Histone deacetylases (HDACs) play a key role not only in gene expression but also in DNA repair. Herein, we report the rational design and characterization of a compound named chlordinaline containing nitrogen mustard and 2-aminobenzamide moieties as a DNA/HDAC dual-targeting inhibitor. Chlordinaline exhibited moderate total HDAC inhibitory activity. The HDAC isoform selectivity assay indicated that chlordinaline mostly inhibits HDAC3. Chlordinaline exhibited both DNA and HDAC inhibitory activities and showed potent antiproliferative activity against all the six test cancer cell lines with IC₅₀ values of as low as 3.1–14.2 μM, which is significantly more potent than reference drugs chlorambucil and tacedinaline. Chlordinaline could induce the apoptosis and G2/M phase cell cycle arrest of A375 cancer cells. This study demonstrates that combining nitrogen mustard and 2-aminobenzamide moieties into one molecule is an effective method to obtain DNA/HDAC dual-targeting inhibitors as potent antitumor agents. Chlordinaline as the first example of such DNA/HDAC dual-targeting inhibitors could be a promising candidate for cancer therapy and could also be a lead compound for further optimization.

中文翻译：

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含有氮芥和 2-氨基苯甲酰胺部分的 DNA/HDAC 双靶向抑制剂的合理设计和表征†

组蛋白脱乙酰酶 (HDAC) 不仅在基因表达中发挥着关键作用，而且在 DNA 修复中也发挥着关键作用。在此，我们报告了一种名为氯地那林的化合物作为 DNA/HDAC 双靶向抑制剂的合理设计和表征，该化合物含有氮芥和 2-氨基苯甲酰胺部分。氯地那林表现出中等的总 HDAC 抑制活性。HDAC异构体选择性测定表明氯地那林主要抑制HDAC3。Chlordinaline 表现出 DNA 和 HDAC 抑制活性，并对所有六种测试癌细胞系显示出有效的抗增殖活性，IC ₅₀值低至 3.1–14.2 μM，明显比参考药物苯丁酸氮芥和他西地林更有效。氯地那林可诱导A375癌细胞凋亡和G2/M期细胞周期阻滞。这项研究表明，将氮芥和 2-氨基苯甲酰胺部分结合到一个分子中是获得 DNA/HDAC 双靶向抑制剂作为有效抗肿瘤药物的有效方法。Chlordinaline 作为此类 DNA/HDAC 双靶向抑制剂的第一个例子，可能是癌症治疗的有希望的候选者，也可能是进一步优化的先导化合物。