Owing to the lack of target-directed therapies, triple-negative breast cancer (TNBC) is difficult to effectively treat. In this article, a novel organometallic histone deacetylase (HDAC) inhibitor, Fc-SelSA, based on the selenocyanide (SelSA) zinc-binding motif, was synthesized using a ferrocenyl group as the cap to confer activity against TNBC. The synthesized Fc-SelSA was evaluated for bioactivity in vitro and in vivo. An enzymatic assay showed that Fc-SelSA was a potent HDAC inhibitor with a half-maximum inhibitory concentration (IC₅₀) of 14.8 nM. Molecular docking studies of Fc-SelSA with HDAC suggested that the ferrocenyl unit overlaps with the phenyl group of suberoylanilide hydroxamic acid (SAHA) and the amido group of Fc-SelSA can form hydrogen bonds with the D98 and G151 residues of HDAC, but SAHA and SelSA do not show similar interactions. Moreover, Fc-SelSA reactivated the estrogen receptor alpha (ERα) expression, sensitized TNBC cells to the antagonist tamoxifen, and exerted more potent antitumor effects against TNBC MDA-MB-231 tumor xenografts in comparison to SelSA with no obvious side effects. Our results indicate that Fc-SelSA is a potent oral anticancer candidate for HDAC-targeted TNBC therapy and deserves further investigation for clinical application.

中文翻译：

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三阴性乳腺癌治疗新型二茂铁组蛋白去乙酰化酶抑制剂的开发。

由于缺乏靶向治疗，三阴性乳腺癌（TNBC）难以有效治疗。在本文中，以二茂铁基团为帽，合成了一种基于硒氰化物（SelSA）锌结合基序的新型有机金属组蛋白脱乙酰基酶（HDAC）抑制剂Fc-SelSA，以赋予其针对TNBC的活性。评价合成的Fc-SelSA的体外和体内生物活性。酶促测定表明Fc-SelSA是有效的HDAC抑制剂，抑制浓度为半数最大（IC ₅₀）为14.8 nM。Fc-SelSA与HDAC的分子对接研究表明，二茂铁基单元与亚磺酰苯胺异羟肟酸（SAHA）的苯基重叠，并且Fc-SelSA的酰胺基可与HDAC的D98和G151残基形成氢键，但SAHA和SelSA没有显示相似的交互作用。此外，与SelSA相比，Fc-SelSA重新激活了雌激素受体α（ERα）表达，使TNBC细胞对拮抗剂他莫昔芬敏感，并对TNBC MDA-MB-231肿瘤异种移植物发挥了更强的抗肿瘤作用，而没有明显的副作用。我们的结果表明，Fc-SelSA是针对HDAC靶向的TNBC治疗的有效口服抗癌候选药物，值得临床研究进一步研究。