Synthesis, computer modeling and biological evaluation of novel protein kinase C agonists based on a 7-membered...

4-Hydroxymethyl-5a-methyl-1,3,4,5,5a beta,6,7,8,9,9a alpha-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 PKC delta 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 PKC delta binding site.