Structure/Activity Relationships of Polyfunctional Diterpenes of the Tigliane Type

Abstract

For protein kinase C (PKC), a family of isoenzymes with serine/threonine-kinase activity identified as the major cellular receptor for certain skin irritants and tumor promoters, a new pharmacophore model is presented. By structure/activity relationship studies of naturally occurring and synthetic diterpene esters of the tigliane type (PKC activators) it is demonstrated that in addition to the oxygen at C20 it is the O-acyl function in position C13 which is critically essential for skin-irritant and tumor-promoting bioactivities rather than other oxygen atoms. This result is confirmed and extended by computer-assisted molecular modeling of tigliane-type and ingenane-type tumor promoters. It is contrasted to certain features attributed to the pharmacophore based upon the recently determined crystallographic structure of the effector-binding domain Cys2 of PKCδ complexed with the pseudo-agonist phorbol 13-acetate.