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Tytuł pozycji:

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

Tytuł:
Azidothymidine "Clicked" into 1,2,3-Triazoles: First Report on Carbonic Anhydrase-Telomerase Dual-Hybrid Inhibitors.
Autorzy:
Berrino E; NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.
Angeli A; NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.
Zhdanov DD; Institute of Biomedical Chemistry, Pogodinskaya st. 10/8, 119121 Moscow, Russia.; Peoples Friendship University of Russia (RUDN University), Miklukho-Maklaya st. 6, 117198 Moscow, Russia.
Kiryukhina AP; Institute of Biomedical Chemistry, Pogodinskaya st. 10/8, 119121 Moscow, Russia.
Milaneschi A; NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.
De Luca A; NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.
Bozdag M; NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.
Carradori S; Department of Pharmacy, 'G. d'Annunzio' University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy.
Selleri S; NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.
Bartolucci G; NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.
Peat TS; CSIRO, 343 Royal Parade, Parkville, Victoria 3052, Australia.
Ferraroni M; Dipartimento di Chimica 'Ugo Schiff', Università di Firenze, Via della Lastruccia 3-13, 50019 Sesto Fiorentino (Florence), Italy.
Supuran CT; NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.
Carta F; NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.
Źródło:
Journal of medicinal chemistry [J Med Chem] 2020 Jul 09; Vol. 63 (13), pp. 7392-7409. Date of Electronic Publication: 2020 Jun 10.
Typ publikacji:
Journal Article; Research Support, Non-U.S. Gov't
Język:
English
Imprint Name(s):
Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
MeSH Terms:
Antineoplastic Agents/*chemistry
Antineoplastic Agents/*pharmacology
Enzyme Inhibitors/*chemistry
Enzyme Inhibitors/*pharmacology
Telomerase/*antagonists & inhibitors
Zidovudine/*chemistry
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 ; HT29 Cells ; Humans ; PC-3 Cells ; Structure-Activity Relationship ; Telomerase/genetics ; Telomerase/metabolism ; Triazoles/chemistry
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Substance Nomenclature:
0 (Antineoplastic Agents)
0 (Carbonic Anhydrase Inhibitors)
0 (Enzyme Inhibitors)
0 (Triazoles)
4B9XT59T7S (Zidovudine)
EC 2.7.7.49 (TERT protein, human)
EC 2.7.7.49 (Telomerase)
EC 4.2.1.- (Carbonic Anhydrase II)
Entry Date(s):
Date Created: 20200529 Date Completed: 20201127 Latest Revision: 20210528
Update Code:
20240105
PubMed Central ID:
PMC8154556
DOI:
10.1021/acs.jmedchem.0c00636
PMID:
32463228
Czasopismo naukowe
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 K I values in the low nanomolar range, and strong antitelomerase activity in PC-3 and HT-29 cells (IC 50 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.

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