Conformationally Constrained Analogues of Diacylglycerol (DAG). 27. Modulation of Membrane Translocation of Protein Kinase C (PKC) Isozymes <img src="http://pubs.acs.org/images/gifchars/alpha.gif" bor
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- 作者：Krishnan Malolanarasimhan ; Noemi Kedei ; Dina M. Sigano ; James A. Kelley ; Christopher C. Lai ; Nancy E. Lewin ; Robert J. Surawski ; Vladimir A. Pavlyukovets ; Susan H. Garfield ; Stephen Wincovitch ; Peter
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：March 8, 2007
- 年：2007
- 卷：50
- 期：5
- 页码：962 - 978
- 全文大小：520K
- 年卷期：v.50,no.5(March 8, 2007)
- ISSN：1520-4804
文摘
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 <IMG SRC="/images/gifchars/alpha.gif" BORDER=0> and 
isoformsto plasma and internal membranes. The kinetics of PKC translocation were correlated with biologicalresponses, viz. ERK phosphorylation, induction of IL-6 secretion, inhibition of cell proliferation, and inductionof cellular attachment, that display very different time courses. Because OPE rods assemble throughnoncovalent forces and form stable films, they may influence the microdomain environment around theDAG-lactone membrane-binding site. A comparison of two DAG-lactones (1 and 10), one with two PEunits (1) and the other with an equivalent flexible acyl chain (10) of matching lipophilicity, clearlydemonstrated the effect of the rigid OPE chain in substantially prolonging the translocated state of bothPKC 
and .
isoformsto plasma and internal membranes. The kinetics of PKC translocation were correlated with biologicalresponses, viz. ERK phosphorylation, induction of IL-6 secretion, inhibition of cell proliferation, and inductionof cellular attachment, that display very different time courses. Because OPE rods assemble throughnoncovalent forces and form stable films, they may influence the microdomain environment around theDAG-lactone membrane-binding site. A comparison of two DAG-lactones (1 and 10), one with two PEunits (1) and the other with an equivalent flexible acyl chain (10) of matching lipophilicity, clearlydemonstrated the effect of the rigid OPE chain in substantially prolonging the translocated state of bothPKC and .