Jin Yehua, Yeh Chien-Hung, Kuttruff Christian A, Jørgensen Lars, Dünstl Georg, Felding Jakob, Natarajan Swaminathan R, Baran Phil S
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA).
Front End Innovation, LEO Pharma A/S, Industriparken 55, 2750 Ballerup (Denmark).
Angew Chem Int Ed Engl. 2015 Nov 16;54(47):14044-8. doi: 10.1002/anie.201507977. Epub 2015 Sep 29.
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.
通过两相萜烯合成制备了具有不同氧化程度的大戟醇衍生物。该策略使得能够获得无法通过天然大戟醇半合成制备的类似物。发现由共同中间体的不同C-H氧化产生的复杂大戟烷以与大戟烷核心的氧化状态密切相关的方式与蛋白激酶C相互作用。尽管先前关于大戟烷的研究表明激活PKCδ的潜力与中性粒细胞氧化爆发的诱导之间存在很强的相关性，但目前的研究表明激活PKCβII的潜力至关重要，而与PKCδ的相互作用则是可有可无的。因此，大戟烷核心的关键修饰实现了蛋白激酶C亚型选择性，其中PKCδ驱动的角质形成细胞激活被强烈降低甚至不存在，而PKCβII驱动的中性粒细胞激活得以保留。
