4-(3-Phenyl-4-(3,4,5-三甲氧基苯甲酰基)-1H-吡咯-1-基)苯磺酰胺，一种新型碳酸酐酶和 Wnt/β-Catenin 信号通路双靶向抑制剂，具有有效的多药活性抵抗癌细胞。
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.
发表日期：2023 Oct 30
作者：
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
来源：
Cellular & Molecular Immunology
摘要：
我们合成了新的吡咯和吲哚衍生物作为人碳酸酐酶 (hCA) 抑制剂，具有抑制 Wnt/β-catenin 信号通路的潜力。 N1-(4-磺酰氨基苯基) 和 3-(3,4,5-三甲氧基苯基) 取代基的存在对于强 hCA 抑制剂至关重要。最有效的 hCA XII 抑制剂 15 (Ki = 6.8 nM) 抑制 Wnt/β-catenin 信号通路及其靶基因 MYC、Fgf20 和 Sall4，并表现出典型的细胞凋亡标志物、裂解的聚（ADP-核糖）聚合酶和裂解的 caspase-3。化合物 15 对一组癌细胞（包括结直肠癌和三阴性乳腺癌细胞）的活力表现出强烈的抑制作用，可有效对抗 NCI/ADR-RES DOX 耐药细胞系，并恢复对阿霉素 (DOX) 的敏感性。 HT29/DX 和 MDCK/P-gp 细胞。化合物 15 是一种新型双靶向化合物，具有抗 hCA 和 Wnt/β-catenin 活性。因此，它具有广泛的靶向谱，是一种在 P-糖蛋白过表达细胞系中具有特定潜力的抗癌剂。
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.