Suberoylanilide hydroxamic acid (SAHA, vorinostat) is a potent small‐molecule pan‐inhibitor of histone deacetylases (HDACs) approved for treatment of cutaneous T‐cell lymphoma (CTCL). However, SAHA exhibits poor selectivity for cancer cells over noncancer cells. With an aim to improving its selectivity for cancer cells, we generated a novel SAHA prodrug (SAHA‐OBP) that is activated in the presence of hydrogen peroxide, a reactive oxygen species (ROS) known to be overexpressed in cancer cells. The high endogenous ROS content in cancer cells triggers rapid removal of the 4‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)benzyl carbonyl (OBP) cap to release active SAHA. The SAHA‐OBP prodrug demonstrates selective activity against multiple cancer cell lines such as HeLa, MCF‐7, MDA‐MB‐231, and B16‐F10, while remaining benign toward noncancer cells. The downstream effects of SAHA released from SAHA‐OBP in cancer cells is the induction of apoptosis. SAHA‐OBP was also found to be effective on multicellular tumor spheroids (MCTS). The SAHA prodrug designed in this study undergoes rapid ROS‐dependent activation and imparts much‐needed selectivity to SAHA for cancer cells.

中文翻译：

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内源性活性氧（ROS）激活的组蛋白去乙酰化酶抑制剂前药用于癌症化学治疗

Suberoylanilide异羟肟酸（SAHA，vorinostat）是一种有效的小分子组蛋白脱乙酰酶泛抑制剂（HDACs），已批准用于治疗皮肤T细胞淋巴瘤（CTCL）。然而，与非癌细胞相比，SAHA对癌细胞显示出较差的选择性。为了提高其对癌细胞的选择性，我们生成了一种新型的SAHA前药（SAHA-OBP），该药物在过氧化氢的存在下被激活，过氧化氢是一种已知在癌细胞中过表达的活性氧（ROS）。癌细胞中较高的内源ROS含量会触发快速去除4-（4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基）苄基羰基（OBP）帽以释放活性SAHA。SAHA-OBP前药对多种癌细胞系（例如HeLa，MCF-7，MDA-MB-231和B16-F10）表现出选择性活性，同时对非癌细胞保持良性。SAHA-OBP释放的SAHA对癌细胞的下游作用是诱导凋亡。还发现SAHA-OBP对多细胞肿瘤球体（MCTS）有效。在这项研究中设计的SAHA前药经历了快速的ROS依赖性活化，并赋予了SAHA对癌细胞非常需要的选择性。