title: C-H Oxidation of Ingenanes Enables Potent and Selective Protein Kinase C Isoform Activation.
abstract: 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 PKCδ and induction of neutrophil oxidative burst, the current study shows that the potential to activate PKCβII is of key importance while interaction with PKCδ 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.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA).
authors.forename: Yehua
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA).
authors.forename: Chien-Hung
authors.initials: CH
authors.lastname: Yeh
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA).
authors.forename: Christian A
authors.initials: CA
authors.lastname: Kuttruff
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA).
authors.forename: Lars
authors.initials: L
authors.lastname: Jørgensen
authors.affiliation: Front End Innovation, LEO Pharma A/S, Industriparken 55, 2750 Ballerup (Denmark).
authors.forename: Georg
authors.initials: G
authors.lastname: Dünstl
authors.affiliation: Front End Innovation, LEO Pharma A/S, Industriparken 55, 2750 Ballerup (Denmark).
authors.forename: Jakob
authors.initials: J
authors.lastname: Felding
authors.affiliation: Kemxtree LLC, 1370 Hamilton St., Somerset, NJ 08873 (USA).
authors.forename: Swaminathan R
authors.initials: SR
authors.lastname: Natarajan
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA). pbaran@scripps.edu.
authors.forename: Phil S
authors.initials: PS
authors.lastname: Baran
mesh_terms: D004224:Diterpenes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D011493:Protein Kinase C / Q000737:chemistry / Q000378:metabolism*
chemical_list: D004224:Diterpenes; D007527:Isoenzymes; C530110:ingenane; D011493:Protein Kinase C
keywords: CH oxidation; ingenol; natural products; protein kinase C