The carbazole compounds PK9320 (1-(9-ethyl-7-(furan-2-yl)-9H-carbazol-3-yl)-N-methylmethanamine) and PK9323 (1-(9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)-N-methylmethanamine), second-generation analogues of PK083 (1-(9-ethyl-9H-carbazol-3-yl)-N-methylmethanamine), restore p53 signaling in Y220C p53-mutated cancer cells by binding to a mutation-induced surface crevice and acting as molecular chaperones. In the present paper, these three molecules have been tested for mutant p53-independent genotoxic and epigenomic effects on wild-type p53 MCF-7 breast adenocarcinoma cells, employing a combination of Western blot for phospho-γH2AX histone, Comet assay and methylation-sensitive arbitrarily primed PCR to analyze their intrinsic DNA damage-inducing and DNA methylation-changing abilities. We demonstrate that small modifications in the substitution patterns of carbazoles can have profound effects on their intrinsic genotoxic and epigenetic properties, with PK9320 and PK9323 being eligible candidates as “anticancer compounds” and “anticancer epi-compounds” and PK083 a “damage-corrective” compound on human breast adenocarcinoma cells. Such different properties may be exploited for their use as anticancer agents and chemical probes.

中文翻译：

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咔唑衍生分子对 MCF-7 乳腺癌细胞的基因毒性和表观基因毒性

咔唑化合物PK9320 (1-(9-ethyl-7-(furan-2-yl)-9H-carbazol-3-yl)-N-methylmethanamine) 和PK9323 (1-(9-ethyl-7-(thiazol- 4-yl)-9H-carbazol-3-yl)-N-methylmethanamine)， PK083的第二代类似物(1-(9-ethyl-9H-carbazol-3-yl)-N-methylmethanamine)，通过与突变诱导的表面缝隙结合并充当分子伴侣来恢复 Y220C p53 突变癌细胞中的 p53 信号传导。在本文中，采用蛋白质印迹法对磷酸-γH2AX 组蛋白、彗星试验和甲基化敏感的组合，测试了这三种分子对野生型 p53 MCF-7 乳腺癌细胞的突变 p53 非依赖性基因毒性和表观基因组影响。任意引物 PCR 分析其内在的 DNA 损伤诱导和 DNA 甲基化改变能力。我们用PK9320和PK9323证明了咔唑取代模式的微小改变可以对其内在的基因毒性和表观遗传特性产生深远的影响作为“抗癌化合物”和“抗癌表观化合物”的合格候选人，PK083是一种对人乳腺癌细胞的“损伤纠正”化合物。可以利用这些不同的特性将它们用作抗癌剂和化学探针。