Structural analogues of decarboxylated S-adenosyl-L-methionine (dc-SAM), product of the reaction catalyzed by S-adenosyl-L-methionine decarboxylase (SAM-DC), with modifications in the side-chain portion of the molecule have been synthesized, and their ability to inhibit SAM-DC has been investigated. Mainly, compounds with a nitrogen atom in place of the sulfur were investigated. The data from these inhibition studies have resulted in a delineation of the structural features required for binding on SAM-DC. It was concluded that a terminal primary amino group, a terminal carboxyl group, and the sulfonium functionality are not required for binding on SAM-DC. It was also found that analogues of dc-SAM in which replacement of the sulfur by nitrogen was the only modification were still able to form an azomethine with the enzyme. As found for SAM and dc-SAM, these compounds also caused a time-dependent inactivation of SAM-DC.

The syntheses of four derivatives of gamma-vinyl-GABA, in which vinylic hydrogen atoms were replaced by fluorine, are described. With use of 5-ethenyl-2-pyrrolidinone as starting material, the E and Z isomers of 4-amino-6-fluoro-5-hexenoic acid were prepared. The 6,6-difluoro and 5,6,6-trifluoro analogues could be synthesized from 4-oxobutanoic acid tert-butyl ester and (2,2-difluoroethenyl)- and (trifluoroethenyl)lithium correspondingly. The compounds were tested as inhibitors of GABA-T, and their in vitro and in vivo biochemistry is reported. The most active derivative was (Z)-4-amino-6-fluoro-5-hexenoic acid; the structure-activity relationship in the series is discussed.

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The asymmetric synthesis of a-substituted a-amino acids and propargylamines is described. As chiral auxiliary we used (S)-( -)-l-dimethoxymethyl-2-methoxymethylpyrrolidine (SDMP, I). Treatment of the amino acids or amines with SDMP 1 afforded the corresponding amidines C, which can be metalated and alkylated to yield the products D, which were hydrolyzed to give the desired a-substituted a-amino acids 20 and propargylamines 22. The method allows the enantio- In short we reported on the asymmetric synthesis of a-alkyl a-amino acids and amines with (S)-( -)-1 -dimethoxymethyl-2-methoxymethylpyrrolidine (SDMP, 1) as chiral auxiliary. Here we describe details on these experiments, The asymmetric synthesis of a-substituted a-amino 0cids3) has found increased interest recently4) due to their potential as therapeutically useful drugs. Although investigated to a lesser extent, the importance of the enantioselective synthesis of optically active nonproteinogenic arnines can be appraised under the same aspects.

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