H2O2/Peroxynitrite-Activated Hydroxamic Acid HDAC Inhibitor Prodrugs Show Antileukemic Activities against AML Cells,ACS Medicinal Chemistry Letters

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H2O2/Peroxynitrite-Activated Hydroxamic Acid HDAC Inhibitor Prodrugs Show Antileukemic Activities against AML Cells
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-06-13 00:00:00 , DOI: 10.1021/acsmedchemlett.8b00057
Yi Liao ₁ , Liping Xu ₁ , Siyu Ou ₁ , Holly Edwards ₂ , Daniel Luedtke _{2,

3} , Yubin Ge ₂ , Zhihui Qin ₁

Affiliation

Occurrence of acute myeloid leukemia (AML) results in abundant endogenous reactive oxygen species (ROS)/reactive nitrogen species (RNS) in AML cells and in disease-relevant microenvironments. Histone deacetylase inhibitor (HDACi) prodrug approach was designed accordingly by masking the hydroxamic acid zinc binding group with hydrogen peroxide (H₂O₂)/peroxynitrite (PNT)-sensitive, self-immolative aryl boronic acid moiety. Model prodrugs 5–82 and 5–23 were activated in AML cells to release cytotoxic HDACis, evidenced by inducing acetylation markers and reducing viability of AML cells. Intracellular activation and antileukemic activities of prodrug were increased or decreased by ROS/PNT inducers and scavengers, respectively. Prodrugs 5–82 and 5–23 also enhanced the potency of chemotherapy drug cytarabine, supporting the potentials of this prodrug class in combinatorial treatment.

中文翻译：

H ₂ O ₂ /过氧亚硝酸盐激活的异羟肟酸HDAC抑制剂前药显示出对AML细胞的抗白血病活性

急性髓细胞性白血病（AML）的发生会导致AML细胞和与疾病相关的微环境中大量的内源性活性氧（ROS）/活性氮（RNS）。通过用过氧化氢（H ₂ O ₂）/过氧亚硝酸盐（PNT）敏感的自焚芳基硼酸部分掩盖异羟肟酸锌结合基团，从而设计了组蛋白脱乙酰基酶抑制剂（HDACi）前药方法。前药模型5 – 82和5 – 23在AML细胞中被激活以释放细胞毒性HDACis，这可通过诱导乙酰化标记并降低AML细胞的活力来证明。ROS / PNT诱导剂和清除剂分别增加或减少前药的细胞内活化和抗白血病活性。前药5 – 82和5 – 23也增强了化疗药物阿糖胞苷的药效，支持了此类前药在组合治疗中的潜力。

更新日期：2018-06-13

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