Format

Send to

Choose Destination
Angew Chem Int Ed Engl. 2015 Nov 16;54(47):14044-8. doi: 10.1002/anie.201507977. Epub 2015 Sep 29.

C-H Oxidation of Ingenanes Enables Potent and Selective Protein Kinase C Isoform Activation.

Author information

1
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA).
2
Front End Innovation, LEO Pharma A/S, Industriparken 55, 2750 Ballerup (Denmark).
3
Kemxtree LLC, 1370 Hamilton St., Somerset, NJ 08873 (USA).
4
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA). pbaran@scripps.edu.

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.

KEYWORDS:

CH oxidation; ingenol; natural products; protein kinase C

PMID:
26418078
PMCID:
PMC4832842
DOI:
10.1002/anie.201507977
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center