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/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 PKC delta complexed with the pseudo-agonist phorbol 13-acetate.
Krauter
G
G
Research Program 3 German Cancer Research Center, Heidelberg, Germany.
Von der Lieth
C W
CW
Schmidt
R
R
Hecker
E
E
D000818:Animals; D002273:Carcinogens / Q000737:chemistry* / Q000494:pharmacology; D016001:Confidence Intervals; D004224:Diterpenes / Q000737:chemistry* / Q000494:pharmacology*; D004789:Enzyme Activation; D007509:Irritants; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008958:Models, Molecular; D008968:Molecular Conformation; D011493:Protein Kinase C / Q000378:metabolism*; D013329:Structure-Activity Relationship
D002273:Carcinogens; D004224:Diterpenes; D007509:Irritants; D007527:Isoenzymes; C056099:3-O-tetradecanoylingenol; D011493:Protein Kinase C