Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK.
Department of Oncology, Oxford Institute for Radiation Oncology, University of Oxford, Oxford, OX3 7DQ, UK.
ChemMedChem. 2021 Dec 14;16(24):3691-3700. doi: 10.1002/cmdc.202100403. Epub 2021 Jul 29.
We report the synthesis and biological evaluation of a light-activated (caged) prodrug of the KDAC inhibitor panobinostat (Zap-Pano). We demonstrate that addition of the 4,5-dimethoxy-2-nitrobenzyl group to the hydroxamic acid oxygen results in an inactive prodrug. In two cancer cell lines we show that photolysis of this compound releases panobinostat and an unexpected carboxamide analogue of panobinostat. Photolysis of Zap-Pano causes an increase in H3K9Ac and H3K18Ac, consistent with KDAC inhibition, in an oesophageal cancer cell line (OE21). Irradiation of OE21 cells in the presence of Zap-Pano results in apoptotic cell death. This compound is a useful research tool, allowing spatial and temporal control over release of panobinostat.
我们报告了一种光激活（笼蔽）前药的合成和生物学评价，该前药是 KDAC 抑制剂帕比司他（Zap-Pano）的前药。我们证明，将 4,5-二甲氧基-2-硝基苄基添加到羟肟酸氧上会导致前药失活。在两种癌细胞系中，我们表明该化合物的光解释放出帕比司他和一种意想不到的帕比司他的羧酰胺类似物。Zap-Pano 的光解导致食管癌细胞系（OE21）中 H3K9Ac 和 H3K18Ac 的增加，与 KDAC 抑制一致。在 Zap-Pano 存在的情况下辐照 OE21 细胞会导致细胞凋亡。该化合物是一种有用的研究工具，允许对帕比司他的释放进行空间和时间控制。
