Design and concise synthesis of fully protected analogues of l-gamma-carboxyglutamic acid.
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 In the new amino acids, the propionic acid side chain of Glu has been replaced by a malonyl or a carboxymethylmalonyl moiety located at different distances from the alpha-carbon to optimize interactions in the phosphotyrosine-binding cavity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.
Jiang
Sheng
S
Laboratory of Medicinal Chemistry, CCR, NCI-Frederick, NIH, Frederick, Maryland 21702, USA.
Li
Peng
P
Lai
Christopher C
CC
Kelley
James A
JA
Roller
Peter P
PP
D015055:1-Carboxyglutamic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D015394:Molecular Structure; D013237:Stereoisomerism
D015055:1-Carboxyglutamic Acid