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Structure Determination, Synthesis and Biological Activity of Neuroactive Compounds

神经活性化合物的结构测定、合成及生物活性

基本信息

批准号：
07458145
负责人：
SHIRAHAMA Haruhisa
金额：
$ 4.74万
依托单位：
Kwansei Gakuin University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1997
项目状态：
已结题

项目摘要

1. Acromelic acid : Non-protein amino acid isolated from a poisonous mushroom by the author. It is an extraordinary excitatory compound to the glutamate receptor of a neuron.To study the glutamate trceptor, use of this acid as a reagent is desired and so we developed several methods to synthesize this acid. This time further development of the synthetic method was performed. (1) An analog was synthesized by a newly developed method. The key step contains the reaction of malonic ester radical and 4-phenyl-3-dehydroproline which was furnished from 4-hydroxplorine. A phenyl kainoid was obtained through 10 steps with 12% overall yield. (2) Depolarizing activity of kainoid depends on the existence of unsaturated system in C-4 side chain. In order to study the conformation of this side chain, we synthesized a bicyclic kainoid whose acetic acid residue linked to the methyl of isopropenyl group. In this compound the unsaturated system and the pyrrolidine ring plane are almost in the same plane. Notable decrease in their activity shows that the plane of the unsaturated system must be at right angle to pyrrolidine plane to exhibit strong activity. (3) To study a role of pyrrolidine ring in the kainoid activity, we synthesized acyclic kainoids which are derived by elimination of the C-5 carbon. Notable decrease in their activity means that an adequate arrangement of the kainoid conformation are made by pyrrolidine ring. (4) A rule deducing the configuration of kainoid by NMR-chemical shifts was developed. The mechanism of the reaction which was the key reaction in the previously developed synthetic method of kainoid was revealed.2. Gymnopilin, a nerve toxin isolated from poisonous mushroom by us, is a chiral HMGA ester. In order to synthesize a chiral HMGA ester from the achiral HMGA, a new synthetic method of a chiral beta-lactone of HMGA as a new reagent was developed.

1. Acromelic Acid ：作者从有毒蘑菇中分离出来的非蛋白质氨基酸。它是一种对神经元谷氨酸受体具有非凡兴奋性的化合物。为了研究谷氨酸受体，需要使用这种酸作为试剂，因此我们开发了几种合成这种酸的方法。这次对合成方法进行了进一步的开发。 (1)通过新开发的方法合成了类似物。关键步骤是丙二酸酯自由基与4-羟基脯氨酸生成4-苯基-3-脱氢脯氨酸的反应。经过 10 个步骤得到了苯基类红蛋白，总产率为 12%。 (2)类红蛋白的去极化活性取决于C-4侧链不饱和体系的存在。为了研究该侧链的构象，我们合成了一种双环类胡萝卜素，其乙酸残基与异丙烯基的甲基相连。在该化合物中，不饱和体系和吡咯烷环平面几乎在同一平面上。它们的活性显着降低表明不饱和体系的平面必须与吡咯烷平面成直角才能表现出强活性。 (3)为了研究吡咯烷环在类红蛋白活性中的作用，我们合成了通过消除C-5碳衍生的无环类红蛋白。其活性显着降低意味着类胡萝卜素构象的充分排列是由吡咯烷环形成的。 (4) 建立了通过核磁共振化学位移推导类红蛋白构型的规则。揭示了该反应的机理，是先前开发的类红蛋白合成方法中的关键反应。 2． Gymnopilin 是我们从毒蘑菇中分离得到的一种神经毒素，是一种手性 HMGA 酯。为了从非手性HMGA合成手性HMGA酯，开发了一种新试剂HMGA手性β-内酯的合成新方法。