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Isolation, synthesis and bioactivity studies of phomactin terpenoids

Nature Chemistry volume 10, pages 938–945 (2018)Cite this article

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Abstract

Studies of secondary metabolites (natural products) that cover their isolation, chemical synthesis and bioactivity investigation present myriad opportunities for discovery. For example, the isolation of novel secondary metabolites can inspire advances in chemical synthesis strategies to achieve their practical preparation for biological evaluation. In the process, chemical synthesis can also provide unambiguous structural characterization of the natural products. Although the isolation, chemical synthesis and bioactivity studies of natural products are mutually beneficial, they are often conducted independently. Here, we demonstrate the benefits of a collaborative study of the phomactins, diterpenoid fungal metabolites that serve as antagonists of the platelet activating factor receptor. Our isolation of novel phomactins has spurred the development of a bioinspired, unified approach that achieves the total syntheses of six congeners. We also demonstrate in vitro the beneficial effects of several phomactins in suppressing the rate of repopulation of tumour cells following gamma radiation therapy.

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Fig. 1: Members of the phomactin family and retrosynthetic analysis based on the plausible biosynthetic pathway.
Fig. 2: Synthesis of common intermediate 16.
Fig. 3: Completion of the total syntheses of phomactins A, K, P, R and T and Sch 49027.

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References

  1. Maier, M. E. Structural revisions of natural products by total synthesis. Nat. Prod. Rep. 26, 1105–1124 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. Wilson, R. M. & Danishefsky, S. J. Small molecule natural products in the discovery of therapeutic agents: the synthesis connection. J. Org. Chem. 71, 8329–8351 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Maier, M. E. Design and synthesis of analogues of natural products. Org. Biomol. Chem. 13, 5302–5343 (2015).

    Article  CAS  PubMed  Google Scholar 

  4. Newman, D. J. & Cragg, G. M. Natural products as sources of new drugs from 1981 to 2014. J. Nat. Prod. 79, 629–661 (2016).

    Article  CAS  PubMed  Google Scholar 

  5. Sugano, M. et al. Phomactin A: a novel PAF antagonist from a marine fungus Phoma sp. J. Am. Chem. Soc. 113, 5463–5464 (1991).

    Article  CAS  Google Scholar 

  6. Sugano, M. et al. Phomactins, novel PAF antagonists from marine fungus Phoma sp. J. Org. Chem. 59, 564–569 (1994).

    Article  CAS  Google Scholar 

  7. Sugano, M. et al. Phomactin E, F, and G: new phomactin-group PAF antagonists from a marine fungus Phoma sp. J. Antibiot. 48, 1188–1190 (1995).

    Article  CAS  PubMed  Google Scholar 

  8. Chu, M. et al. A novel class of platelet activating factor antagonists from Phoma sp. J. Antibiot. 46, 554–563 (1993).

    Article  CAS  PubMed  Google Scholar 

  9. Koyama, K. et al. Phomactin H, a novel diterpene from an unidentified marine-derived fungus. Tetrahedron Lett. 45, 6947–6948 (2004).

    Article  CAS  Google Scholar 

  10. Ishino, M. et al. Phomactin I, 13-epi-phomactin I, and phomactin J, three novel diterpenes from a marine-derived fungus. Tetrahedron 66, 2594–2597 (2010).

    Article  CAS  Google Scholar 

  11. Ishino, M. et al. Phomactins K–M, three novel phomactin-type diterpenes from a marine-derived fungus. Tetrahedron 68, 8572–8576 (2012).

    Article  CAS  Google Scholar 

  12. Ishino, M. et al. Three novel phomactin-type diterpenes from a marine-derived fungus. Tetrahedron Lett. 57, 4341–4344 (2016).

    Article  CAS  Google Scholar 

  13. Passarini, M. R. Z., Santos, C., Lima, N., Berlinck, R. G. S. & Sette, L. D. Filamentous fungi from the Atlantic marine sponge Dragmacidon reticulatum. Arch. Microbiol. 195, 99–111 (2013).

    Article  CAS  PubMed  Google Scholar 

  14. Goldring, W. P. D. & Pattenden, G. The phomactins. A novel group of terpenoid platelet activating factor antagonists related biogenetically to the taxanes. Acc. Chem. Res. 39, 354–361 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Prescott, S. M., Zimmerman, G. A., Stafforini, D. M. & McIntyre, T. M. Platelet-activating factor and related lipid mediators. Annu. Rev. Biochem. 69, 419–445 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Onuchic, A. C. et al. Expression of PAFR as part of a pro-survival response to chemotherapy: a novel target for combination therapy in melanoma. Mediat. Inflamm. 2012, 175408 (2012).

    Article  CAS  Google Scholar 

  17. Sahu, R. P. et al. Radiation therapy generates platelet-activating factor agonists. Oncotarget 7, 20788–20800 (2016).

