Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 S. Wood Street, Chicago, IL 60612-7211, USA.
ChemMedChem. 2012 Mar 5;7(3):425-39. doi: 10.1002/cmdc.201100522. Epub 2012 Jan 10.
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 α 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.
基于巯基乙酰胺的配体被设计为一种新型组蛋白去乙酰化酶（HDAC）抑制剂，可能用于治疗神经退行性疾病。这些化合物的硫醇基团为与催化锌离子相互作用提供了关键结合元素，因此与更常用的基于羟肟酸的锌结合基团不同。本文介绍了一些取代的巯基乙酰胺的化学和生物学性质，旨在提高 HDAC6 同工型选择性，同时保持与羟肟酸类似物相似的活性。我们发现，将手性中心引入到硫醇基团中会对 HDAC 抑制剂的活性产生重大影响。这些新化合物还在应激诱导的神经元损伤的体外模型中进行了其治疗潜力的研究，结果发现它们是无毒的神经保护剂。
