A series of nine L-2,4-syn-4-alkylglutamic acid analogues (1a-i) were synthesized in high yield and high enantiomeric excess (>99% ee) from their corresponding 4-substituted ketoglutaric acids (2a-i), using the enzyme aspartate aminotransferase (AAT) from pig heart or E. coli. The synthesized compounds were evaluated as potential ligands for the glutamate transporters EAAT1, EAAT2, and EAAT3 (excitatory amino acid transporter, subtypes 1-3) in the FLIPR membrane potential (FMP) assay. We found a distinct change in the pharmacological profile when the 4-methyl group (compound 1a, an EAAT1 substrate and EAAT2,3 inhibitor) was extended to a 4-ethyl group, compound 1b, as this analogue is an inhibitor at all three subtypes, EAAT1-3. Furthermore, we conclude that both large and bulky hydrophobic substituents in the 4-position of L-2,4-syn Glu are allowed by all three glutamate transporter subtypes EAAT1-3 while maintaining inhibitory activity.

( S)-Glutamic acid (Glu) is the major excitatory neurotransmitter in the central nervous system (CNS) activating the plethora of ionotropic Glu receptors (iGluRs) and metabotropic Glu receptors (mGluRs). In this paper, we present a chemo-enzymatic strategy for the enantioselective synthesis of five new Glu analogues 2a- f ( 2d is exempt) holding a functionalized substituent in the 4-position. Nine Glu analogues 2a- j are characterized pharmacologically at native 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA), kainic acid (KA), and N-methyl- d-aspartic acid (NMDA) receptors in rat synaptosomes as well as in binding assays at cloned rat iGluR5-7 subtypes. A detailed in silico study address as to why 2h is a high-affinity ligand at iGluR5-7 ( K i = 3.81, 123, 57.3 nM, respectively), while 2e is only a high affinity ligand at iGluR5 ( K i = 42.8 nM). Furthermore, a small series of commercially available iGluR ligands are characterized in iGluR5-7 binding.

4-Hydroxy-2,5-dimethyl-3(2H)-furanone (HDMF) production by Zygosaccharomyces rouxii was studied under various culture conditions. Among the precursors added, D-fructose 1,6-bisphosphate was the best. Aerobic conditions led to a higher HDMF level, and the concentration of the added D-fructose 1,6-bisphosphate up to 10% increased HDMF production; HDMF biosynthesis then decreased and was strongly inhibited by 20% of D-fructose 1,6-bisphosphate. HDMF was produced by Z. rouxii during the growth phase and the stationary phase. This microbiological method enabled the biosynthesis of "natural" HDMF at 100 ppm.

Dihydroxyacetone phosphate (DHAP, 7) and bromoacetol phosphate (BAP, 6) were synthesized in four and five steps, respectively, starting from 1,3-dibromoacetone (2). The key step involves desymetrization and ketone protection of 2 to prepare alcohol 3. Phosphorylation of 3 followed by hydrogenolysis and then deprotection of the ketal function afforded 6. A solution of 7 was prepared after treatment of 6 with NaOH. This original route allows a short and convenient preparation of DHAP in large scale and high purity for application to the synthesis of sugar derivatives and preparation of BAP for triosephosphate isomerase inhibition.