Conformationally constrained analogues of diacylglycerol (DAG)--II. Differential interaction of delta-lactones and gamma-lactones with protein kinase C (PK-C).
Starting with L- or D-tri-O-acetylglucal, the corresponding L- and D-isomers of 4-O-tetradecanoyl-2,3-dideoxyglucono-1,5-lactone (2a and 2b) were synthesized as rigid diacylglycerol (DAG) analogues. Consistent with results obtained previously with the equivalent L- and D-1,4-lactones (1a and 1b), the L-isomer (2a) was more potent in activating protein kinase C (PK-C) and inhibiting the binding of [3H]phorbol-12,13-dibutyrate to the enzyme's regulatory domain. In these experiments the difference in potency observed between the optical antipodes of the gluconolactones (2a and 2b) was greatly increased relative to the corresponding ribonolactones (1a and 1b). These results indicate that PK-C is more able to discriminate between optical antipodes, in favor of the L-isomer, as the lactone ring increases from five to six.
Lee
J
J
Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Marquez
V E
VE
Blumberg
P M
PM
Krausz
K W
KW
Kazanietz
M G
MG
D001665:Binding Sites; D002855:Chromatography, Thin Layer; D004075:Diglycerides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004789:Enzyme Activation; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D009226:Myristates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015240:Phorbol 12,13-Dibutyrate / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D011753:Pyrones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013237:Stereoisomerism
D004075:Diglycerides; D009226:Myristates; D011753:Pyrones; C089350:4-O-tetradecanoyl-2,3-dideoxyglucono-1,5-lactone; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C