Department of Chemistry and Chemical Biology, University of New Mexico, MSC03 2060, 1 University of New Mexico, Albuquerque, NM 87131, USA.
Department of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, MSC08 4670, Fitz Hall, Room 249, 1 University of New Mexico, Albuquerque, NM 87131, USA.
Eur J Med Chem. 2018 Jan 1;143:854-865. doi: 10.1016/j.ejmech.2017.11.048. Epub 2017 Nov 21.
Inflammation and oxidative stress are common in many chronic diseases. Targeting signaling pathways that contribute to these conditions may have therapeutic potential. The transcription factor Nrf2 is a major regulator of phase II detoxification and anti-oxidant genes as well as anti-inflammatory and neuroprotective genes. Nrf2 is widespread in the CNS and is recognized as an important regulator of brain inflammation. The natural product curcumin exhibits numerous biological activities including ability to induce the expression of Nrf2-dependent phase II and anti-oxidant enzymes. Curcumin has been examined in a number of clinical studies with limited success, mainly owing to limited bioavailability and rapid metabolism. Enone analogues of curcumin were examined with an Nrf2 reporter assay to identify Nrf2 activators. Analogues were separated into groups with a 7-carbon dienone spacer, as found in curcumin; a 5-carbon enone spacer with and without a ring; and a 3-carbon enone spacer. Activators of Nrf2 were found in all three groups, many of which were more active than curcumin. Dose-response studies demonstrated that a range of substituents on the aromatic rings of these enones influenced not only the sensitivity to activation, reflected in EC values, but also the extent of activation, which suggests that multiple mechanisms are involved in the activation of Nrf2 by these analogues.
炎症和氧化应激在许多慢性疾病中很常见。针对导致这些疾病的信号通路可能具有治疗潜力。转录因子 Nrf2 是 II 相解毒和抗氧化基因以及抗炎和神经保护基因的主要调节剂。Nrf2 在中枢神经系统中广泛存在，被认为是大脑炎症的重要调节剂。天然产物姜黄素具有许多生物活性，包括诱导 Nrf2 依赖性 II 相和抗氧化酶表达的能力。姜黄素已在多项临床研究中进行了检查，但收效甚微，主要是由于生物利用度有限和代谢迅速。用 Nrf2 报告基因测定法检查了姜黄素的烯酮类似物，以鉴定 Nrf2 激活剂。类似物分为三组，分别是姜黄素中发现的具有 7 个碳原子二烯酮间隔基的组；具有和不具有环的 5 个碳原子烯酮间隔基组；以及 3 个碳原子烯酮间隔基组。在所有三组中都发现了 Nrf2 的激活剂，其中许多比姜黄素更活跃。剂量反应研究表明，这些烯酮的芳环上的一系列取代基不仅影响激活的敏感性，反映在 EC 值中，而且还影响激活的程度，这表明这些类似物通过多种机制激活 Nrf2。
