2. Academic Validation
  3. Novel Insights on Human Carbonic Anhydrase Inhibitors Based on Coumalic Acid: Design, Synthesis, Molecular Modeling Investigation, and Biological Studies

Novel Insights on Human Carbonic Anhydrase Inhibitors Based on Coumalic Acid: Design, Synthesis, Molecular Modeling Investigation, and Biological Studies

  • Int J Mol Sci. 2022 Jul 19;23(14):7950. doi: 10.3390/ijms23147950.
Virginia Pontecorvi 1,  Mattia Mori 2,  Francesca Picarazzi 2,  Susi Zara 3,  Simone Carradori 3,  Amelia Cataldi 3,  Andrea Angeli 4 5,  Emanuela Berrino 1,  Paola Chimenti 1,  Alessia Ciogli 1,  Daniela Secci 1,  Paolo Guglielmi 1,  Claudiu T Supuran 4
Affiliations

Affiliations

  • 1 Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
  • 2 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
  • 3 Department of Pharmacy, "G. d'Annunzio" University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy.
  • 4 NEUROFARBA Department, Pharmaceutical and Nutraceutical Section, University of Florence, Via Ugo Schiff 6, 50019 Florence, Italy.
  • 5 Department of Food and Drug, University of Parma, Parco Area delle Scienze, 27/A, 43124 Parma, Italy.
PMID: 35887299 DOI: 10.3390/ijms23147950
Abstract

Human Carbonic Anhydrase (hCA, EC 4.2.1.1) isoforms IX and XII are overexpressed in solid hypoxic tumors, and they are considered as prognostic tools and therapeutic targets for Cancer. Based on a molecular simplification of the well-known coumarin scaffold, we developed a new series of derivatives of the pyran-2-one core. The new compounds are endowed with potent and selective inhibitory activity against the tumor-related hCA isoforms IX and XII, in the low nanomolar range, whereas they are inactive against the two cytosolic off-targets hCA I and II. The compounds exhibiting the best hCA inhibition were further investigated against the breast adenocarcinoma cell line (MCF7) in hypoxic conditions, evaluating their ability to eventually synergize with doxorubicin. The compounds' biocompatibility on healthy cells was also tested and confirmed on Human Gingival Fibroblasts (HGFs). Furthermore, the possible binding mode of all compounds to the active site of the tumor-associated human CA IX was investigated by computational techniques which predicted the binding conformations and the persistency of binding poses within the active site of the enzyme, furnishing relevant data for the design of tight binding inhibitors.

Keywords

breast adenocarcinoma cells (MCF7); carbonic anhydrase inhibitors; coumalic acid; docking; molecular dynamics; pyran-2-ones.

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