He Li, Du Jing-Jing, Zhou Jun-Jie, Chen Meng-Ting, Luo Lu, Li Bao-Qiong, Zhang Xiang-Zhi, Ma Wen-Zhe, Ma Ai-Jun, Feng Na
School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, China.
State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
Front Chem. 2022 Jun 8;10:918116. doi: 10.3389/fchem.2022.918116. eCollection 2022.
Melatonin (MT) is a hormone with antioxidant activity secreted by the pineal gland in the human brain, which is highly efficient in scavenging free radicals and plays an important role in the neuro-immuno-endocrine system. Emerging evidence showed that MT supplementation was a potential therapeutic strategy for Parkinson's disease (PD), which inhibits pathways associated with oxidative stress in PD. In this study, we reported a C7-selective olefination of melatonin under rhodium catalysis with the aid of P-directing groups and synthesized 10 new melatonin-C7-cinnamic acid derivatives (6a-6j). The antioxidant potential of the compounds was evaluated both by ABTS and ORAC methods. Among these newly synthesized melatonin derivatives, 6a showed significantly higher activity than MT at 10 M. In the transgenic model of PD, 6a significantly reduces alpha-synuclein aggregation and dopaminergic neuronal damage in nematodes while reducing intracellular ROS levels and recovers behavioral dysfunction induced by dopaminergic neurodegeneration. Further study of the mechanism of action of this compound can provide new therapeutic ideas and treatment strategies for PD.
褪黑素（MT）是一种由人脑松果体分泌的具有抗氧化活性的激素，它在清除自由基方面效率很高，并且在神经-免疫-内分泌系统中发挥重要作用。新出现的证据表明，补充褪黑素是帕金森病（PD）的一种潜在治疗策略，它能抑制与PD中氧化应激相关的途径。在本研究中，我们报道了在磷导向基团的辅助下，铑催化的褪黑素C7选择性烯化反应，并合成了10种新的褪黑素-C7-肉桂酸衍生物（6a-6j）。通过ABTS法和ORAC法评估了这些化合物的抗氧化潜力。在这些新合成的褪黑素衍生物中，6a在10 μM时显示出比MT显著更高的活性。在PD转基因模型中，6a显著减少线虫体内α-突触核蛋白聚集和多巴胺能神经元损伤，同时降低细胞内活性氧水平，并恢复由多巴胺能神经变性引起的行为功能障碍。对该化合物作用机制的进一步研究可为PD提供新的治疗思路和治疗策略。
