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

4-Hydroxymethyl-5a-methyl-1,3,4,5,5a beta,6,7,8,9,9a alpha-decahydro-2H-ben z[d]azepin-2-one (4-12), which were designed to mimic the biologically acti ve conformation of teleocidins and benzolactams, were synthesized and evalu ated for the ability to compete with [H-3]phorbol 12,13-dibutyrate in a PKC delta binding assay. Among the ed potent binding affinity, with inhibition constants (K-i) of low nanomolar order. Computational docking simulation a lso indicates that the relative positions of the hydrogen-bonding sites and hydrophobic regions of the compounds are well matched to the PKC delta bin ding site. (C) 1999 Elsevier Science Ltd. All rights reserved.