    PubMed  PubMed Central  Google Scholar 

  18. Ciesielski, J. & Frontier, A. The phomactin natural products from isolation to total synthesis: a review. Org. Prep. Proced. Int 46, 214–251 (2014).

    Article  CAS  Google Scholar 

  19. Goldring, W. P. D.., & Pattenden, G.. A total synthesis of phomactin. Chem. Commun. 2002, 1736–1737 (2002).

    Article  CAS  Google Scholar 

  20. Goldring, W. P. D. & Pattenden, G. Total synthesis of (±)-phomactin G, a platelet activating factor antagonist from the marine fungus Phoma sp. Org. Biomol. Chem. 2, 466–473 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Huang, J., Wu, C. & Wulff, W. D. Total synthesis of (±)-phomactin B2 via an intramolecular cyclohexadienone annulation of a chromium carbene complex. J. Am. Chem. Soc. 129, 13366–13367 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tang, Y., Cole, K. P., Buchanan, G. S., Li, G. & Hsung, R. P. Total synthesis of phomactin A. Org. Lett. 11, 1591–1594 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Miyaoka, H., Saka, Y., Miura, S. & Yamada, Y. Total synthesis of phomactin D. Tetrahedron Lett. 37, 7107–7110 (1996).

    Article  CAS  Google Scholar 

  24. Mohr, P. J. & Halcomb, R. L. Total synthesis of (+)-phomactin A using a B-alkyl Suzuki macrocyclization. J. Am. Chem. Soc. 125, 1712–1713 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Tokiwano, T., Fukushi, E., Endo, T. & Oikawa, H. Biosynthesis of phomactins: common intermediate phomactatriene and taxadiene. Chem. Commun. 1324–1325 (2004).

  26. Tokiwano, T. et al. Proposed mechanism for diterpene synthases in the formation of phomactatriene and taxadiene. Org. Biomol. Chem. 3, 2713–2722 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Masarwa, A., Weber, M. & Sarpong, R. Selective C–C and C–H bond activation/cleavage of pinene derivatives: synthesis of enantiopure cyclohexenone scaffolds and mechanistic insights. J. Am. Chem. Soc. 137, 6327–6334 (2015).

    Article  CAS  PubMed  Google Scholar 

  28. Bermejo, F. A. et al. Ti(iii)-promoted cyclizations. Application to the synthesis of (E)-endo-bergamoten-12-oic acids. Moth oviposition stimulants isolated from Lycopersicon hirsutum. Tetrahedron 62, 8933–8942 (2002).

    Article  CAS  Google Scholar 

  29. Murakami, M., Makino, M., Ashida, S. & Matsuda, T. Construction of carbon frameworks through β-carbon elimination mediated by transition metals. Bull. Chem. Soc. Jpn 79, 1315–1321 (2006).

    Article  CAS  Google Scholar 

  30. Cramer, N. & Seiser, T. β-Carbon elimination from cyclobutanols: a clean access to alkylrhodium intermediates bearing a quaternary stereogenic center. Synlett 449–460 (2011).

  31. Lipshutz, B. H. & Miller, T. A. Deprotection of ‘SEM’ ethers: a convenient, general procedure. Tetrahedron Lett. 30, 7149–7152 (1989).

    Article  CAS  Google Scholar 

  32. Nicolaou, K. C. & Harrison, S. T. Total synthesis of abyssomicin C and atrop-abyssomicin C. Angew. Chem. Int. Ed. 45, 3256–3260 (2006).

    Article  CAS  Google Scholar 

  33. Catino, A. J., Forslund, R. E. & Doyle, M. P. Dirhodium(ii) caprolactamate: an exceptional catalyst for allylic oxidation. J. Am. Chem. Soc. 126, 13622–13623 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Honda, T. & Mizutani, H. Regioselective ring-opening of 2,3-epoxy alcohols with tetramethylammonium triacetoxyborohydride. Heterocycles 48, 1753–1757 (1998).

    Article  CAS  Google Scholar 

  35. Evans, D. A., Chapman, K. T. & Carreira, E. M. Directed reduction of β-hydroxy ketones employing tetramethylammonium tracetoxyborohydride. J. Am. Chem. Soc. 110, 3560–3578 (1988).

    Article  CAS  Google Scholar 

  36. Jancar, S. & Chammas, R. PAF receptor and tumor growth. Curr. Drug Targets 15, 982–987 (2014).

    CAS  PubMed  Google Scholar 

  37. Bussolati, B. et al. PAF produced by human breast cancer cells promotes migration and proliferation of tumor cells and neo-angiogenesis. Am. J. Pathol. 157, 1713–1725 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chan, F. K.-M., Moriwaki, K. & De Rosa, M. J. in Immune Homeostasis. Methods and Protocols Vol. 979 (eds Snow, A. & Lenardo, M.) 65–70 (Humana, Totowa, 2013).

