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

本研究旨在寻找新的神经营养天然产物，合成和厚朴酚、新维菌素和达拉米丁三种已知活性化合物，并阐明其神经营养机制。结果如下：(1)用PC-12细胞筛选天然产物，发现了5个新的活性化合物，其中一个是含有过氧物的麦角甾醇。该化合物不仅能显著促进PC12突起的生长，而且在原代培养的大鼠皮质神经元上具有神经营养活性。通过钯催化铃木-宫浦交叉偶联反应合成和厚朴酚。对神经营养活性至关重要的结构单元已经被确定。在发光基团(7-MCA或NbD)的3‘-位上连接的几个荧光衍生物是合成的…更大的大小，然后研究使用它们的神经元的分布。结果发现，荧光衍生物穿透神经元，并集中在与轴突的连接区。和厚朴酚与荧光衍生物之间的竞争实验表明，和厚朴酚的荧光衍生物很可能与和厚朴酚在神经元中的同一位置相互作用。这些结果表明和厚朴酚可以穿透神经元并与某些特定的蛋白质如酶相互作用。(3)通过不对称Evans反应、立体选择性氢化反应和高度可控的Firedel-Craft芳基化反应完成了他劳米丁的对映选择性合成。这一合成确定了(2S，3S，4S，5S)-塔拉米丁的绝对构型，并使我们能够合成其构效关系可能的立体异构体。(4)将串联的钯催化的Heck和Trost反应应用于双烯体系，发展了具有四氢呋喃环的环己烷环核的结构。这一新方法将用于合成新维菌素。较少

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