The conformations and electrostatic potential maps of phorbol esters, teleocidins and ingenols.
Phorbol esters and the structurally dissimilar teleocidins and ingenols bind to and activate protein kinase C (PKC) during the course of tumour promotion. These compounds are referred to as TPA-like tumour promoters (from 12-O-tetradencanoyl phorbol-13-acetate, the most active of the class) and are amongst the most potent tumour promoters known. Despite their structural dissimilarity, all three groups of molecules have been shown to bind to the diacylglycerol site of PKC with high affinity. It is thought that this binding to and consequent activation of PKC is the crucial step in tumour promotion by these compounds. The aim of this work was to provide a description of the binding site by comparing structural features (in particular the electrostatic potential) with the activity of numerous derivatives of the three classes. Initially the description was obtained by consideration of the phorbol derivatives, and then refined using the teleocidins and ingenols. The activity data were collected from a variety of sources and the structures calculated using the semi-empirical MNDO approximation embodied in the MOPAC program. Where possible, the crystal structure was obtained from the Cambridge Crystallographic Database, and used as a starting point for the calculation. In other cases, a preliminary calculation was carried out using the molecular mechanics program AMBER. Electrostatic potentials were calculated and displayed using an in-house program 3D2, while superpositions of molecules were carried out using CHEM-X.
Thomson
C
C
Chemistry Department, University of St Andrews, Fife, UK.
Wilkie
J
J
D004224:Diterpenes; D004560:Electricity; D006860:Hydrogen Bonding; D008235:Lyngbya Toxins; D008968:Molecular Conformation; D010703:Phorbol Esters; D013329:Structure-Activity Relationship
D004224:Diterpenes; D008235:Lyngbya Toxins; D010703:Phorbol Esters; C022176:teleocidins; C008125:ingenol