Synthesis, Computer Modeling and Biological Evaluation of Novel Protein Kinase C Agonists Based on a 7-Membered Lactam Moiety.

4-Hydroxymethyl-5a-methyl-1,3,4,5,5aβ,6,7,8,9,9aα-decahydro-2H-benz[d]azepin-2-ones (4–12), which were designed to mimic the biologically active conformation of teleocidins and benzolactams, were synthesized and evaluated for the ability to compete with [3H]phorbol 12,13-dibutyrate in a PKCδ binding assay. Among the compounds, 10–12 showed potent binding affinity, with inhibition constants (Ki) of low nanomolar order. Computational docking simulation also indicates that the relative positions of the hydrogen-bonding sites and hydrophobic regions of the compounds are well matched to the PKCδ binding site.