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CH Oxidation of Ingenanes Enables Potent and Selective Protein Kinase C Isoform Activation
Author(s) -
Jin Yehua,
Yeh ChienHung,
Kuttruff Christian A.,
Jørgensen Lars,
Dünstl Georg,
Felding Jakob,
Natarajan Swaminathan R.,
Baran Phil S.
Publication year - 2015
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201507977
Subject(s) - protein kinase c , chemistry , gene isoform , semisynthesis , biochemistry , kinase , microbiology and biotechnology , stereochemistry , gene , biology
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 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 δ and induction of neutrophil oxidative burst, the current study shows that the potential to activate PKCβII is of key importance while interaction with PKC δ is dispensable. Thus, key modifications of the ingenane core allowed PKC isoform selectivity wherein PKCδ‐driven activation of keratinocytes is strongly reduced or even absent while PKCβII‐driven activation of neutrophils is retained.