Benzoxaborinine, New Chemotype for Carbonic Anhydrase Inhibition: <i>Ex Novo</i> Synthesis, Crystallography, <i>In Silico</i> Studies, and Anti-Melanoma Cell Line Activity
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 <b>11</b>, exhibited potent inhibitory activity (below 65 nM) against hCA IX and XII and stronger antiproliferative effects than <b>SLC-0111</b> on human melanoma cells under hypoxia. Crystallographic studies of benzoxaborinine <b>3</b> adducts with hCA I and II demonstrated the binding mode of this chemotype, revealing that although both benzoxaborinine <b>3</b> and benzoxaborole <b>10</b> 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.
Authors
- Alessandro Bonardi (ORCID: https://orcid.org/0000-0002-5520-740X)
- Simone Giovannuzzi (ORCID: https://orcid.org/0000-0002-0669-7481)
- Roberto Ronca (ORCID: https://orcid.org/0000-0001-8979-7068)
- Alessio Nocentini (ORCID: https://orcid.org/0000-0003-3342-702X)
- Marta Ferraroni (ORCID: https://orcid.org/0000-0001-7258-738X)
- Claudiu T. Supuran (ORCID: https://orcid.org/0000-0003-4262-0323)
- Michaël Smietana (ORCID: https://orcid.org/0000-0001-8132-7221)
- Marta Turati (ORCID: https://orcid.org/0000-0002-7139-3820)
- Anna Ņikitjuka (ORCID: https://orcid.org/0000-0003-1622-6349)
- Andrea Angeli (ORCID: https://orcid.org/0000-0002-1470-7192)
- Jean‐Yves Winum (ORCID: https://orcid.org/0000-0003-3197-3414)
- Maria Luisa Massardi (ORCID: https://orcid.org/0009-0005-0718-9138)
Institutions
- École Nationale Supérieure de Chimie de Montpellier (FR)
- Centre National de la Recherche Scientifique (FR)
- Université de Montpellier (FR)
- Latvijas Organiskās Sintēzes Institūts (LV)
- Institut des Biomolécules Max Mousseron (FR)
- University of Florence (IT)
- University of Brescia (IT)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-10-08
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01516
- Citations
- 12
- Primary Topic
- Enzyme function and inhibition
- Type
- article
- Field-Weighted Citation Impact
- 2.81
Funders
- Consorzio Interuniversitario Biotecnologie
- European Commission
- Associazione Italiana per la Ricerca sul Cancro