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Design and concise synthesis of fully protected analogues of L-gamma-carboxyglutamic acid

  1. Author:
    Jiang, S.
    Li, P.
    Lai, C. C.
    Kelley, J. A.
    Roller, P. P.

  2. Author Address

    NCI, Med Chem Lab, CCR, NIH, Frederick, MD 21702 USA.;Roller, PP, NCI, Med Chem Lab, CCR, NIH, Frederick, MD 21702 USA.;proll@helix.nih.gov
    1. Year: 2006
    2. Date: Sep
  2. Journal: Journal of Organic Chemistry
    1. 71
    2. 19
    3. Pages: 7307-7314
  4. Type of Article: Article
  5. ISSN: 0022-3263
  1. 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 In the new amino acids, the propionic acid side chain of Glu has been replaced by a malonyl or a carboxymethylmalonyl moiety located at different distances from the alpha-carbon to optimize interactions in the phosphotyrosine-binding cavity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.

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External Sources

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  2. DOI: 10.1021/jo061037q
  3. View record in Web of Science®
  4. WOS: 000240371900020

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