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

Abstract 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 [ 3 H]phorbol 12,13-dibutyrate in a PKCδ binding assay. Among the compounds, 10–12 showed potent binding affinity, with inhibition constants ( K i ) 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.