组蛋白脱乙酰酶（HDAC）在转录、细胞增殖和迁移方面发挥关键作用。FDA批准的组蛋白脱乙酰酶抑制剂（HDACi）在治疗不同T细胞淋巴瘤和多发性骨髓瘤方面显示出临床疗效。然而，由于非选择性抑制，它们显示出广泛的不良反应。避免靶外效应的一个方法是使用近保护药物，在靶组织中使抑制剂得到控制释放。在这里，我们描述了通过光解保护基掩盖已建立的HDACi DDK137（I）和VK1（II）的锌结合基的HDACi前药的合成和生物评价。最初的脱保试验证实，光掩蔽的HDACi pc-I可以脱保为其原始抑制剂I。在HDAC抑制测定中，pc-I显示出对HDAC1和HDAC6仅有的低抑制活性。光照后，pc-I的抑制活性大大增强。随后的MTT存活性测定、全细胞HDAC抑制测定和免疫印迹分析确认了pc-I在细胞水平上的无活性。在照射后，pc-I表现出明显的HDAC抑制和抗增殖活性，这与其原始抑制剂I相当。此外，只有光处理后的pc-I才能在Annexin V/PI和caspase-Glo 3/7测定中诱导凋亡，使pc-I成为开发光活化HDACi的有价值的工具。

Histone deacetylases (HDACs) play a key role in the control of transcription, cell proliferation, and migration. FDA-approved histone deacetylase inhibitors (HDACi) demonstrate clinical efficacy in the treatment of different T-cell lymphomas and multiple myeloma. However, due to unselective inhibition, they display a wide range of adverse effects. One approach to avoiding off-target effects is the use of prodrugs enabling a controlled release of the inhibitor in the target tissue. Herein, we describe the synthesis and biological evaluation of HDACi prodrugs with photo-cleavable protecting groups masking the zinc-binding group of the established HDACi DDK137 (I) and VK1 (II). Initial decaging experiments confirmed that the photocaged HDACi pc-I could be deprotected to its parent inhibitor I. In HDAC inhibition assays, pc-I displayed only low inhibitory activity against HDAC1 and HDAC6. After irradiation with light, the inhibitory activity of pc-I strongly increased. Subsequent MTT viability assays, whole-cell HDAC inhibition assays, and immunoblot analysis confirmed the inactivity of pc-I at the cellular level. Upon irradiation, pc-I demonstrated pronounced HDAC inhibitory and antiproliferative activities which were comparable to the parent inhibitor I. Additionally, only phototreated pc-I was able to induce apoptosis in Annexin V/PI and caspase-Glo 3/7 assays, making pc-I a valuable tool for the development of light-activatable HDACi.