Hosseini Razieh, Moosavi Fatemeh, Rajaian Hamid, Silva Tiago, Magalhães E Silva Diogo, Soares Pedro, Saso Luciano, Edraki Najmeh, Miri Ramin, Borges Fernanda, Firuzi Omidreza
Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
Department of Pharmacology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran.
Chem Biol Drug Des. 2016 Dec;88(6):926-937. doi: 10.1111/cbdd.12829. Epub 2016 Sep 9.
The number of people affected by neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease is rapidly increasing owing to the global increase in life expectancy. Small molecules with neurotrophic effects have great potential for management of these neurological disorders. In this study, different (C1-C12) alkyl ester derivatives of hydroxycinnamic acids (HCAs) were synthesized (a total of 30 compounds). The neurotrophic capacity of the test compounds was examined by measuring promotion of survival in serum-deprived conditions and enhancement of nerve growth factor (NGF)-induced neurite outgrowth in PC12 neuronal cells. p-Coumaric, ferulic, and sinapic acids and their esters did not alter cell survival, while caffeic acid and all its alkyl esters, especially decyl and dodecyl caffeate, significantly promoted neuronal survival at 25 μm. Methyl, ethyl, propyl, and butyl caffeate esters also significantly enhanced NGF-induced neurite outgrowth, among which the most effective ones were propyl and butyl esters, which at 5 μm led to 25- and 22-fold increases in the number of neurites, respectively. The findings of the docking study suggested phosphatidylinositol 3-kinase (PI3K) as the potential molecular target. In conclusion, our findings demonstrate that alkyl esters of caffeic acid can be useful as scaffolds for the discovery of therapeutic agents for neurodegenerative diseases.
由于全球预期寿命的增加，受阿尔茨海默病和帕金森病等神经退行性疾病影响的人数正在迅速增加。具有神经营养作用的小分子在治疗这些神经疾病方面具有巨大潜力。在本研究中，合成了不同的（C1-C12）羟基肉桂酸（HCA）烷基酯衍生物（共30种化合物）。通过测量血清剥夺条件下的细胞存活促进情况以及神经生长因子（NGF）诱导的PC12神经元细胞神经突生长增强情况，来检测受试化合物的神经营养能力。对香豆酸、阿魏酸和芥子酸及其酯类不改变细胞存活情况，而咖啡酸及其所有烷基酯，尤其是癸基和十二烷基咖啡酸酯，在25μm时能显著促进神经元存活。甲基、乙基、丙基和丁基咖啡酸酯也能显著增强NGF诱导的神经突生长，其中最有效的是丙基和丁基酯，在5μm时分别使神经突数量增加25倍和22倍。对接研究结果表明磷脂酰肌醇3激酶（PI3K）是潜在的分子靶点。总之，我们的研究结果表明，咖啡酸烷基酯可作为发现神经退行性疾病治疗药物的骨架。
