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Conformationally constrained analogues of diacylglycerol (DAG). Effect on protein kinase C (PK-C) binding by the isosteric replacement of Sn-1 and Sn-2 esters in DAG-lactones

  1. Author:
    Kang, J. H.
    Chung, H. E.
    Kim, S. Y.
    Kim, Y.
    Lee, J.
    Lewin, N. E.
    Pearce, L. V.
    Blumberg, P. M.
    Marquez, V. E.

  2. Author Address

    Seoul Natl Univ, Coll Pharm, Med Chem Lab, Seoul 151742, South Korea Seoul Natl Univ, Coll Pharm, Med Chem Lab, Seoul 151742, South Korea NCI, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bethesda, MD 20892 USA NCI, Med Chem Lab, NIH, Frederick, MD 21701 USA Lee J Seoul Natl Univ, Coll Pharm, Med Chem Lab, Seoul 151742, South Korea
    1. Year: 2003
  2. Journal: Bioorganic & Medicinal Chemistry
    1. 11
    2. 12
    3. Pages: 2529-2539
  4. Type of Article: Article
  1. Abstract:

    In order to determine the importance of the two ester pharmacophores in high affinity, conformationally constrained DAG-lactones (Lac-1-5) as PK-C ligands, we have independently replaced the sn-1 and sn-2 carbonyl esters in these compounds by ketone (2, 10, 11), amide (3, 25-28), and hydroxyl (12, 13) isosteres. Although the ketone analogue of the sn-1 ester (2) exhibited comparable activity to the parent Lac-1 when taking into account the difference in lipophilicities, the other isosteres were significantly poorer PK-Ca ligands compared to the parent DAG-lactones. This study demonstrates that the ester functionality in DAG-lactone plays an important role in the ligand's capacity to form a strong hydrogen bond with Gly253 at the active site. The discrete K-i analysis from the sn-1 and sn-2 isosteres further confirms that the DAG-lactones bind preferentially to the C1-domain in the sn-2 binding mode, as previously suggested. (C) 2003 Elsevier Science Ltd. All rights reserved.

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