © 2021 American Chemical Society.

Plyasova A.A.1 , Berrino E.2 , Khan I.I. 3, 4 , Veselovsky A.V. 1 , Pokrovsky V.S. 3, 4 , Angeli A.2 , Ferraroni M.5 , Supuran C.T.2 , Pokrovskaya M.V. 1 , Alexandrova S.S. 1 , Gladilina Y.A. 1 , Sokolov N.N. 1 , Hilal A. 1 , Carta F.2 , Zhdanov D.D. 1
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  • 1 Institute of Biomedical Chemistry, Pogodinskaya Street 10/8, Moscow, 119121, Russian Federation
  • 2 Dipartimento di Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università Degli Studi di Firenze, Via Ugo Schiff 6, Florence, 50019, Italy
  • 3 Peoples' Friendship University of Russia, RUDN University, Miklukho-Maklaya Street 6, Moscow, 117198, Russian Federation
  • 4 N.N. Blokhin Cancer Research Center, Kashirskoe Shosse 24, Moscow, 115478, Russian Federation
  • 5 Dipartimento di Chimica Ugo Schiff, Università Degli Studi di Firenze, Via della Lastruccia 3-13, Florence, 50019, Italy
antineoplastic agent; carbonate dehydratase; enzyme inhibitor; sulfonamide; telomerase; zidovudine; animal; Bagg albino mouse; cell proliferation; chemical structure; chemistry; dose response; drug effect; drug screening; experimental neoplasm; female; human; metabolism; mouse; nude mouse; pathology; structure activity relation; synthesis; tumor cell culture; Animals; Antineoplastic Agents; Carbonic Anhydrases; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Structure; Neoplasms, Experimental; Structure-Activity Relationship; Sulfonamides; Telomerase; Tumor Cells, Cultured; Zidovudine
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