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Conformationally constrained diacylglycerol (DAG) analogs: 4-C-hydroxyethyl-5-O-acyl-2,3-dideoxy-D-glyceropentono-1,4-lactone analogs as protein kinase C (PKC) ligands

  1. Author:
    Lee, J.
    Kim, S. Y.
    Kang, J. H.
    Acs, G.
    Acs, P.
    Blumberg, P. M.
    Marquez, V. E.

  2. Author Address

    Marquez, VE, Seoul Natl Univ, Coll Pharm, Pharmaceut Sci Res Inst, Med Chem Lab, Seoul 151742, South Korea Seoul Natl Univ, Coll Pharm, Pharmaceut Sci Res Inst, Med Chem Lab, Seoul 151742, South Korea. NCI, Ctr Canc Res, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21701 USA.
    1. Year: 2004
  2. Journal: European Journal of Medicinal Chemistry
    1. 39
    2. 1
    3. Pages: 69-77
  4. Type of Article: Article
  1. Abstract:

    The (R)-DAG-lactones (5 and 7E/Z) are conformationally constrained diacylglycerol (DAG) analogs with high potency as protein kinase C (PKC) ligands. Here, we have prepared and characterized their one-carbon lengthened analogs (6 and 8E/Z). The target compounds were synthesized from 1,2-O-isopropylidene D-xylose through a key intermediate, 4-C-hydroxyethyl-2,3-dideoxy-D-glyceropentono-1,4-lactone (13); they were evaluated as competitive ligands to displace bound [H-3]phorbol 12,13-dibutyrate (PDBU) from a recombinant single isozyme (PKC-alpha). The binding affinities of the synthesized compounds were K-i = 2.623 muM for 6, K-i = 1.080 muM for 8Z and K-i = 0.92 muM for 8E, which were ca. 27, 90, and 70 times less potent than the corresponding parent compounds (5, 7Z and 7E). Molecular modeling indicated that the reduced binding affinity of the representative 3-alkylidene lactone 8Z, as compared to 7Z, may be explained by its poor fit in the sn-1 binding mode as well as by its entropic loss due to the relatively flexible hydroxyethyl group. (C) 2003 Elsevier SAS. All rights reserved

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