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

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. Copyright © 2020 American Chemical Society.

Authors
Berrino E.1 , Angeli A.1 , Zhdanov D.D. 2, 3 , Kiryukhina A.P.2 , Milaneschi A.1 , De Luca A. , Bozdag M.1 , Carradori S.4 , Selleri S.1 , Bartolucci G.1 , Peat T.S.5 , Ferraroni M.6 , Supuran C.T.1 , Carta F.1
Journal
Journal of Medicinal Chemistry
Publisher
American Chemical Society
Number of issue
13
Language
English
Pages
7392-7409
Status
Published
Link
External link
DOI
10.1021/acs.jmedchem.0c00636
Volume
63
Year
2020
Organizations
  • 1 Neurofarba Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università Degli Studi di Firenze, Via Ugo Schiff 6, Sesto Fiorentino (Florence), 50019, Italy
  • 2 Institute of Biomedical Chemistry, Pogodinskaya st. 10/8, Moscow, 119121, Russian Federation
  • 3 Peoples Friendship University of Russia, Rudn University, Miklukho-Maklaya st. 6, Moscow, 117198, Russian Federation
  • 4 Department of Pharmacy g. d'Annunzio, University of Chieti-Pescara, Via dei Vestini 31, Chieti, 66100, Italy
  • 5 Csiro, 343 Royal Parade, Parkville, VIC 3052, Australia
  • 6 Dipartimento di Chimica ugo Schiff, Università di Firenze, Via della Lastruccia 3-13, Sesto Fiorentino (Florence), 50019, Italy
Keywords
1 [4 [4 [[(2,2 dioxidobenzo[e][1,2]oxathiin 6 yl)oxy]methyl] 1h 1,2,3 triazol 1 yl] 5 (hydroxymethyl)tetrahydrofuran 2 yl] 5 methylpyrimidine 2,4(1h,3h)dione; 1 [5 (hydroxymethyl) 4 [4 [3 [(2 oxo 2h chromen 6 yl)oxy]propyl] 1h 1,2,3 triazol 1 yl]tetrahydrofuran 2 yl] 5 methylpyrimidine 2,4(1h,3h)dione; 1 [5 (hydroxymethyl) 4 [4 [3 [(2 oxo 2h chromen 7 yl)oxy]propyl] 1h 1,2,3 triazol 1 yl]tetrahydrofuran 2 yl] 5 methylpyrimidine 2,4(1h,3h)dione; 1 [5 (hydroxymethyl) 4 [4 [4 [(2 oxo 2h chromen 4 yl)oxy]butyl] 1h 1,2,3 triazol 1 yl]tetrahydrofuran 2 yl] 5 methylpyrimidine 2,4(1h,3h)dione; 1 [5 (hydroxymethyl) 4 [4 [4 [(2 oxo 2h chromen 7 yl)oxy]butyl] 1h 1,2,3 triazol 1 yl]tetrahydrofuran 2 yl] 5 methylpyrimidine 2,4(1h,3h)dione; 1 [5 (hydroxymethyl) 4 [4 [[(2 oxo 2h chromen 6 yl)oxy]methyl] 1h 1,2,3 triazol 1 yl]tetrahydrofuran 2 yl] 5 methylpyrimidine 2,4(1h,3h)dione; 1 [5 (hydroxymethyl) 4 [4 [[(2 oxo 2h chromen 7 yl)oxy]methyl] 1h 1,2,3 triazol 1 yl]tetrahydrofuran 2 yl] 5 methylpyrimidine 2,4(1h,3h)dione; 1,2,3 triazole derivative; 3 [3 [4 [[[1 [2 (hydroxymethyl) 5 (5 methyl 2,4 dioxo 3,4 dihydropyrimidin 1(2h)yl)tetrahydrofuran 3 yl] 1h 1,2,3 triazol 4 yl]methyl]selanyl]phenyl]thioureido]benzenesulfonamide; 3 [3 [[1 [2 (hydroxymethyl) 5 (5 methyl 