2. Academic Validation
  3. O-derivatization of natural tropolone and β-thujaplicin leading to effective inhibitors of human carbonic anhydrases IX and XII

O-derivatization of natural tropolone and β-thujaplicin leading to effective inhibitors of human carbonic anhydrases IX and XII

  • Eur J Med Chem. 2025 Jun 5:290:117552. doi: 10.1016/j.ejmech.2025.117552.
Francesco Melfi 1,  Ilaria D'Agostino 2,  Simone Carradori 3,  Fabrizio Carta 4,  Andrea Angeli 5,  Giosuè Costa 6,  Gioele Renzi 5,  Ana Čikoš 7,  Daniela Vullo 5,  Josip Rešetar 1,  Marta Ferraroni 8,  Chiara Baroni 8,  Francesca Mancuso 9,  Rosaria Gitto 9,  Francesca Alessandra Ambrosio 10,  Emanuela Marchese 10,  Roberta Torcasio 11,  Nicola Amodio 12,  Clemente Capasso 13,  Stefano Alcaro 6,  Claudiu T Supuran 5
Affiliations

Affiliations

  • 1 Department of Pharmacy, "G. d'Annunzio" University of Chieti-Pescara, 66100, Chieti, Italy.
  • 2 Department of Pharmacy, University of Pisa, 56126, Pisa, Italy.
  • 3 Department of Pharmacy, "G. d'Annunzio" University of Chieti-Pescara, 66100, Chieti, Italy. Electronic address: simone.carradori@unich.it.
  • 4 Neurofarba Department, University of Florence, Sesto Fiorentino, 50019, Florence, Italy. Electronic address: fabrizio.carta@unifi.it.
  • 5 Neurofarba Department, University of Florence, Sesto Fiorentino, 50019, Florence, Italy.
  • 6 Dipartimento di Scienze della Salute, Università"Magna Græcia" di Catanzaro, Campus "S. Venuta", 88100, Catanzaro, Italy; Net4Science Academic Spin-Off, Università"Magna Græcia" di Catanzaro, Campus "S. Venuta", 88100, Catanzaro, Italy.
  • 7 NMR Centre, Ruđer Bošković Institute, Bijenička cesta 54, 10000, Zagreb, Croatia.
  • 8 'Ugo Schiff' Chemistry Department, University of Florence, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
  • 9 Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, Viale F. D'Alcontres 13, 98166, Messina, Italy.
  • 10 Dipartimento di Scienze della Salute, Università"Magna Græcia" di Catanzaro, Campus "S. Venuta", 88100, Catanzaro, Italy.
  • 11 Department of Experimental and Clinical Medicine, University "Magna Græcia" of Catanzaro, Campus "S. Venuta", 88100, Catanzaro, Italy; Department of Biology, Ecology and Earth Sciences (Di.B.E.S.T.), University of Calabria, 87036, Rende, Italy.
  • 12 Department of Experimental and Clinical Medicine, University "Magna Græcia" of Catanzaro, Campus "S. Venuta", 88100, Catanzaro, Italy.
  • 13 Department of Biology, Agriculture and Food Sciences, Institute of Biosciences and Bioresources, CNR, Napoli, Italy.
PMID: 40179613 DOI: 10.1016/j.ejmech.2025.117552
Abstract

Herein we report the chemical derivatization of the naturally occurring Tropolone (TRP) and its related compound β-Thujaplicin (β-TJP) as well as their in vitro assessment for inhibition of the physio/pathologically relevant hCAs isoforms I, II, VA; VII, IX and XII to obtain a first set of inhibition data useful for driving selected derivatives towards appropriate biomedical exploitation. The selected compound 17β was characterized for its chemical stability and assessed for its antiproliferative activity on a multiple myeloma model and showed potent pro-apoptotic features jointly with a safe toxicity profile on healthy cells. The binding mode of β-TJP within the hCA II was assessed by means of X-ray crystallography of the hCA II/β-TJP complex and showed almost complete superposition with the hCA II/TRP adduct reported in the literature. The data produced were used to elaborate a binding prediction model of such compounds on the hCAs VA, IX, and XII which are directly connected to important diseases. Overall, the achievements reported in this work are in the sustainment of the exploitation of naturally occurring troponoloid-based structures for biomedical purposes and thus contribute to the field in extending the variety of available chemical features.

Keywords

Cancer; Carbonic anhydrase; Multiple myeloma; Regioisomer; Thujaplicin; Tropolone.

Figures
Products