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

Nature Chemistry volume 3, pages 615–619 (2011)Cite this article

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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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References

  1. Liao, S-G., Chen, H-D. & Yue, J. M. Plant orthoesters. Chem. Rev. 109, 1092–1140 (2009).

    Article  CAS  Google Scholar 

  2. Miyamae, Y., Villareal, M. O., Abdrabbah, M. B., Isoda, H. & Shigemori, H. Hirseins A and B, daphnane diterpenoids from Thymelaea hirsuta that inhibit melanogenesis in B16 melanoma cells. J. Nat. Prod. 72, 938–941 (2009).

    Article  CAS  Google Scholar 

  3. Chen, H-D., He, X-F., Ai, J., Geng, M-Y. & Yue, J-M. Trigochilides A and B, two highly modified daphnane-type diterpenoids from Trigonostemon chinensis. Org. Lett. 11, 4080–4083 (2009).

    Article  CAS  Google Scholar 

  4. Hayes, P. Y., Chow, S., Somerville, M. J., De Voss, J. J. & Fletcher, M. T. Pimelotides A and B, diterpenoid ketal–lactone orthoesters with an unprecedented skeleton from Pimelea elongata. J. Nat. Prod. 72, 2081–2083 (2009).

    Article  CAS  Google Scholar 

  5. Hong, J-Y., Nam, J-W., Seo, E-K. & Lee, S. K. Daphnane diterpene esters with anti-proliferative activities against human lung cancer cells from Daphne genkwa. Chem. Pharm. Bull. 58, 234–237 (2010).

    Article  CAS  Google Scholar 

  6. Zhang, L. et al. Highly functionalized daphnane diterpenoids from Trigonostemon thyrsoideum. Org. Lett. 12, 152–155 (2010).

    Article  Google Scholar 

  7. Chen, H-D. et al. Trigochinins A–C: three new daphnane-type diterpenes from Trigonostemon chinensis. Org. Lett. 12, 1168–1171 (2010).

    Article  CAS  Google Scholar 

  8. Chen, H-D. et al. Trigochinins D–I: six new daphnane-type diterpenoids from Trigonostemon chinensis. Tetrahedron 66, 5065–5070 (2010).

    Article  CAS  Google Scholar 

  9. Lin, B-D. et al. Trigoxyphins A–G: diterpenes from Trigonostemon xyphophylloides. J. Nat. Prod. 73, 1301–1305 (2010).

    Article  CAS  Google Scholar 

  10. Li, L. Z., Gao, P. Y., Peng, Y., Wang, L. H. & Song, S. J. A novel daphnane-type diterpene from the flower bud of Daphne genkwa. Chem. Nat. Compd 46, 380–382 (2010).

    Article  Google Scholar 

  11. Li, L-Z. et al. Daphnane-type diterpenoids from the flower buds of Daphne genkwa. Helv. Chim. Acta 93, 1172–1179 (2010).

    Article  CAS  Google Scholar 

  12. Appendino, G. & Szallasi, A. Euphorbium: modern research on its active principle, resiniferatoxin, revives an ancient medicine. Life Sci. 60, 681–696 (1997).

    Article  CAS  Google Scholar 

  13. Mourtzoukou, E. G., Iavazzo, C. & Falagas, M. F. Resiniferatoxin in the treatment of interstitial cystitis: a systematic review. Int. Urogynecol. J. 19, 1571–1576 (2008).

    Article  Google Scholar 

  14. MacDonald, R., Monga, M., Fink, H. A. & Wilt, T. J. Neurotoxin treatments for urinary incontinence in subjects with spinal cord injury or multiple sclerosis: a systematic review of effectiveness and adverse effects. J. Spinal Cord Med. 31, 157–165 (2008).

    Article  Google Scholar 

  15. Wong, G. Y. & Gavva, N. R. Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: recent advances and setbacks. Brain Res. Rev. 60, 267–277 (2009).

