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

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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.