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

Sophie Faure; Anders A. Jensen; Vincent Maurat; Xin Gu; Emmanuelle Sagot; David J Aitken; Jean Bolte; Thierry Gefflaut; Lennart Bunch

doi:10.1021/jm060822s

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

Sophie Faure, Anders A. Jensen, Vincent Maurat, Xin Gu, Emmanuelle Sagot, David J Aitken, Jean Bolte, Thierry Gefflaut, Lennart Bunch

25 Citations (Scopus)

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.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	49
Issue number	22
Pages (from-to)	6532-8
Number of pages	7
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm060822s
Publication status	Published - 2006

Keywords

Catalysis
Chemistry, Physical
Cyclobutanes
Excitatory Amino Acid Transporter 1
Excitatory Amino Acid Transporter 3
Glutamate Plasma Membrane Transport Proteins
Glutamates
Glycine
Humans
Indicators and Reagents
Models, Molecular
Molecular Conformation
Physicochemical Phenomena
Stereoisomerism
Structure-Activity Relationship

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Faure, S., Jensen, A. A., Maurat, V., Gu, X., Sagot, E., Aitken, D. J., Bolte, J., Gefflaut, T., & Bunch, L. (2006). 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. Journal of Medicinal Chemistry, 49(22), 6532-8. https://doi.org/10.1021/jm060822s

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. / Faure, Sophie; Jensen, Anders A.; Maurat, Vincent et al.

In: Journal of Medicinal Chemistry, Vol. 49, No. 22, 2006, p. 6532-8.

Research output: Contribution to journal › Journal article › Research › peer-review

Faure, S, Jensen, AA, Maurat, V, Gu, X, Sagot, E, Aitken, DJ, Bolte, J, Gefflaut, T & Bunch, L 2006, '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', Journal of Medicinal Chemistry, vol. 49, no. 22, pp. 6532-8. https://doi.org/10.1021/jm060822s

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title = "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",

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.",

keywords = "Catalysis, Chemistry, Physical, Cyclobutanes, Excitatory Amino Acid Transporter 1, Excitatory Amino Acid Transporter 3, Glutamate Plasma Membrane Transport Proteins, Glutamates, Glycine, Humans, Indicators and Reagents, Models, Molecular, Molecular Conformation, Physicochemical Phenomena, Stereoisomerism, Structure-Activity Relationship",

author = "Sophie Faure and Jensen, {Anders A.} and Vincent Maurat and Xin Gu and Emmanuelle Sagot and Aitken, {David J} and Jean Bolte and Thierry Gefflaut and Lennart Bunch",

year = "2006",

doi = "10.1021/jm060822s",

language = "English",

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journal = "Journal of Medicinal Chemistry",

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T1 - 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

AU - Faure, Sophie

AU - Jensen, Anders A.

AU - Maurat, Vincent

AU - Gu, Xin

AU - Sagot, Emmanuelle

AU - Aitken, David J

AU - Bolte, Jean

AU - Gefflaut, Thierry

AU - Bunch, Lennart

PY - 2006

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N2 - 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.

AB - 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.

KW - Catalysis

KW - Chemistry, Physical

KW - Cyclobutanes

KW - Excitatory Amino Acid Transporter 1

KW - Excitatory Amino Acid Transporter 3

KW - Glutamate Plasma Membrane Transport Proteins

KW - Glutamates

KW - Glycine

KW - Humans

KW - Indicators and Reagents

KW - Models, Molecular

KW - Molecular Conformation

KW - Physicochemical Phenomena

KW - Stereoisomerism

KW - Structure-Activity Relationship

U2 - 10.1021/jm060822s

DO - 10.1021/jm060822s

M3 - Journal article

C2 - 17064071

SN - 0022-2623

VL - 49

SP - 6532

EP - 6538

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 22

ER -

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

Abstract

Keywords

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