Kozikowski Alan P, Chen Yufeng, Gaysin Arsen, Chen Bin, D'Annibale Melissa A, Suto Carla M, Langley Brett C
Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, USA.
J Med Chem. 2007 Jun 28;50(13):3054-61. doi: 10.1021/jm070178x. Epub 2007 Jun 1.
We compare the ability of two structurally different classes of epigenetic modulators, namely, histone deacetylase (HDAC) inhibitors containing either a hydroxamate or a mercaptoacetamide as the zinc binding group, to protect cortical neurons in culture from oxidative stress-induced death. This study reveals that some of the mercaptoacetamide-based HDAC inhibitors are fully protective, whereas the hydroxamates show toxicity at higher concentrations. Our present results appear to be consistent with the possibility that the mercaptoacetamide-based HDAC inhibitors interact with a different subset of the HDAC isozymes [less activity at HDAC1 and 2 correlates with less inhibitor toxicity], or alternatively, are interacting selectively with only the cytoplasmic HDACs that are crucial for protection from oxidative stress.
我们比较了两类结构不同的表观遗传调节剂，即分别含有异羟肟酸酯或巯基乙酰胺作为锌结合基团的组蛋白脱乙酰酶（HDAC）抑制剂，对培养的皮质神经元免受氧化应激诱导死亡的保护能力。这项研究表明，一些基于巯基乙酰胺的HDAC抑制剂具有完全的保护作用，而异羟肟酸酯在较高浓度时表现出毒性。我们目前的结果似乎与以下可能性一致：基于巯基乙酰胺的HDAC抑制剂与HDAC同工酶的不同亚群相互作用[HDAC1和2活性较低与抑制剂毒性较低相关]，或者，它们仅与对保护免受氧化应激至关重要的细胞质HDAC选择性相互作用。
