Design and synthesis of sulfonamides incorporating a biotin moiety: Carbonic anhydrase inhibitory effects, antiproliferative activity and molecular modeling studies

Paloma Begines; Alessandro Bonardi; Alessio Nocentini; Paola Gratteri; Simone Giovannuzzi; Roberto Ronca; Camilla Tavani; Maria Luisa Massardi; Óscar López; Claudiu T Supuran

doi:10.1016/j.bmc.2023.117467

Design and synthesis of sulfonamides incorporating a biotin moiety: Carbonic anhydrase inhibitory effects, antiproliferative activity and molecular modeling studies

Bioorg Med Chem. 2023 Oct 30:94:117467. doi: 10.1016/j.bmc.2023.117467. Epub 2023 Sep 7.

Authors

Affiliations

¹ NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, University of Florence, Florence 50019, Italy; Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, Seville E-41071, Spain.
² NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, University of Florence, Florence 50019, Italy; NEUROFARBA Department, Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Via U. Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy.
³ NEUROFARBA Department, Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Via U. Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy.
⁴ NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, University of Florence, Florence 50019, Italy.
⁵ Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
⁶ Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, Seville E-41071, Spain. Electronic address: osc-lopez@us.es.
⁷ NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, University of Florence, Florence 50019, Italy. Electronic address: claudiu.supuran@unifi.it.

PMID: 37722299
DOI: 10.1016/j.bmc.2023.117467

Abstract

Sulfonamides constitute an important class of classical carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. Herein we have accomplished the conjugation of biotin with an ample number of sulfonamide motifs with the aim of testing them in vitro as inhibitors of the human carbonic anhydrase (hCA) isoforms I and II (cytosolic isozymes), as well as hCA IX and XII (transmembrane, tumor-associated enzymes). Most of these newly synthesized compounds exhibited interesting inhibition profiles, with activities in the nanomolar range. The presence of a 4-F-C₆H₄ moiety, also found in SLC-0111, afforded an excellent selectivity towards the tumor-associated hypoxia-induced hCA isoform XII with an inhibition constant (K_I) of 4.5 nM. The 2-naphthyl derivative was the most potent inhibitor against hCA IX (K_I = 6.2 nM), 4-fold stronger than AAZ (K_I = 25 nM) with very good selectivity. Some compounds were chosen for antiproliferative activity testing against a panel of 3 human tumor cell lines, one compound showing anti-proliferative activity on glioblastoma, triple-negative breast cancer, and pancreatic carcinoma cell lines.

Keywords: Antitumor agent; Biotin; Carbonic anhydrase; Glioblastoma; Pancreatic carcinoma; Sulfonamide; Triple-negative breast cancer.