Chlorambucil is a nitrogen mustard-based DNA alkylating drug, which is widely used as a front-line treatment of chronic lymphocytic leukaemia (CLL). Despite its widespread application and success for the initial treatment of leukaemia, a majority of patients eventually develop acquired resistance to chlorambucil. In this regard, we have designed and synthesised a novel hybrid molecule, chloram-HDi that simultaneously impairs DNA and HDAC enzymes. Chloram-HDi efficiently inhibits the proliferation of HL-60 and U937 leukaemia cells with GI50 values of 1.24 µM and 1.75 µM, whereas chlorambucil exhibits GI50 values of 21.1 µM and 37.7 µM against HL-60 and U937 leukaemia cells, respectively. The mechanism behind its remarkably enhanced cytotoxicity is that chloram-HDi not only causes a significant DNA damage of leukaemia cells but also downregulates DNA repair protein, Rad52, resulting in the escalation of its DNA-damaging effect. Furthermore, chloram-HDi inhibits HDAC enzymes to induce the acetylation of α-tubulin and histone H3.

中文翻译：

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DNA和HDAC的混合抑制剂可显着增强白血病细胞的细胞毒性。

苯丁酸氮芥是一种基于氮芥子碱的DNA烷基化药物，被广泛用作慢性淋巴细胞性白血病（CLL）的一线治疗。尽管其在白血病的初始治疗中得到广泛应用并取得了成功，但大多数患者最终对苯丁酸氮芥产生了获得性耐药。在这方面，我们设计并合成了一种同时破坏DNA和HDAC酶的新型杂合分子chloram-HDi。Chloram-HDi有效抑制GI-60值为1.24 µM和1.75 µM的HL-60和U937白血病细胞的增殖，而苯丁酸氮芥对​​HL-60和U937白血病细胞的GI50值分别为21.1 µM和37.7 µM。它的细胞毒性显着增强的机制是，绿豆素-HDi不仅引起白血病细胞严重的DNA损伤，而且还下调了DNA修复蛋白Rad52，从而导致其DNA损伤作用的增强。此外，绿豆素-HDi抑制HDAC酶以诱导α-微管蛋白和组蛋白H3的乙酰化。