TY - JOUR
T1 - 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
AU - Masci, Domiziana
AU - Puxeddu, Michela
AU - Di Magno, Laura
AU - D’Ambrosio, Michele
AU - Parisi, Anastasia
AU - Nalli, Marianna
AU - Bai, Ruoli
AU - Coluccia, Antonio
AU - Sciò, Pietro
AU - Orlando, Viviana
AU - D’Angelo, Sara
AU - Biagioni, Stefano
AU - Urbani, Andrea
AU - Hamel, Ernest
AU - Nocentini, Alessio
AU - Filiberti, Serena
AU - Turati, Marta
AU - Ronca, Roberto
AU - Kopecka, Joanna
AU - Riganti, Chiara
AU - Fionda, Cinzia
AU - Bordone, Rosa
AU - Della Rocca, Giorgia
AU - Canettieri, Gianluca
AU - Supuran, Claudiu T.
AU - Silvestri, Romano
AU - La Regina, Giuseppe
PY - 2023
Y1 - 2023
N2 - We synthesized new pyrrole and indole derivatives as human carbonic anhydrase (hCA) inhibitors with the potential to inhibit the Wnt/beta-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 (K-i = 6.8 nM) suppressed the Wnt/beta-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/beta-catenin. It thus has a broad targeting spectrum and is an anticancer agent with specific potential in P-glycoprotein overexpressing cell lines.
AB - We synthesized new pyrrole and indole derivatives as human carbonic anhydrase (hCA) inhibitors with the potential to inhibit the Wnt/beta-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 (K-i = 6.8 nM) suppressed the Wnt/beta-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/beta-catenin. It thus has a broad targeting spectrum and is an anticancer agent with specific potential in P-glycoprotein overexpressing cell lines.
KW - Anticancer agents
KW - Benzenesulfonamides
KW - Carbonic Anhydrase Inhibitors
KW - Dual-Targeting Inhibitors
KW - Multidrug Resistant Cancer Cells
KW - Wnt/β-Catenin Signaling Pathway Inhibitors
KW - Anticancer agents
KW - Benzenesulfonamides
KW - Carbonic Anhydrase Inhibitors
KW - Dual-Targeting Inhibitors
KW - Multidrug Resistant Cancer Cells
KW - Wnt/β-Catenin Signaling Pathway Inhibitors
UR - http://hdl.handle.net/10807/277044
UR - https://www.ncbi.nlm.nih.gov/pmc/articles/pmc10641813/
U2 - 10.1021/acs.jmedchem.3c01424
DO - 10.1021/acs.jmedchem.3c01424
M3 - Article
SN - 0022-2623
VL - 66
SP - 14824
EP - 14842
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
ER -