  39. da Silva-Jr, I. A., Chammas, R., Lepique, A. P. & Jancar, S. Platelet-activating factor (PAF) receptor as a promising target for cancer cell repopulation after radiotherapy. Oncogenesis 6, e296 (2017).

    Article  CAS  PubMed Central  Google Scholar 

  40. Rios, F. J. O., Koga, M. M., Ferracini, M. & Jancar, S. Co-stimulation of PAFR and CD36 is required for oxLDL-induced human macrophages activation. PLoS ONE 7, e36632 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Huang, Q. et al. Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy. Nat. Med. 17, 860–866 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank K. Koyama (Meiji Pharmaceutical University) for providing spectral data for phomactin P and S. Dreher and A. Buevich (Merck Pharmaceuticals) for the 1H NMR spectrum of Sch 49027. R.S. thanks the National Science Foundation (CHE-1566430) for financial support. Y.K. thanks the Japan Society for the Promotion of Science (JSPS) for an Overseas Research Fellowship. P.R.L. thanks the National Science Foundation for a graduate research fellowship. S.C. acknowledges a National Science and Engineering Council–Canada (NSERC) Postdoctoral Fellowship. R.G.S.B and J.R.G. thank FAPESP (Fundaçao de Amparo a Pesquisa de São Paulo) for financial support (BIOTA-BIOprospecTA 2013/50228-8, 2015/01017-0 and 2017/06014-4) and K.J.N. thanks CNPq for a PhD scholarship. S.J. and I.A.S.J. are grateful to FAPESP for financial support and a graduate research fellowship. N.N. thanks JSPS for a travel fellowship. K.B. is grateful to the Amgen Scholar Program (UC Berkeley) for support. R.J.A. thanks the NSERC for funding. The KBP cells were supplied by J.B. Travers (Indiana University, Indianapolis, IN) and the TC-1 cell line was donated to us by T.-C. Wu (Johns Hopkins, Baltimore). The authors thank K. Owens for insightful discussions regarding the structure of Sch 49027.

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Authors and Affiliations

  1. Department of Chemistry, University of California, Berkeley, CA, USA

    Yusuke Kuroda, Paul R. Leger, Stanley Chang, Nozomu Nagashima, Alexander Rode, Katherine Blackford & Richmond Sarpong

  2. Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, SP, Brazil

    Karen J. Nicacio, Juliana R. Gubiani, Victor M. Deflon & Roberto G. S. Berlinck

  3. Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP, Brazil

    Ildefonso Alves da Silva-Jr & Sonia Jancar

  4. Departamento de Química, Universidade Federal de São Carlos, São Carlos, SP, Brazil

    Antonio G. Ferreira

  5. Departamento de Bioquímica e Microbiologia, Instituto de Biociências, Universidade Estadual Paulista Júlio de Mesquita Filho, Campus Rio Claro, Rio Claro, SP, Brazil

    Lara D. Sette

  6. Departments of Chemistry and Earth, Ocean & Atmospheric Sciences, University of British Columbia, Vancouver, British Columbia, Canada

    David E. Williams & Raymond J. Andersen

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  1. Yusuke Kuroda
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Contributions

R.G.S.B. (isolation and identification), Y.K. (chemical synthesis), R.S. (chemical synthesis) and S.J. (biological assays) wrote each of the corresponding sections and R.S. composed the manuscript. P.R.L., S.C. and R.S. conceived the general plan for the chemical synthesis of phomactin R. Y.K. and R.S. designed the plan for the chemical syntheses of phomactins A, K, P, T and Sch 49027. P.R.L. and S.C. carried out the initial studies on the cyclobutanol opening, cyclohexenone functionalization, and macrocyclization that provided a part of the basis of the reported syntheses. Y.K. conducted the chemical reactions reported herein and compiled the Supplementary Information. N.N. conducted the large-scale preparation of 18 and 20 to support front-line synthetic studies. A.R. and K.B. carried out exploratory studies on the cyclobutanol intermediates and subsequent functionalizations. K.J.N. isolated the new phomactins and elucidated their structures jointly with J.R.G. V.M.D. performed X-ray diffraction analysis. A.G.F., D.E.W. and R.J.A. provided support and performed NMR analyses of the new phomactins. L.D.S. provided and identified the fungal strain. I.A.S.J. and S.J. performed the assays for PAFR antagonistic activity and the repopulation assays with cancer cell lineages.

Corresponding authors

Correspondence to Sonia Jancar, Roberto G. S. Berlinck or Richmond Sarpong.

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Supplementary information

Supplementary Information

Supplementary experimental details and compound characterization data

Reporting Summary

Crystallographic data

CIF for compound 3; CCDC reference: 1830519

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Kuroda, Y., Nicacio, K.J., da Silva-Jr, I.A. et al. Isolation, synthesis and bioactivity studies of phomactin terpenoids. Nature Chem 10, 938–945 (2018). https://doi.org/10.1038/s41557-018-0084-x

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