NOVEL CONFORMATIONALLY CONSTRAINED ANALOGS OF DIACYLGLYCEROL - PROTEIN-KINASE-C BINDING-AFFINITY OF SIMPLIFIED COMPOUNDS BASED ON A 6-MEMBERED LACTAM MOIETY

Four configurational isomers of oxymethyl-3-isopropyl-4-tetradecylpipe razin-2-ones (4-7), which were designed based on information obtained from the biologically active conformation of teleocidins and benzolact ams, were synthesized and evaluated for their ability to compete with [H-3]phorbol 12,13-dibutyrate in a PKC delta 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 region s of 5 fits into the cavity of PKC delta binding site. Compound 5 prov ides a conformationally constrained analogue of diacylglycerol. (C) 19 97 Elsevier Science Ltd.