DESIGN AND SYNTHESIS OF NOVEL EXCITATORY AMINO ACIDS BASED ON THE TOTAL SYNTHESIS OF NATURAL NEE TROTOXTNS
基于天然NEE TROTOXTNS全合成的新型兴奋性氨基酸的设计与合成
基本信息
- 批准号:16201045
- 负责人:
- 金额:$ 23.63万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Scientific Research (A)
- 财政年份:2004
- 资助国家:日本
- 起止时间:2004 至 2006
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Naturally occurring neurotoxins possess polar functional groups in their structures corresponding to those of internal ligands of receptors, ion channels, and enzymes. These functional groups bind to these proteins through ionic or hygrogen bondings. In this research, we investigated the synthesis of neurotoxic natural products, kaitocephalin, an antagonist of ionotropic glutamate receptors, and 5,6,11-trideoxytetrodotoxin, a congener of tetrodotoxin family which is a potent Na+ channel blocker, and novel squaric acid-containing glutamate analogs. The total syntheses of kaitocephalin and 5, 6, 11-trideoxytetrodotoxin were achieved by the stereoselective construction of the quarternary carbon center using an asymmetric version of the Strecker synthesis, and subsequent assembly of the requisite multi-functional groups. The C7 and C9 diastereomers of kaitocephalin were also synthesized and subjected to SAR studies. The 13C-labelled 5, 6, 11-trideoxytetrodotoxin was also synthesized to exploit the biosynthetic pathway of tetrodotoxin as well as to elucidate molecular functions of the Na+ channel. Since squaric acid can be viewed as an equivalent of carboxylic acid, this group was incorporated into L-glutamate instead of its C1 or C5 carboxyl group. Among several squaryl glutamates synthesized in this study, it was found that a sulfur-linked analog exhibited potent and selective activity to kainic acid (KA) subtype receptors, suggesting that the squaryl group-containing glutamate analogs can be used as a useful tool to investigate glutamate receptors.
自然产生的神经毒素在其结构中具有与受体、离子通道和酶的内部配体相对应的极性官能团。这些官能团通过离子或氢键与这些蛋白质结合。在这项研究中,我们研究了神经毒性天然产物的合成,kaitocephalin,一种嗜离子性谷氨酸受体拮抗剂,5,6,11-三脱氧河豚毒素,河豚毒素家族的同属物,是一种有效的Na+通道阻滞剂,以及新型的含方酸的谷氨酸类似物。采用不对称的Strecker合成方法,通过立体选择性构建季碳中心,然后组装所需的多官能团,实现了kaitocephalin和5,6,11 -trideoxytetrodotoxin的全合成。本文还合成了海头素的C7和C9非对映体,并对其进行了SAR研究。合成了13c标记的5,6,11 -三脱氧河豚毒素,以探索河豚毒素的生物合成途径,并阐明Na+通道的分子功能。由于方酸可以被看作是羧酸的等价物,所以这个基团被并入l -谷氨酸而不是它的C1或C5羧基。在本研究合成的几种角鲨基谷氨酸中,发现硫连接类似物对kainic acid (KA)亚型受体表现出有效的选择性活性,表明含角鲨基谷氨酸类似物可作为研究谷氨酸受体的有用工具。
项目成果
期刊论文数量(113)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Application of modular nucleophilic glycine equivalents for truly practical asymmetric synthesis of β-substituted pyroglutamic acids
- DOI:10.1016/j.tetlet.2004.12.093
- 发表时间:2005-02
- 期刊:
- 影响因子:1.8
- 作者:V. Soloshonok;Hisanori Ueki;Trevor K. Ellis;Takeshi Yamada;Y. Ohfune
- 通讯作者:V. Soloshonok;Hisanori Ueki;Trevor K. Ellis;Takeshi Yamada;Y. Ohfune
Ester-Enolate Claisen Rearrangement of Proline-Containing α-Acyloxy-α-vinylsilane. Synthesis of Pyrrolidine-fused Glutamate Anlogs
含脯氨酸的 α-酰氧基-α-乙烯基硅烷的酯烯醇克莱森重排合成吡咯烷融合的谷氨酸类似物。
- DOI:
- 发表时间:2007
- 期刊:
- 影响因子:0
- 作者:K. Sakaguchi;M. Yamamoto;Y. Watanabe;and Y;Ohfune
- 通讯作者:Ohfune
Recent Progress on Squaric Acid Research in Bioorganic Fields
方酸在生物有机领域的研究最新进展
- DOI:
- 发表时间:2007
- 期刊:
- 影响因子:0
- 作者:T. Shinada;T. Ishida;and Y. Ohfune
- 通讯作者:and Y. Ohfune
Micheal Addition Reactions Between Chiral Equivalents of a Nucleophilic Glycine and (5)-or (R)-4-phenyl-1,3-oxazolidin-2-ones. General method for Efficiewnt Preparation of (3-Substituted Pyroglutamic Acids. Cases of Topographically Controlled Stereoselect
亲核甘氨酸的手性等价物与 (5)-或 (R)-4-苯基-1,3-恶唑烷-2-酮之间的迈克尔加成反应。
- DOI:
- 发表时间:2005
- 期刊:
- 影响因子:0
- 作者:V. Soloshonok;C. Cai;T. Yamada;H. Ueki;Y. Ohfune;V. J. Hruby
- 通讯作者:V. J. Hruby
Operationally convenient, efficient asymmetric synthesis of enantiomerically pure 4-aminoglutamic acids via methylene dimerization of chiral glycine equivalents with dichloromethane
- DOI:10.1016/j.tet.2006.04.023
- 发表时间:2006-06
- 期刊:
- 影响因子:2.1
- 作者:V. Soloshonok;Takeshi Yamada;Hisanori Ueki;A. Moore;Tanner K. Cook;Kelsey L. Arbogast;A. Soloshonok;Collin H. Martin;Y. Ohfune
- 通讯作者:V. Soloshonok;Takeshi Yamada;Hisanori Ueki;A. Moore;Tanner K. Cook;Kelsey L. Arbogast;A. Soloshonok;Collin H. Martin;Y. Ohfune
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