Cancer stem cells (CSCs) are a niche of highly tumorigenic cells featuring self‐renewal, activation of pluripotency genes, multidrug resistance, and ability to cause cancer relapse. Seven HDACi (1‐7), showing either hydroxamate or 2'‐aminoanilide function, were tested in colorectal cancer (CRC) and glioblastoma multiforme (GBM) CSCs to determine their effects on cell proliferation, H3 acetylation levels and in‐cell HDAC activity. Two uracil‐based hydroxamates, 5 and 6, which differ in substitution at C5 and C6 positions of the pyrimidine ring, exhibited the greatest cytotoxicity in GBM (5) and CRC (6) CSCs, followed by the pyridine‐hydroxamate 2, with 2‐ to 6‐fold higher potency than the positive control SAHA. Finally, increased H3 acetylation as well as HDAC inhibition directly in cells by selected 2'‐aminoanilide 4 and hydroxamate 5 confirmed target engagement. Further investigation will be conducted into the broad‐spectrum anticancer properties of the most potent derivatives and their effects in combination with approved, conventional anticancer drugs.

中文翻译：

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含尿嘧啶和吡啶的 ​​HDAC 抑制剂在结直肠癌和胶质母细胞瘤干细胞中表现出细胞毒性

癌症干细胞（CSC）是一种高度致瘤细胞，具有自我更新、多能基因激活、多药耐药性和导致癌症复发的能力。在结直肠癌 (CRC) 和多形性胶质母细胞瘤 (GBM) CSC 中测试了七种显示异羟肟酸或 2'-氨基苯胺功能的 HDACi (1-7)，以确定它们对细胞增殖、H3 乙酰化水平和细胞内 HDAC 活性的影响。两种基于尿嘧啶的异羟肟酸酯 5 和 6，在嘧啶环的 C5 和 C6 位点上的取代不同，在 GBM (5) 和 CRC (6) CSC 中表现出最大的细胞毒性，其次是吡啶异羟肟酸酯 2，其中 2 ‐ 效力比阳性对照 SAHA 高 6 倍。最后，通过选定的 2'-氨基苯胺 4 和异羟肟酸 5 增加 H3 乙酰化以及直接在细胞中抑制 HDAC，证实了靶标的参与。将进一步研究最有效的衍生物的广谱抗癌特性及其与已批准的传统抗癌药物组合的效果。