Chiral Mercaptoacetamides Display Enantioselective Inhibition of Histone Deacetylase 6 and Exhibit Neuroprotection in Cortical Neuron Models of Oxidative Stress
Chiral Mercaptoacetamides Display Enantioselective Inhibition of Histone Deacetylase 6 and Exhibit Neuroprotection in Cortical Neuron Models of Oxidative Stress
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DOI：
10.1002/cmdc.201100522
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发表时间：
2012-03-05
期刊：
影响因子：
3.4
通讯作者：
Kozikowski, Alan P.
中科院分区：
文献类型：
--
作者：
Kalin, Jay H.;Zhang, Hankun;Kozikowski, Alan P.
基于巯基乙酰胺的配体已被设计为一类新的组蛋白脱乙酰酶（HDAC）抑制剂，用于治疗神经退行性疾病。这些化合物的硫醇基团提供了与催化锌离子相互作用的关键结合元素，因此不同于更通常使用的基于异羟肟酸的锌结合基团。本文中，我们公开了一些取代的巯基乙酰胺的化学和生物学，目的是增加HDAC 6同种型选择性，同时保持与其异羟肟酸类似物类似的效力。发现将立构中心a引入巯基对HDAC抑制剂效力具有相当大的影响。这些新化合物也被描述为它们在应激诱导的神经元损伤的体外模型中的治疗潜力，并被发现作为无毒的神经保护剂。
Mercaptoacetamide-based ligands have been designed as a new class of histone deacetylase (HDAC) inhibitors for possible use in the treatment of neurodegenerative diseases. The thiol group of these compounds provides a key binding element for interaction with the catalytic zinc ion, and thus differs from the more typically employed hydroxamic acid based zinc binding groups. Herein we disclose the chemistry and biology of some substituted mercaptoacetamides with the intention of increasing HDAC6 isoform selectivity while maintaining potency similar to their hydroxamic acid analogues. The introduction of a stereocenter a to the thiol group was found to have a considerable impact on HDAC inhibitor potency. These new compounds were also profiled for their therapeutic potential in an in vitro model of stress-induced neuronal injury and were found to act as nontoxic neuroprotective agents.