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 w ith low-namomolar binding affinities by constructing diacylglycerol (DAG) m imetics in which the sn-2 carbonyl of DAG was constrained into a lactone ri ng. An additional structural element that helped achieve high binding affin ity was the presence of branched acyl or alpha-alkylidene chains. In the pr esent study, the effects of similarly branched chains on a different lacton e system, where the lactone carbonyl is now equivalent to the sn-l carbonyl of DAG, are investigated. In this new lactone template, the two chiral cen ters 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 r im 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 compo unds (7-14) representing all possible combinations of linear and branched a cyl and alpha-alkylidene were synthesized and evaluated. The sn-1 DAG lacto nes 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 chai ns.