4-(3-Phenyl-4-(3,4,5-trimethoxybenzoyl)-1<i>H</i>-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
Domiziana Masci, Michela Puxeddu, Laura Di Magno, Michele D’Ambrosio, Anastasia Parisi, Marianna Nalli, Ruoli Bai, Antonio Coluccia, Pietro Sciò, Viviana Orlando, Sara D’Angelo, Stefano Biagioni, Andrea Urbani, Ernest Hamel, Alessio Nocentini, Serena Filiberti, Marta Turati, Roberto Ronca, Joanna Kopecka, Chiara Riganti, Cinzia Fionda, Rosa Bordone, Giorgia Della Rocca, Gianluca Canettieri, Claudiu T. Supuran, Romano Silvestri, Giuseppe La Regina
Abstract
High Resolution Image Download MS PowerPoint Slide 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 N 1-(4-sulfonamidophenyl) and 3-(3,4,5-trimethoxyphenyl) substituents was essential for strong hCA inhibitors. The most potent hCA XII inhibitor 15 ( K i = 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.