Conformationally Constrained Analogues of Diacylglycerol (DAG). 25. Exploration of the sn-1 and sn-2 Carbonyl Functionality Reveals the Essential Role of the sn-1 Carbonyl at the Lipid Interface in the Binding of DAG-Lactones to Protein Kinase C

Diacylglycerol (DAG) lactones with altered functionality (C&dbd;O → CH<INF>2</INF> or C&dbd;O → C&dbd;S) at the sn-1 and sn-2 carbonyl pharmacophores were synthesized and used as probes to dissect the individual role of each carbonyl in the binding to protein kinase C (PKC). The results suggest that the hydrated sn-1 carbonyl is engaged in very strong hydrogen-bonding interactions with the charged lipid headgroups and organized water molecules at the lipid interface. Conversely, the sn-2 carbonyl has a more modest contribution to the binding process as a result of its involvement with the receptor (C1 domain) via conventional hydrogen bonding to the protein. The parent DAG-lactones, E-<BO>6</BO> and Z-<BO>7</BO>, were designed to bind exclusively in the sn-2 binding mode to ensure the correct orientation and disposition of pharmacophores at the binding site.