Novel conformationally constrained analogues of diacylglycerol. Protein kinase C binding affinity of simplified compounds based on a 6-membered lactam moiety

Four configurational isomers of 6-hydroxymethyl-3-isopropyl-4-tetradecylpiperazin-2-ones (4–7), which were designed based on information obtained from the biologically active conformation of teleocidins and benzolactams, were synthesized and evaluated for their ability to compete with [3H]phorbol 12,13-dibutyrate in a PHCδ binding assay. Among the compounds, the 3S,6S-isomer (5) showed moderate binding affinity, 8–30 fold more potent than for the other isomers. This indicates that the relative position of the hydrogen-bonding sites and hydrophobic regions of 5 fits into the cavity of PKCδ binding site. Compound 5 provides a conformationally constrained analogue of diacylglycerol.