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  3. Benzoxaborinine, New Chemotype for Carbonic Anhydrase Inhibition: Ex Novo Synthesis, Crystallography, In Silico Studies, and Anti-Melanoma Cell Line Activity

Benzoxaborinine, New Chemotype for Carbonic Anhydrase Inhibition: Ex Novo Synthesis, Crystallography, In Silico Studies, and Anti-Melanoma Cell Line Activity

  • J Med Chem. 2024 Oct 8. doi: 10.1021/acs.jmedchem.4c01516.
Simone Giovannuzzi 1 2,  Anna Nikitjuka 1 3,  Andrea Angeli 2,  Michael Smietana 1,  Maria-Luisa Massardi 4,  Marta Turati 4,  Roberto Ronca 4,  Alessandro Bonardi 5,  Alessio Nocentini 2,  Marta Ferraroni 6,  Claudiu T Supuran 2,  Jean-Yves Winum 1
Affiliations

Affiliations

  • 1 IBMM, University of Montpellier, CNRS, ENSCM, 34293 Montpellier, France.
  • 2 Department of NEUROFARBA - Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, 50019 Sesto Fiorentino, Firenze, Italy.
  • 3 Latvian Institute of Organic Synthesis, LV-1006 Riga, Latvia.
  • 4 Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.
  • 5 Department NEUROFARBA, Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Via U. Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy.
  • 6 Department of Chemistry "Ugo Schiff" (DICUS), University of Florence, 50019 Sesto Fiorentino, Firenze, Italy.
PMID: 39378331 DOI: 10.1021/acs.jmedchem.4c01516
Abstract

The benzoxaborinine scaffold, a homologue of benzoxaborole with an additional carbon atom in the boracycle, shows significant potential in developing new therapeutic agents. This study reports the synthesis, inhibition assays against four human Carbonic Anhydrase (hCA, EC 4.2.1.1) isoforms, and anti-melanoma evaluation of 7-aryl(thio)ureido-substituted benzoxaborinines. Some derivatives, particularly compound 11, exhibited potent inhibitory activity (below 65 nM) against hCA IX and XII and stronger antiproliferative effects than SLC-0111 on human melanoma cells under hypoxia. Crystallographic studies of benzoxaborinine 3 adducts with hCA I and II demonstrated the binding mode of this chemotype, revealing that although both benzoxaborinine 3 and benzoxaborole 10 share a similar zinc-binding mode, the expanded ring in benzoxaborinine led to a different orientation within the active site. These findings suggest that benzoxaborinines hold promise for designing novel Carbonic Anhydrase inhibitors.

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