title: Design and concise synthesis of fully protected analogues of l-gamma-carboxyglutamic acid.
abstract: The design and synthesis of four nonnaturally occurring amino acid analogues of l-gamma-carboxyglutamic acid (Gla), appropriately protected for Fmoc-based solid-phase peptide synthesis (SPPS), is described. These amino acids are Bu-Mal 2, BCAH 3, Pen-Mal 4, and Cm-Gla 5. These Gla analogues have been designed to replace the glutamic acid of position 1 in the cyclic decapeptide G1TE, which is a potent inhibitor of tyrosine kinase, to further enhance binding to the Grb2-SH2 domain of signal transduction receptors. In the new amino acids, the propionic acid side chain of Glu has been replaced by a malonyl or a carboxymethylmalonyl moiety located at different distances from the alpha-carbon to optimize interactions in the phosphotyrosine-binding cavity of the Grb2-SH2 domain. Additionally, a direct and efficient synthetic route for the preparation of Fmoc-protected l-gamma-carboxyglutamic acid, which is amenable to large-scale production, has been developed to provide this important and unique amino acid(1) in 55% overall yield.
authors.affiliation: Laboratory of Medicinal Chemistry, CCR, NCI-Frederick, NIH, Frederick, Maryland 21702, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Jiang
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Lai
authors.forename: James A
authors.initials: JA
authors.lastname: Kelley
authors.forename: Peter P
authors.initials: PP
authors.lastname: Roller
mesh_terms: D015055:1-Carboxyglutamic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D015394:Molecular Structure; D013237:Stereoisomerism
chemical_list: D015055:1-Carboxyglutamic Acid