滇产黄皮属植物抗单胺氧化酶活性分子的发现及机制研究

Major Depressive Disorder (MDD), Parkinson's disease (PD) and Alzheimer's disease(AD) are the most common neurological diseases. There are no treatments that can prevent, delay, slow or stop their progression. Patients with these diseases are unknown etiology and pathogenesis is complex, the activity of monoamine oxidase (MAO) is abnormalities in the body. MAO is a FAD-containing enzyme with two known isoforms (MAO-A and MAO-B) and is present in the mitochondrial outer membrane of glial, neuronal and other cells. MAO enzymes have essential roles in vital physiological processes and are involved in the pathogenesis of various human diseases. This enzymatic function increases the synaptic concentration of these neurotransmitters and conditions to a great extent the neurone's excitement of those possessing receptors for these mediators. Therefore, MAOs have received an extensive attraction on developing new drugs as targets. The MAO inhibitors(iMAOs) are a class of compounds that act by blocking the MAO enzymatic action, being used by several years in the treatment of the depression and anxiety diseases (iMAO-A) or in PD (iMAO-B). Nowadays is being studied also in AD. Some coumarins, in particular 7-Hydroxycoumarins had been previously described as monoamine oxidase inhibitors from natural products. The plants of the genus Clausena (Rutaceae) are rich in different 7-Hydroxycoumarins. Our previous researchers on the genus Clausena anisum-olens revealed that the EtOAc fraction displayed strong inhibit activity against MAO. In this project, systemic phytochemical research will be carried out on three plants of Clausena collected from Yunnan Province, base on our previous study. By studying their inhibition on the monoamine oxidase, efforts aimed at discovering the new inhibitors of MAOs, giving the relationship between structure and function of active lead compounds, and finding the binding site with the MAOs.

抑郁症（MDD）、帕金森氏综合症（PD）、阿尔茨海默病（AD）等疾病带来严重的社会和家庭问题。这些疾病病因不明，发病机理复杂，患者体内单胺氧化酶(MAO)的活性异常。MAO是催化包括体内单胺神经传递物质以及神经毒素等生物活性单胺的一种线粒体膜复合酶，对于中枢神经系统和外周组织中作用于神经和心血管的胺类代谢起重要作用，是治疗上述疾病的重要靶点。单胺氧化酶抑制剂(MAOIs)是控制MAO异常、治疗上述疾病的临床用药。7-氧代香豆素是一类源自天然的重要MAOIs，黄皮属植物含有结构多样的该类香豆素，我们前期研究表明细叶黄皮提取物显示了较强的MAO 抑制活性。申请者拟对3种具有代表性黄皮属植物的化学成分进行研究，研究其抑制MAO活性的化学物质基础，找出高活性成分，结合构效关系研究、探讨作用机理，为发现具有抑制MAO活性的新型分子及化学结构规律，开发特异性可逆MAOIs药作基础性研究工作。

人口老化是 21 世纪人类面临的主要难题。与衰老有关的疾病，逐渐成为人类健康的大敌和社会繁荣的沉重负担。抑郁症、帕金森氏综合症、阿尔茨海默病等疾病带来严重的社会和家庭问题。单胺氧化酶是治疗抑郁症、帕金森以及老年痴呆等疾病的重要靶点。单胺氧化酶抑制剂(MAOIs)是控制 MAO 异常、治疗上述疾病的临床用药。我们前期研究表明细叶黄皮提取物显示了较强的 MAO 抑制活性。项目通过对 滇产3 种芸香科黄皮属植物细叶黄皮、黄皮和毛叶黄皮化学成分的系统研究，采用各种色谱手段和现代波谱技术，从三种植物中共分离鉴定了 150 个化合物，其中包括 35个新化合物。化合物类型涉及到香豆素、咔吧唑生物碱、环肽、吲哚生物碱、苯丙素及其苷、倍半萜及其苷、二降倍半萜及其苷、黄酮、黄酮醇、黄酮苷、甾体、酚性化合物、长链烷烃及脂肪酸等，为合理开发利用黄皮属植物资源提供了化学物质基础。从细叶黄皮中发现自然界 首个萜基侧链带有乙酰胺单元的新奇香豆素，由于乙酰胺单元的引入，使得该类单萜基香豆素侧链不符合异戊二烯规则，成为单萜基香豆素的一个特例。从黄皮属中首次发现了天然环肽类化合物的存在，进一步优化了黄皮属天然环肽类化合物的快速识别方法。提出黄皮属植物所蕴含的环肽类成分表现出其独有特征，具有氨基酸单元高度重复的独特性而区别于其他科属植物环肽的特点；环肽类成分可以作为黄皮属植物的重要特征化合物之一，为黄皮属植物的化学分类学提出了新的化学佐证。对所分离的化学成分重点开展了单胺氧化酶抑制、抗肿瘤、抗HIV等体外活性评价，从中发现了具有较好单胺氧化酶抑制和抗HIV活性的分子。首次发现新奇香豆素Anisucoumaramide具有较好的单胺氧化酶抑制活性，为新型的低毒高效的单胺氧化酶抑制剂的发现提供了天然的化学模版，有可能作为单胺氧化酶抑制剂或是单胺氧化酶抑制剂的先导化合物。活性化合物的发现，有助于阐明黄皮属源植物的药效学基础，为深入研究和开发利用黄皮属植物奠定了科学基础。