Journal of medicinal chemistry · 2023
4-(3-Phenyl-4-(3,4,5-trimethoxybenzoyl)-1H-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.
СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Masci Domiziana, Puxeddu Michela, Di Magno Laura, D'Ambrosio Michele, Parisi Anastasia, Nalli Marianna, Bai Ruoli, Coluccia Antonio, Sciò Pietro, Orlando Viviana, D'Angelo Sara, Biagioni Stefano, Urbani Andrea, Hamel Ernest, Nocentini Alessio, Filiberti Serena, Turati Marta, Ronca Roberto, Kopecka Joanna, Riganti Chiara, Fionda Cinzia, Bordone Rosa, Della Rocca Giorgia, Canettieri Gianluca, Supuran Claudiu T, Silvestri Romano, La Regina Giuseppe
Аннотация
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.