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Conformationally constrained analogues of diacylglycerol (DAG). 27. Modulation of membrane translocation of protein kinase C (PKC) isozymes alpha and delta by diacylglycerol lactones (DAG-lactones) containing rigid-rod acyl groups

  1. Author:
    Malolanarasimhan, K.
    Kedei, N.
    Sigano, D. M.
    Kelley, J. A.
    Lai, C. C.
    Lewin, N. E.
    Surawski, R. J.
    Pavlyukovets, V. A.
    Garfield, S. H.
    Wincovitch, S.
    Blumberg, P. M.
    Marquez, V. E.

  2. Author Address

    Natl Canc Inst, Med Chem Lab, NIH, Frederick, MD 21702 USA. NCI, Ctr Canc Res, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Lab Cellular Carcinogenesis, NIH, Bethesda, MD 20892 USA.;Marquez, VE, Natl Canc Inst, Med Chem Lab, NIH, Frederick, MD 21702 USA.;marquezv@mail.nih.gov
    1. Year: 2007
    2. Date: Mar
  2. Journal: Journal of Medicinal Chemistry
    1. 50
    2. 5
    3. Pages: 962-978
  4. Type of Article: Article
  5. ISSN: 0022-2623
  1. Abstract:

    Highly rigid and geometrically well-defined rods composed of ethynylene-substituted aromatic spacers [oligo(p-phenyleneethynylene), OPE] were incorporated as acyl moieties on diacylglycerol lactones (DAG-lactones) and investigated for their ability to bind to protein kinase C (PKC) and translocate PKC alpha and delta isoforms to plasma and internal membranes. The kinetics of PKC translocation were correlated with biological responses, viz. ERK phosphorylation, induction of IL-6 secretion, inhibition of cell proliferation, and induction of cellular attachment, that display very different time courses. Because OPE rods assemble through noncovalent forces and form stable films, they may influence the microdomain environment around the DAG-lactone membrane-binding site. A comparison of two DAG-lactones (1 and 10), one with two PE units (1) and the other with an equivalent flexible acyl chain (10) of matching lipophilicity, clearly demonstrated the effect of the rigid OPE chain in substantially prolonging the translocated state of both PKC alpha and delta.

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  2. DOI: 10.1021/jm061289j
  3. View record in Web of Science®
  4. WOS: 000244530400008

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