CH Oxidation of Ingenanes Enables Potent and Selective Protein Kinase C Isoform Activation

Ingenol derivatives with varying degrees of oxidation were prepared by two-phase terpene synthesis. This strategy has allowed access to analogues that cannot be prepared by semisynthesis from natural ingenol. Complex ingenanes resulting from divergent CH oxidation of a common intermediate were found to interact with protein kinaseC in a manner that correlates well with the oxidation state of the ingenane core. Even though previous work on ingenanes has suggested a strong correlation between potential to activate PKC[delta] and induction of neutrophil oxidative burst, the current study shows that the potential to activate PKC[beta]II is of key importance while interaction with PKC[delta] is dispensable. Thus, key modifications of the ingenane core allowed PKC isoform selectivity wherein PKC[delta]-driven activation of keratinocytes is strongly reduced or even absent while PKC[beta]II-driven activation of neutrophils is retained.