2. Academic Validation
  3. 1,3-Dipolar Cycloaddition, HPLC Enantioseparation, and Docking Studies of Saccharin/Isoxazole and Saccharin/Isoxazoline Derivatives as Selective Carbonic Anhydrase IX and XII Inhibitors

1,3-Dipolar Cycloaddition, HPLC Enantioseparation, and Docking Studies of Saccharin/Isoxazole and Saccharin/Isoxazoline Derivatives as Selective Carbonic Anhydrase IX and XII Inhibitors

  • J Med Chem. 2020 Mar 12;63(5):2470-2488. doi: 10.1021/acs.jmedchem.9b01434.
Melissa D'Ascenzio 1,  Daniela Secci 1,  Simone Carradori 2,  Susi Zara 2,  Paolo Guglielmi 1,  Roberto Cirilli 3,  Marco Pierini 1,  Giulio Poli 4,  Tiziano Tuccinardi 4,  Andrea Angeli 5 6,  Claudiu T Supuran 5
Affiliations

Affiliations

  • 1 Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
  • 2 Department of Pharmacy, "G. d'Annunzio" University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy.
  • 3 Centro nazionale per il controllo e la valutazione dei farmaci, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
  • 4 Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.
  • 5 Neurofarba Department, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
  • 6 Centre of Advanced Research in Bionanoconjugates and Biopolymers Department, "Petru Poni" Institute of Macromolecular Chemistry, 41A Grigore Ghica-Voda Alley, 700487 Iasi, Romania.
PMID: 31972093 DOI: 10.1021/acs.jmedchem.9b01434
Abstract

Two series of saccharin/isoxazole and saccharin/isoxazoline hybrids were synthesized by 1,3-dipolar cycloaddition. The new compounds showed to be endowed with potent and selective inhibitory activity against the cancer-related human Carbonic Anhydrase (hCA) IX and XII isoforms in the nanomolar range, while no affinity was encountered for off-targets, such as hCA I and II. Successive enantioseparation on a milligram scale of the most representative compounds led to the discovery that (S)-isomers were more potent than their corresponding (R)-enantiomers. Lastly, molecular modeling studies were conducted to define those structural requirements that were responsible for the discrimination among selected human isoforms of carbonic anhydrases. Two nanomolar hCA IX and XII inhibitors were also screened for their selective toxicity against non tumoral primary cells (fibroblasts) and against a breast adenocarcinoma cell line (MCF7) in hypoxic environment. The efficacious combination of these compounds with doxorubicin on MCF7 cells was demonstrated after 72 h of treatment.

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