Recent studies point towards the possible disadvantages of using hydroxamic acid-based zinc-binding groups in HDAC inhibitors due to e.g. mutagenicity issues. In this work, we elaborated on our previously developed Tubathian series, a class of highly selective thiaheterocyclic HDAC6 inhibitors, by replacing the benzohydroxamic acid function by an alternative zinc chelator, i.e., an aromatic trifluoromethyl ketone. Unfortunately, these compounds showed a reduced potency to inhibit HDAC6 as compared to their hydroxamic acid counterparts. In agreement, the most active trifluoromethyl ketone was unable to influence the growth of SK-OV-3 ovarian cancer cells nor to alter the acetylation status of tubulin and histone H3. These data suggest that replacement of the zinc-binding hydroxamic acid function with a trifluoromethyl ketone zinc-binding moiety within reported benzohydroxamic HDAC6 inhibitors should not be considered as a standard strategy in HDAC inhibitor development.

中文翻译：

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评估三氟甲基酮作为替代锌结合基团选择性抑制 HDAC6 的功能†

最近的研究指出，由于致突变性等问题，在 HDAC 抑制剂中使用基于异羟肟酸的锌结合基团可能存在缺点。在这项工作中，我们通过用另一种锌螯合剂（即芳香族三氟甲基酮）取代苯并异羟肟酸功能，详细阐述了我们之前开发的Tubathian系列，一类高选择性硫杂环HDAC6抑制剂。不幸的是，与异羟肟酸对应物相比，这些化合物抑制 HDAC6 的效力较低。一致地，最活跃的三氟甲基酮既不能影响 SK-OV-3 卵巢癌细胞的生长，也不能改变微管蛋白和组蛋白 H3 的乙酰化状态。这些数据表明，在已报道的苯并异羟肟酸 HDAC6 抑制剂中，用三氟甲基酮锌结合部分取代锌结合异羟肟酸功能不应被视为 HDAC 抑制剂开发中的标准策略。