2. Academic Validation
  3. 4-(3-Phenyl-4-(3,4,5-trimethoxybenzoyl)-1 H-pyrrol-1-yl)benzenesulfonamide, a Novel Carbonic Anhydrase and Wnt/β-Catenin Signaling Pathway Dual-Targeting Inhibitor with Potent Activity against Multidrug Resistant Cancer Cells

4-(3-Phenyl-4-(3,4,5-trimethoxybenzoyl)-1 H-pyrrol-1-yl)benzenesulfonamide, a Novel Carbonic Anhydrase and Wnt/β-Catenin Signaling Pathway Dual-Targeting Inhibitor with Potent Activity against Multidrug Resistant Cancer Cells

  • J Med Chem. 2023 Nov 9;66(21):14824-14842. doi: 10.1021/acs.jmedchem.3c01424.
Domiziana Masci 1,  Michela Puxeddu 2,  Laura Di Magno 3,  Michele D'Ambrosio 2,  Anastasia Parisi 2,  Marianna Nalli 2,  Ruoli Bai 4,  Antonio Coluccia 2,  Pietro Sciò 2,  Viviana Orlando 5,  Sara D'Angelo 5,  Stefano Biagioni 5,  Andrea Urbani 1,  Ernest Hamel 4,  Alessio Nocentini 6,  Serena Filiberti 7,  Marta Turati 7,  Roberto Ronca 7,  Joanna Kopecka 8,  Chiara Riganti 8,  Cinzia Fionda 3,  Rosa Bordone 3,  Giorgia Della Rocca 3,  Gianluca Canettieri 3,  Claudiu T Supuran 6,  Romano Silvestri 2,  Giuseppe La Regina 2
Affiliations

Affiliations

  • 1 Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Catholic University of the Sacred Heart, Largo Francesco Vito 1, Rome 00168, Italy.
  • 2 Laboratory Affiliated with the Institute Pasteur Italy─Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, Roma 00185, Italy.
  • 3 Laboratory Affiliated to Istituto Pasteur Italia─Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, Rome 00161, Italy.
  • 4 Molecular Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States.
  • 5 Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Piazzale Aldo Moro 5, Rome 00185, Italy.
  • 6 Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Universitá degli Studi di Firenze, Via Ugo Schiff 6, Sesto Fiorentino I-50019, Firenze, Italy.
  • 7 Experimental Oncology and Immunology Unit, Department of Molecular and Translational Medicine, University of Brescia, Via Branze 39, Brescia 25123, Italy.
  • 8 Department of Oncology and Molecular Biotecnology Center "Guido Tarone″, Oncological Pharmacology Unit, Via Nizza 44, Torino 10126, Italy.
PMID: 37902628 DOI: 10.1021/acs.jmedchem.3c01424
Abstract

We synthesized new pyrrole and indole derivatives as human Carbonic Anhydrase (hCA) inhibitors with the potential to inhibit the Wnt/β-catenin signaling pathway. The presence of both N1-(4-sulfonamidophenyl) and 3-(3,4,5-trimethoxyphenyl) substituents was essential for strong hCA inhibitors. The most potent hCA XII inhibitor 15 (Ki = 6.8 nM) suppressed the Wnt/β-catenin signaling pathway and its target genes MYC, Fgf20, and Sall4 and exhibited the typical markers of Apoptosis, cleaved poly(ADP-ribose)polymerase, and cleaved Caspase-3. Compound 15 showed strong inhibition of viability in a panel of Cancer cells, including colorectal Cancer and triple-negative breast Cancer cells, was effective against the NCI/ADR-RES DOX-resistant cell line, and restored the sensitivity to doxorubicin (DOX) in HT29/DX and MDCK/P-gp cells. Compound 15 is a novel dual-targeting compound with activity against hCA and Wnt/β-catenin. It thus has a broad targeting spectrum and is an Anticancer agent with specific potential in P-glycoprotein overexpressing cell lines.

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