Conformationally constrained analogues of diacylglycerol (DAG). 17. Contrast between sn-1 and sn-2 DAG lactones in binding to protein kinase C.
In previous work, we have obtained potent protein kinase C (PK-C) ligands with low-namomolar binding affinities by constructing diacylglycerol (DAG) mimetics in which the sn-2 carbonyl of DAG was constrained into a lactone ring. An additional structural element that helped achieve high binding affinity was the presence of branched acyl or alpha-alkylidene chains. In the present study, the effects of similarly branched chains on a different lactone system, where the lactone carbonyl is now equivalent to the sn-1 carbonyl of DAG, are investigated. In this new lactone template, the two chiral centers must have the S-configuration for enzyme recognition. As with the sn-2 DAG lactones, the branched chains were designed to optimize van der Waals contacts with a group of conserved hydrophobic amino acids located on the rim of the C1 domain of PK-C. The acyl and alpha-alkylidene chains were also designed to be lipophilically equivalent (8 carbons each). Eight new compounds (7-14) representing all possible combinations of linear and branched acyl and alpha-alkylidene were synthesized and evaluated. The sn-1 DAG lactones were less effective as PK-C ligands than the sn-2 DAG lactones despite having a similar array of linear or branched acyl and alpha-alkylidene chains
Tamamura
H
H
Laboratories of Medicinal Chemistry and of Cellular Carcinogenesis and Tumor Promotion, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Bienfait
B
B
Nacro
K
K
Lewin
N E
NE
Blumberg
P M
PM
Marquez
V E
VE
D004075:Diglycerides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D018716:Molecular Mimicry; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004075:Diglycerides; D007527:Isoenzymes; D007783:Lactones; D008024:Ligands; D011493:Protein Kinase C