2,4 dioxo 3,4 dihydropyrimidin 1(2h)yl)tetrahydrofuran 3 yl] 1h 1,2,3 triazol 4 yl]methyl]ureido]benzenesulfonamide; 3 [[1 [2 (hydroxymethyl) 5 (5 methyl 2,4 dioxo 3,4 dihydropyrimidin 1(2h)yl)tetrahydrofuran 3 yl] 1h 1,2,3 triazol 4 yl]methyl] 2 oxo 2,3 dihydrobenzo[d]oxazole 5 sulfonamide; 4 [2 [bis[[1 [2 (hydroxymethyl) 5 (5 methyl 2,4 dioxo 3,4 dihydropyrimidin 1(2h)yl)tetrahydrofuran 3 yl] 1h 1,2,3 triazol 4 yl]methyl]amino]ethyl]benzenesulfonamide; 4 [3 [4 [[[1 [2 (hydroxymethyl) 5 (5 methyl 2,4 dioxo 3,4 dihydropyrimidin 1(2h)yl)tetrahydrofuran 3 yl] 1h 1,2,3 triazol 4 yl]methyl]selanyl]phenyl]thioureido]benzenesulfonamide; 4 [3 [[1 [2 (hydroxymethyl) 5 (5 methyl 2,4 dioxo 3,4 dihydropyrimidin 1(2h)yl)tetrahydrofuran 3 yl] 1h 1,2,3 triazol 4 yl]methyl]ureido]benzenesulfonamide; 4 [bis[[1 [2 (hydroxymethyl) 5 (5 methyl 2,4 dioxo 3,4 dihydropyrimidin 1(2h)yl)tetrahydrofuran 3 yl] 1h 1,2,3 triazol 4 yl]methyl]amino]benzenesulfonamide; 4 [[1 [2 (hydroxymethyl) 5 (5 methyl 2,4 dioxo 3,4 dihydropyrimidin 1(2h)yl)tetrahydrofuran 3 yl] 1h 1,2,3 triazol 4 yl]methoxy]benzenesulfonamide; 4 [[[1 [2 (hydroxymethyl) 5 (5 methyl 2,4 dioxo 3,4 dihydropyrimidin 1(2h)yl)tetrahydrofuran 3 yl] 1h 1,2,3 triazol 4 yl]methyl]amino]benzenesulfonamide; 4 [[[1 [2 (hydroxymethyl) 5 (5 methyl 2,4 dioxo 3,4 dihydropyrimidin 1(2h)yl)tetrahydrofuran 3 yl] 1h 1,2,3 triazol 4 yl]methyl]thio]benzenesulfonamide; acetazolamide; carbonate dehydratase inhibitor; carbonate dehydratase IX; carbonate dehydratase XII; n [[1 [2 (hydroxymethyl) 5 (5 methyl 2,4 dioxo 3,4 dihydropyrimidin 1(2h)yl)tetrahydrofuran 3 yl] 1h 1,2,3 triazol 4 yl]methyl] 4 sulfamoylbenzamide; telomerase inhibitor; unclassified drug; zidovudine; [1 [2 (hydroxymethyl) 5 (5 methyl 2,4 dioxo 3,4 dihydropyrimidin 1(2h)yl)tetrahydrofuran 3 yl] 1h 1,2,3 triazol 4 yl]methyl 4 sulfamoylbenzoate; [1 [[2 (hydroxymethyl) 5 (5 methyl 2,4 dioxo 3,4 dihydropyrimidin 1(2h)yl)tetrahydrofuran 3 yl]methyl] 1h 1,2,3 triazol 4 yl]methyl 4 chloro 3 sulfamoylbenzoate; antineoplastic activity; Article; click chemistry; controlled study; drug design; drug potency; drug protein binding; drug selectivity; drug structure; drug synthesis; enzyme active site; enzyme inhibition; HT-29 cell line; human; human cell; IC50; in vitro study; molecular hybridization; PC-3 [Human prostate carcinoma] cell line; structure activity relation; X ray crystallography
Date of creation
02.11.2020
Date of change
02.11.2020
Short link
https://repository.rudn.ru/en/records/article/record/64540/
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