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Gateway synthesis of daphnane congeners and their protein kinase C affinities and cell-growth activities

Abstract

The daphnane diterpene orthoesters constitute a structurally fascinating family of natural products that exhibit a remarkable range of potent biological activities. Although partial activity information is available for some natural daphnanes, little information exists for non-natural congeners or on how changes in structure affect mode of action, function, potency or selectivity. A gateway strategy designed to provide general synthetic access to natural and non-natural daphnanes is described and utilized in the synthesis of two novel members of this class. In this study, a commercially available tartrate derivative was elaborated through a key late-stage diversification intermediate into B-ring yuanhuapin analogues to initiate exploration of the structure–function relationships of this class. Protein kinase C was identified as a cellular target for these agents, and their activity against human lung and leukaemia cell lines was evaluated. The natural product and a novel non-natural analogue exhibited significant potency, but the epimeric epoxide was essentially inactive.

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Figure 1: Retrosynthetic analysis for a major subset of natural and non-natural DDOs.
Figure 2: Synthesis of the complete daphnane skeleton (5).
Figure 3: Completion of des-epoxy- and C6,C7-epi-yuanhuapin.

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Acknowledgements

This research was supported by the National Institutes of Health (CA31841). Additional funding was provided by the Alexander von Humboldt Foundation (N.B.), Stanford Graduate Fellowships from the Office of the Vice Provost for Graduate Education (N.B.C.) and the Office of Technology Licensing (K.E.L.), Bristol-Myers Squibb Graduate Fellowship in Organic Chemistry (J.A.K.), Amgen Graduate Fellowship (C.K.) and Eli Lilly Graduate Research Fellowships (N.B.C., J.A.K., J.M.K.). J-M. Yue is thanked for supplying a sample of yuanhuapin for biological evaluation. P.L. Boudreault performed epoxidation studies on phorbol-12,13-dibutyrate. L. Cegelski is acknowledged for providing access to tissue culture space and equipment. K. Cimprich contributed A549 and K562 cells. X-ray crystallography was performed at the University of California, Berkeley, and analysed by X. Ottenwaelder or collected and analysed by A. Oliver.

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P.A.W., N.B., N.B.C., L.R.J., C.K., J.M.K., J.A.K. and K.E.L. conceived and designed the experiments. N.B., N.B.C., L.R.J., C.K., J.M.K., J.A.K. and K.E.L. performed the experiments and analysed the data. P.A.W., N.B.C. and K.E.L. co-wrote the paper. All authors commented on the manuscript.

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Correspondence to Paul A. Wender.

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Supplementary information

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Supplementary information (PDF 4898 kb)

Supplementary information

Crystallographic data for compound 19a (CIF 25 kb)

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Crystallographic data for compound 20 (CIF 46 kb)

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Crystallographic data for compound 16a (CIF 25 kb)

Supplementary information

Crystallographic data for compound 6a (CIF 26 kb)

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Wender, P., Buschmann, N., Cardin, N. et al. Gateway synthesis of daphnane congeners and their protein kinase C affinities and cell-growth activities. Nature Chem 3, 615–619 (2011). https://doi.org/10.1038/nchem.1074

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