Design and concise synthesis of fully protected analogues of l-gamma-carboxyglutamic acid.
Design and concise synthesis of fully protected analogues of l-gamma-carboxyglutamic acid.
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DOI：
10.1021/jo061037q
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发表时间：
2006-09
期刊：
影响因子：
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通讯作者：
Sheng Jiang;Peng Li;C. Lai;J. Kelley;P. Roller
中科院分区：
文献类型：
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作者：
Sheng Jiang;Peng Li;C. Lai;J. Kelley;P. Roller
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 In the new amino acids, the propionic acid side chain of Glu has been replaced by a malonyl or a carboxymethylmalonyl moiety located at different distances from the alpha-carbon to optimize interactions in the phosphotyrosine-binding cavity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.
