Abstract：
With the intensive research on the pathogenesis of Alzheimer\'s disease (AD), inhibition of HDAC6 appears to be a potential therapeutic approach for AD. In this paper, a series of tetrahydro-β-carboline derivatives with hydroxamic acid group were fast synthesized. Among all, the most potent 15 selectively inhibited HDAC6 with IC50 of 15.2 nM and markedly increased acetylated alpha-tubulin levels. In cellular assay, 15 showed excellent neurotrophic effect by increasing the expression of GAP43 and Beta-3 tubulin markers. Besides, 15 showed neuroprotective effects in PC12 or SH-SY5Y cells against H2O2 and 6-OHDA injury through activation of Nrf2, catalase and Prx II, and significantly reduced H2O2-induced reactive oxygen species (ROS) production. In vivo, 15 significantly attenuated zebrafish anxiety-like behaviour and memory deficits in a SCOP-induced zebrafish model of AD. To sum up, multifunctional 15 might be a good lead to develop novel tetrahydrocarboline-based agents for the treatment of AD.
摘要：
随着对阿尔茨海默病(AD)发病机制的深入研究,抑制HDAC6似乎是AD的潜在治疗方法.在本文中,快速合成了一系列具有异羟肟酸基团的四氢-β-咔啉衍生物。其中,最有效的15选择性抑制HDAC6,IC50为15.2nM,并显著增加乙酰化α-微管蛋白水平.在细胞测定中，图15通过增加GAP43和β-3微管蛋白标记的表达显示出优异的神经营养效果。此外,图15显示PC12或SH-SY5Y细胞通过激活Nrf2，过氧化氢酶和PrxII对H2O2和6-OHDA损伤的神经保护作用，并显着降低H2O2诱导的活性氧（ROS）的产生。在体内,在SCOP诱导的AD斑马鱼模型中，斑马鱼的焦虑样行为和记忆缺陷显着减弱。总而言之,多功能15可能是开发基于四氢咔啉的新型药物治疗AD的良好线索。
