Analysis of Target Molecular and Preparation of Molecular Probes for Neurotrophic Low-Molecular Natural Products

本研究项目旨在寻找新的神经营养天然产物，合成已知的三种活性化合物：厚朴酚、新维布素和他劳米定，并阐明其神经营养机制。得到了以下结果：(1)利用pc12细胞筛选天然产物，发现了5种新的活性化合物，其中一种是含内过氧化物的麦角甾醇。该化合物不仅显著促进pc12的神经突生长，而且在原代培养的大鼠皮质神经元中表现出神经营养活性。另外从三叶草中分离出四种新维菌素作为神经营养物质。(2)以钯催化Suzuki-Miyaura交叉偶联为关键反应合成了本木酚。对神经营养活动至关重要的结构单元已被确定。合成了3'位发光基团（7-MCA或NBD）上的几种荧光衍生物，并对其在神经元中的分布进行了研究。因此，发现荧光衍生物渗透到神经元并集中在与神经突的连接区域。与荧光衍生物的竞争实验表明，荧光衍生物可能在神经元的同一位点与之相互作用。这些结果表明，厚朴酚可以渗透到神经元中，并与某些特定的蛋白质（如酶）相互作用。(3) talaumidin的对映选择性合成通过不对称Evans方案、立体选择性硼氢化和高度可控的Firedel-Crafts芳基化完成。该合成得到了(2S,3S,4S,5S)-talaumidin的绝对构型，并制备了其可能的构效关系立体异构体。(4)将pd催化的Heck和Trost串联反应应用于二烯体系，建立了环己烷环芯与四氢呋喃环融合的结构。该方法将用于新维菌素的合成。少

This research project has been carried out aiming at search for new neurotrophic natural products and synthesis of the three known active compounds, honokiol, neovibsanin an talaumidin as well as for clarifying their neurotrophic mechanism. The following results have been obtained.(1)Screening natural products by using PC 12 cells has resulted in the discovery of five new active compounds, one of which is an ergosterol bearing an endoperoxide. This compound not only promotes significantly neurite outgrowth of PC 12, but also exhibits neurotrophic activity in the primary cultured rat cortical neurons. Another four neovibsanins have been isolated as neurotrophic substances from Viburnum sieboldii.(2)Honokiol has been synthesized by palladium-catalyzed Suzuki-Miyaura cross coupling as a key reaction. The structure units that are essential for neurotrophic activity have been identified. Several fluorescent derivatives attached to luminous groups (7-MCA or NBD) at the 3'-position were synth … More esized and then the distribution in neurons using them was investigated. Consequently, it was found that the fluorescent derivatives penetrated into the neuron and concentrated on the connecting region to the neurite. The competitive experiment between honokiol and the fluorescent derivatives suggest that the fluorescent derivatives of honokiol are likely to interact at the same site in the neurons as honokiol. These results indicate that honokiol can penetrate into the neuron and interacts at some specific proteins such as the enzyme.(3)The enantioselective synthesis of talaumidin has been accomplished by asymmetric Evans protocol, stereoselective hydroboration and highly controlled Firedel-Crafts arylation. This synthesis led to the conclusion of the absolute configuration of (2S,3S,4S,5S)-talaumidin, and allowed us to prepare its possible stereoisomers for structure-activity relationship.(4)Applying tandem Pd-catalyzed Heck and Trost reactions towards a diene system has developed the construction of the cyclohexane ring core fused with a tetrahydrofuran ring. This new methodology will be used for synthesis of neovibsanins. Less