Synthesis of D- and L-Selenomethionine Double-Labeled with Deuterium and Selenium-82

Abstract

Selenium has been recognized as an essential element of human nutrition. Various forms of selenium, such as selenite, selenate, selenocysteine and selenomethionine, can be utilized as nutritional sources. [1][2][3][4] Since selenomethionine is more effective and less toxic than inorganic selenium, synthetic selenomethionine or its enriched food sources are appropriate supplemental forms of selenium. David et al. 5) reported that some formula contained racemic selenomethionine. McAdam and Levander 6) showed little difference in the acute toxicity and nutritional bioavailability between D-and L-selenomethionine in rats and suggested that D-selenomethionine might be converted into the L-enantiomer. L-Selenomethionine is transformed to L-selenohomocysteine, similarly to the de-methylation pathway for L-methionine to Lhomocysteine. Then, L-selenohomocysteine is re-methylated to reform L-selenomethionine, or condensed with L-serine to form L-selenocystathionine, which is transformed to L-selenocysteine. However, little information is available on the metabolic fate of D-selenomethionine, especially conversion of D-selenomethionine into the L-enantiomer.In our previous study, the use of stable isotope labeled D-methionine and the stereoselective gas chromatographymass spectrometry-selected ion monitoring (GC-MS-SIM) method 7) proved to be a powerful methodology for examining the pharmacokinetic behavior of exogenously administered D-methionine and for studying the conversion of D-methionine into the L-enantiomer. We have shown that almost all Dmethionine exogenously administered were converted into the L-enantiomer in rats. 8)We have initiated studies to characterize the pharmacokinetic behavior of selenomethionine enantiomers by the stable isotope methodology. Successful application of the methodology to the metabolic investigation is dependent upon the availability of compounds labeled at predesigned positions. The present paper describes the preparation of optically pure D-and L-selenomethionine double-labeled with three deuteriums and 82 Se. Results and DiscussionConvenient synthetic routes to selenomethionine labeled on selenium 9-11) or methyl group 12) have been published, but the synthesis of deuterium and 82 Se double-labeled selenomethionine has not been reported. With few exceptions, the synthesis of Se-labeled selenomethionine had been achieved by treating 2-amino-4-bromobutanoic acid with a labeled lithium methaneselenolate.The synthetic route to D-and L-[ 2 H 3 , 82 Se]selenomethionine is illustrated in Chart 1. 2-Amino-4-bromobutanoic acid, a key intermediate in this synthesis, was obtained by either ring opening of 2-amino-4-butyrolactone (homoserine lactone) with HBr 13) or bromination of 2-amino-4-hydroxybutanoic acid (homoserine) with HBr in AcOH. 14) We have synthesized (R)-2-amino-4-hydroxybutanoic acid (2a) from commercially available D-homoserine lactone (1a) yielding Pharmacy and Life Sciences; 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan: and c Research Institute for Cultural Sc...