C-H 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 C-H oxidation of a common intermediate were found to interact with protein kinase C 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 PKCd is dispensable. Thus, key modifications of the ingenane core allowed PKC isoform selectivity wherein PKCd-driven activation of keratinocytes is strongly reduced or even absent while PKC beta II-driven activation of neutrophils is retained.