    Article  CAS  Google Scholar 

  16. Wender, P. A. et al. The first synthesis of a daphnane diterpene: the enantiocontrolled total synthesis of (+)-resiniferatoxin. J. Am. Chem. Soc. 119, 12976–12977 (1997).

    Article  CAS  Google Scholar 

  17. Wender, P. A., Verma, V. A., Paxton, T. J. & Pillow, T. H. Function-oriented synthesis, step economy, and drug design. Acc. Chem. Res. 41, 40–49 (2008).

    Article  CAS  Google Scholar 

  18. Wender, P. A. & Miller, B. L. Synthesis at the molecular frontier. Nature 460, 197–201 (2009).

    Article  CAS  Google Scholar 

  19. Hu, B-H., Huai, S., He, Z-W. & Wu, X-C. Studies on the constituent of the yuanhua's flower buds. Acta Chim. Sinica 44, 843–845 (1986).

    Google Scholar 

  20. Zhan, Z-J., Fan, C-Q., Ding, J. & Yue, J-M. Novel diterpenoids with potent inhibitory activity against endothelium cell HMEC and cytotoxic activities from a well-known TCM plant Daphne genkwa. Bioorg. Med. Chem. 13, 645–655 (2005).

    Article  CAS  Google Scholar 

  21. Jørgensen, N., Iversen, E. H., Paulsen, A. L. & Madsen, R. Efficient synthesis of enantiopure conduritols by ring-closing metathesis. J. Org. Chem. 66, 4630–4634 (2001).

    Article  Google Scholar 

  22. Houk, K. N. et al. Stereoselective nitrile oxide cycloadditions to chiral allyl ethers and alcohols. The ‘inside alkoxy’ effect. J. Am. Chem. Soc. 106, 3880–3882 (1984).

    Article  CAS  Google Scholar 

  23. Wender, P. A. & McDonald, F. E. Studies on tumor promoters. 9. A second-generation synthesis of phorbol. J. Am. Chem. Soc. 112, 4956–4958 (1990).

    Article  CAS  Google Scholar 

  24. Wender, P. A. & Mascareñas, J. L. Studies on tumor promoters. 11. A new [5 + 2] cycloaddition method and its application to the synthesis of BC ring precursors of phoboids. J. Org. Chem. 56, 6267–6269 (1991).

    Article  CAS  Google Scholar 

  25. Domingo, L. R. & Zaragozá, R. J. Toward an understanding of the mechanisms of the intramolecular [5 + 2] cycloaddition reaction of γ-pyrones bearing tethered alkenes. A theoretical study. J. Org. Chem. 65, 5480–5486 (2000).

    Article  CAS  Google Scholar 

  26. Zaragozá, R. J., Aurell, M. J. & Domingo, L. R. The role of the transfer group in the intramolecular [5 + 2] cycloadditions of substituted β-hydroxy-γ-pyrones: a DFT analysis. J. Phys. Org. Chem. 18, 610–615 (2005).

    Article  Google Scholar 

  27. Singh, V., Krishna, U. M., Vikrant, V. & Trivedi, G. K. Cycloaddition of oxidopyrylium species in organic synthesis. Tetrahedron 64, 3405–3428 (2008).

    Article  CAS  Google Scholar 

  28. Wender, P. A. et al. Studies on oxidopyrylium [5 + 2] cycloadditions: toward a general synthetic route to the C12-hydroxy daphnetoxins. Org. Lett. 8, 5373–5376 (2006).

    Article  CAS  Google Scholar 

  29. Trost, B. M. & Rise, F. A reductive cyclization of 1,6- and 1,7-enynes. J. Am. Chem. Soc. 109, 3161–3163 (1987).

    Article  CAS  Google Scholar 

  30. Trost, B. M. & Li, Y. A new catalyst of Pd catalyzed Alder ene reaction. A total synthesis of (+)-cassiol. J. Am. Chem. Soc. 118, 6625–6633 (1996).

