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 (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.

中文翻译：

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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耐药癌细胞

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。N 1-(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抑制剂是必需的。最有效的 hCA XII 抑制剂15 ( K _i = 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。