Structure-activity relationship of synthetic branched-chain distearoylglycerol (distearin) as protein kinase C activators.
Several representative branched-chain analogues of distearin (DS) were synthesized and tested for their abilities to activate protein kinase C (PKC) and to compete for the binding of [3H]phorbol 12,13-dibutyrate (PDBu) to the enzyme. Substitutions of stearoyl moieties at sn-1 and sn-2 with 8-methylstearate decreased activities on these parameters, relative to those of the parental diacylglycerol DS, a weak PKC activator. Substitutions with 8-butyl, 4-butyl, or 8-phenyl derivatives, on the other hand, increased activities of the resulting analogues to levels comparable to those seen for diolein (DO), a diacylglycerol prototype shown to be a potent PKC activator. Kinetic analysis indicated that 8-methyldistearin (8-MeDS) acted by decreasing, whereas 8-butyldistearin (8-BuDS) and 8-phenyldistearin (8-PhDS) acted by increasing, the affinities of PKC for phosphatidylserine (PS, a phospholipid cofactor) and Ca2+ compared to the values seen in the absence or presence of DS. The stimulatory effect of 8-BuDS and 8-PhDS on PKC, as DO, was additive to that of 1,2-(8-butyl)distearoylphosphatidylcholine [1,2(8-Bu)DSPC] and, moreover, they abolished the marked inhibition of the enzyme activity caused by high concentrations of 1,2(8-Bu)DSPC. The present findings demonstrated a structure-activity relationship of the branched-chain DS analogues in the regulation of PKC, perhaps related to their abilities to specifically modify interactions of PKC with PS and/or Ca2+ critically involved in enzyme activation/inactivation.
Zhou
Q Z
QZ
Department of Pharmacology, Emory University, Atlanta, Georgia 30322.
Raynor
R L
RL
Wood
M G
MG
Menger
F M
FM
Kuo
J F
JF
D001667:Binding, Competitive; D002118:Calcium / Q000494:pharmacology; D004075:Diglycerides / Q000378:metabolism / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005989:Glycerides / Q000494:pharmacology*; D007700:Kinetics; D008823:Micelles; D015394:Molecular Structure; D017830:Octoxynol; D015240:Phorbol 12,13-Dibutyrate / Q000378:metabolism; D010718:Phosphatidylserines / Q000494:pharmacology; D011092:Polyethylene Glycols; D011493:Protein Kinase C / Q000378:metabolism*; D013329:Structure-Activity Relationship
D004075:Diglycerides; D005989:Glycerides; D008823:Micelles; D010718:Phosphatidylserines; D015240:Phorbol 12,13-Dibutyrate; D011092:Polyethylene Glycols; D017830:Octoxynol; C058146:1,2-distearin; D011493:Protein Kinase C; D002118:Calcium; C013965:diolein