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.
Domiziana MasciMichela PuxedduLaura Di MagnoMichele D'AmbrosioAnastasia ParisiMarianna NalliRuoli BaiAntonio ColucciaPietro SciòViviana OrlandoSara D'AngeloStefano BiagioniAndrea UrbaniErnest HamelAlessio NocentiniSerena FilibertiMarta TuratiRoberto RoncaJoanna KopeckaChiara RigantiCinzia FiondaRosa BordoneGiorgia Della RoccaGianluca CanettieriClaudiu T SupuranRomano SilvestriGiuseppe La ReginaPublished in: Journal of medicinal chemistry (2023)
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.
Keyphrases
- cell proliferation
- cancer therapy
- stem cells
- cell cycle arrest
- induced apoptosis
- multidrug resistant
- cell death
- endoplasmic reticulum stress
- breast cancer cells
- endothelial cells
- drug delivery
- epithelial mesenchymal transition
- gene expression
- pi k akt
- human health
- photodynamic therapy
- risk assessment
- anti inflammatory
- genome wide
- acinetobacter baumannii
- cystic fibrosis
- induced pluripotent stem cells
- pluripotent stem cells