Stereoselective chemoenzymatic synthesis of the four stereoisomers of l-2-(2-carboxycyclobutyl)glycine and pharmacological characterization at human excitatory amino acid transporter subtypes 1, 2, and 3.

doi:10.1021/JM060822S

Paper

Stereoselective chemoenzymatic synthesis of the four stereoisomers of l-2-(2-carboxycyclobutyl)glycine and pharmacological characterization at human excitatory amino acid transporter subtypes 1, 2, and 3.

Published Oct 4, 2006 · S. Faure, A. Jensen, Vincent Maurat

Journal of medicinal chemistry

Q1 SJR score

25

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1

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Abstract

The four stereoisomers of l-2-(2-carboxycyclobutyl)glycine, l-CBG-I, l-CBG-II, l-CBG-III, and l-CBG-IV, were synthesized in good yield and high enantiomeric excess, from the corresponding cis and trans-2-oxalylcyclobutanecarboxylic acids 5 and 6 using the enzymes aspartate aminotransferase (AAT) and branched chain aminotransferase (BCAT) from Escherichia coli. The four stereoisomeric compounds were evaluated as potential ligands for the human excitatory amino acid transporters, subtypes 1, 2, and 3 (EAAT1, EAAT2, and EAAT3) in the FLIPR membrane potential assay. While the one trans-stereoisomer, l-CBG-I, displayed weak substrate activity at all three transporters, EAAT1-3, we found a particular pharmacological profile for the other trans-stereoisomer, l-CBG-II, which displayed EAAT1 substrate activity and inhibitory activity at EAAT2 and EAAT3. Whereas l-CBG-III was found to be a weak inhibitor at all three EAAT subtypes, the other cis-stereoisomer l-CBG-IV was a moderately potent inhibitor with 20-30-fold preference for EAAT2/3 over EAAT1.

In Vitro Study

Study Snapshot

The four stereoisomers of l-2-(2-carboxycyclobutyl)glycine show distinct pharmacological profiles, with l-CBG-II showing substrate activity at EAAT1 and inhibitory activity at EAAT2, and l-CBG-IV showing moderate inhibitor

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Stereoselective chemoenzymatic synthesis of the four stereoisomers of l-2-(2-carboxycyclobutyl)glycine and pharmacological characterization at human excitatory amino acid transporter subtypes 1, 2, and 3.

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References

Citations

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This biocatalytic method enables the stereoselective synthesis of aromatic b-branched a-amino acids with high diastereo- and enantioselectivity, making it useful for drug development and cyclic fragment synthesis.

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Optimizing substrate and sensitizer triplet energies with LED wavelength and power can enable efficient and scalable photosensitized [2 + 2] cycloadditions in flow, with potential for industrial applications.

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