STRUCTURE ACTIVITY RELATIONSHIPS OF POLYFUNCTIONAL DITERPENES OF THE TIGLIANE TYPE - A PHARMACOPHORE MODEL FOR PROTEIN-KINASE-C ACTIVATORS BASED ON STRUCTURE/ACTIVITY STUDIES AND MOLECULAR MODELING OF THE TUMOR PROMOTERS 12-O-TETRADECANOYLPHORBOL 13-ACETATE AND 3-O-TETRADECANOYLINGENOL/

For protein kinase C (PKC), a family of isoenzymes with serine/threoni ne-kinase activity identified as the major cellular receptor for certa in skin irritants and tumor promoters, a new pharmacophore model is pr esented. By structure/activity relationship studies of naturally occur ring and synthetic diterpene eaters of the tigliane type (PKC activato rs) 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 ski n-irritant and tumor-promoting bioactivities rather than other oxygen atoms. This result is confirmed and extended by computer-assisted mole cular modeling of tigliane-type and ingenane-type tumor promoters, It is contrasted to certain features attributed to the pharmacophore base d upon the recently determined crystallographic structure of the effec tor-binding domain Cys2 of PKC delta complexed with the pseudo-agonist phorbol 13-acetate.