DESIGN AND SYNTHESIS OF NOVEL EXCITATORY AMINO ACIDS BASED ON THE TOTAL SYNTHESIS OF NATURAL NEE TROTOXTNS

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。

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.