天麻水提取物中抗神经退行性疾病活性成分的发现与研究

Neurodegenerantive disease, which is serious disease endangering human health, caused great burden to family and society. Current drugs can not meet the demand for effective security treating such diseases. In our preliminary studies, a detailed chemical study was conducted on the aqueous extract of G. elata rhizomes. Our previous studies on the extract led to the isolation of 80 compounds. A fraction mainly containing 4-glucopyranosyloxybenzyl citrates (total content of parishin and parishins B and C, > 50%) and the purified parishin and parishins B and C were active to improve the impaired memory in mice caused by scopolamine or cycloheximide. Additionally, the minor components polybenzyls and 4-hydroxybenzyl-substituted glutathione derivative were isolated and showed protective PC12 cell activities. The aqueous extract of G. elata would be fractioned by using a variety of chromatographic techniques, and the structures of compouds were determined by detailed spectroscopic methods. It is worth to discover and isolate the trace components and discuss the relationship with structure and activity of those active compounds and analogues, which maybe provide leading compounds to discover novel drugs of inhibitor of neurodegenerantive disease.

神经退行性疾病治疗药物需求巨大。本项目在前期确证传统常用中药天麻中除高含量成分派立辛类具有良好的抗神经退行性疾病，并发现天麻水提取物中的结构新颖的微量聚苄类和对羟基苄基取代谷胱甘肽类化合物也具有明显的PC12 细胞损伤保护作用的基础上，综合运用组合闪式色谱、HPLC 和各种填料的柱色谱，以及NMR 等高效分离和鉴定手段，通过活性跟踪继续对天麻水提取物中的低含量和微量化学成分，尤其是聚苄类和对羟基取代氨基酸或肽类化合物进行系统深入研究，并结合合成和结构衍生化，进一步研究讨论天麻活性成分结构及其抗神经退行性疾病功能的多样性和特点，为阐明天麻抗神经退行性疾病的药效物质和以其为先导结构的创新药物研究和开发奠定基础。

从疗效确切的常用中草药中发现具有抗神经退行性疾病作用的化学物质，是开发新型抗神经退行性疾病药物的重要基础和途径。从化学成分类型多样的传统中药天麻中寻找结构新颖、活性显著的化学成分，对阐明天麻抗神经退行性疾病的药效物质以及开发新型抗神经退行性疾病药物具有重要意义。该项目从天麻水提取物共分离并鉴定60个化合物，其中新化合物33个；合成了9个微量化合物，结构衍生化获得衍生物35个；放大量合成了PD候选物20C至200g级。经过药理活性评价，发现1个化合物对Cuprizone诱导的小鼠中枢神经系统的毒性脱髓鞘和血管痴呆大鼠具有明确的神经保护作用；确定了PD候选物20C对MPTP/p诱导的帕金森样小鼠的神经保护作用；5个化合物对醋酸致小鼠疼痛具有明确镇痛作用，部分化合物对Fe2+-半胱氨酸(Cys)诱导大鼠肝微粒体丙二醛(MDA)生成具有抑制作用。该项目预期目标均已完成，在天麻新型微量成分的结构、生源指导的活性化合物转化合成、活性特点和作用机制等方面，有重要学术意义；在基于天麻神经保护和镇痛活性成分的新型药物研究方面，有实际应用价值。部分研究结果在Chin. Chem. Lett.发表文章2篇，申请国内专利1项，获授权专利1项。