CH Oxidation of Ingenanes Enables Potent and Selective Protein Kinase C Isoform Activation. (29th September 2015)

• Record Type: Journal Article
• Authors: Jin, Yehua; Yeh, Chien‐Hung; Kuttruff, Christian A.; Jørgensen, Lars; Dünstl, Georg; Felding, Jakob; Natarajan, Swaminathan R.; Baran, Phil S.
• Is Part Of: Angewandte Chemie. Volume 127:Number 47(2015)
• Page Start: 14250
• Page End: 14254
• Publication Date: 2015-09-29
• Subjects: C‐H‐Oxidationen -- Ingenol -- Naturstoffe -- Proteinkinase C; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201507977
• Languages: English
• ISSNs: 0044-8249

Abstract

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 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. Abstract : Ingenol‐Derivate mit verschiedenem C‐H‐Oxidationsgrad, die durch Semisynthese aus Ingenol nicht zugänglich sind, werden durch eine zweiphasige Terpensynthese erzeugt. Weil die Wechselwirkung mit Proteinkinase C (PKC) vom Oxidationsgrad abhängt, ergibt sich eine PKC‐Isoform‐Selektivität: Die Aktivierung von Keratinozyten durch PKCδ ist stark reduziert, während die Aktivierung von Neutrophilen durch PKCβII erhalten bleibt.