    Article  CAS  Google Scholar 

  31. Jang, H. Y. & Krische, M. J. Rhodium-catalyzed reductive cyclization of 1,6-diynes and 1,6-enynes mediated by hydrogen: catalytic C–C bond formation via capture of hydrogenation intermediates. J. Am. Chem. Soc. 126, 7875–7880 (2004).

    Article  CAS  Google Scholar 

  32. Scheidt, K. A. et al. Tris(dimethylamino)sulfonium difluorotrimethylsilicate, a mild reagent for the removal of silicon protecting groups. J. Org. Chem. 63, 6436–6437 (1998).

    Article  CAS  Google Scholar 

  33. Nicolaou, K. C., Zhong, Y-L. & Baran, P. S. A new method for the one-step synthesis of α,β-unsaturated carbonyl compounds from saturated alcohols and carbonyl compounds. J. Am. Chem. Soc. 122, 7596–7597 (2000).

    Article  CAS  Google Scholar 

  34. Lipshutz, B. H. & Harvey, D. F. Hydrolysis of acetals and ketals using LiBF4 . Synth. Commun. 12, 267–277 (1982).

    Article  CAS  Google Scholar 

  35. Zhang, W., Basak, A., Kosugi, Y., Hoshino, Y. & Yamamoto, H. Enantioselective epoxidation of allylic alcohols by a chiral complex of vanadium: an effective controller system and a rational mechanistic model. Angew. Chem. Int. Ed. 44, 4389–4391 (2005).

    Article  CAS  Google Scholar 

  36. Schmidt, R. & Hecker, E. Autoxidation of phorbol esters under normal storage conditions. Cancer Res. 35, 1375–1377 (1975).

    CAS  PubMed  Google Scholar 

  37. Zhang, S. et al. Preparation of yuanhuacine and relative daphne diterpene esters from Daphne genkwa and structure–activity relationship of potent inhibitory activity against DNA topoisomerase I. Bioorg. Med. Chem. 14, 3888–3895 (2006).

    Article  CAS  Google Scholar 

  38. Griner, E. M. & Kazanietz, M. G. Protein kinase C and other diacylglycerol effectors in cancer. Nat. Rev. Cancer 7, 281–294 (2007).

    Article  CAS  Google Scholar 

  39. Alkon, D. L., Sun, M-K. & Nelson, T. J. PKC signaling deficits: a mechanistic hypothesis for the origins of Alzheimer's disease. Trends Pharmacol. Sci. 28, 51–60 (2007).

    Article  CAS  Google Scholar 

  40. Richman, D. D. et al. The challenge of finding a cure for HIV infection. Science 323, 1304–1307 (2009).

    Article  CAS  Google Scholar 

  41. Wender, P. A., Kee, J-M. & Warrington, J. M. Practical synthesis of prostratin, DPP, and their analogs, adjuvant leads against latent HIV. Science 320, 649–652 (2008).

    Article  CAS  Google Scholar 

  42. Toullec, D. et al. The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C. J. Biol. Chem. 266, 15771–15781 (1991).

    CAS  PubMed  Google Scholar 

  43. Zhang, G., Kazanietz, M. G., Blumberg, P. M. & Hurley, J. H. Crystal structure of the Cys2 activator-binding domain of protein kinase Cδ in complex with phorbol ester. Cell 81, 917–924 (1995).

    Article  CAS  Google Scholar 

  44. Wender, P. A., Koehler, K. F., Sharkey, N. A., Dell'Aquila, M. L. & Blumberg, P. M. Analysis of the phorbol ester pharmacophore on protein kinase C as a guide to the rational design of new classes of analogs. Proc. Natl Acad. Sci. USA 83, 4214–4218 (1986).

    Article  CAS  Google Scholar 

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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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  1. Departments of Chemistry and Chemical and Systems Biology, Stanford University, Stanford, 94305, California, USA

    Paul A. Wender, Nicole Buschmann, Nathan B. Cardin, Lisa R. Jones, Cindy Kan, Jung-Min Kee, John A. Kowalski & Kate E. Longcore

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Contributions

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)

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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)

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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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