Chen Yufeng, He Rong, Chen Yihua, D'Annibale Melissa A, Langley Brett, Kozikowski Alan P
Drug Discovery Program, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood St., Chicago, IL 60612, USA.
ChemMedChem. 2009 May;4(5):842-52. doi: 10.1002/cmdc.200800461.
We compare three structurally different classes of histone deacetylase (HDAC) inhibitors that contain benzamide, hydroxamate, or thiol groups as the zinc binding group (ZBG) for their ability to protect cortical neurons in culture from cell death induced by oxidative stress. This study reveals that none of the benzamide-based HDAC inhibitors (HDACIs) provides any neuroprotection whatsoever, in distinct contrast to HDACIs that contain other ZBGs. Some of the sulfur-containing HDACIs, namely the thiols, thioesters, and disulfides present modest neuroprotective activity but show toxicity at higher concentrations. Taken together, these data demonstrate that the HDAC6-selective mercaptoacetamides that were reported previously provide the best protection in the homocysteic acid model of oxidative stress, thus further supporting their study in animal models of neurodegenerative diseases.
我们比较了三类结构不同的组蛋白脱乙酰酶（HDAC）抑制剂，它们分别含有苯甲酰胺、异羟肟酸或硫醇基团作为锌结合基团（ZBG），以研究其保护培养的皮质神经元免受氧化应激诱导的细胞死亡的能力。这项研究表明，与含有其他ZBG的HDAC抑制剂形成鲜明对比的是，基于苯甲酰胺的HDAC抑制剂（HDACIs）没有提供任何神经保护作用。一些含硫的HDACIs，即硫醇、硫酯和二硫化物，具有适度的神经保护活性，但在较高浓度下显示出毒性。综上所述，这些数据表明，先前报道的HDAC6选择性巯基乙酰胺在同型半胱氨酸氧化应激模型中提供了最佳保护，从而进一步支持了它们在神经退行性疾病动物模型中的研究。
