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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

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

  2. 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).

  3. 3.

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

  4. 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).

  5. 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).

  6. 6.

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

  7. 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).

  8. 8.

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

  9. 9.

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

  10. 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).

  11. 11.

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

  12. 12.

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

  13. 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).

  14. 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).

  15. 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).

  16. 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).

  17. 17.

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

  18. 18.

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

  19. 19.

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

  20. 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).

  21. 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).

  22. 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).

  23. 23.

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

  24. 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).

  25. 25.

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

  26. 26.

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

  27. 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).

  28. 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).

  29. 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).

  30. 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. 31.

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

  32. 32.

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

  33. 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).

  34. 34.

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

  35. 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).

  36. 36.

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

  37. 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).

  38. 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. 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).

  40. 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).

  41. 41.

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

Download references

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.

Author information

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

Authors

  1. Search for Yusuke Kuroda in:

  2. Search for Karen J. Nicacio in:

  3. Search for Ildefonso Alves da Silva-Jr in:

  4. Search for Paul R. Leger in:

  5. Search for Stanley Chang in:

  6. Search for Juliana R. Gubiani in:

  7. Search for Victor M. Deflon in:

  8. Search for Nozomu Nagashima in:

  9. Search for Alexander Rode in:

  10. Search for Katherine Blackford in:

  11. Search for Antonio G. Ferreira in:

  12. Search for Lara D. Sette in:

  13. Search for David E. Williams in:

  14. Search for Raymond J. Andersen in:

  15. Search for Sonia Jancar in:

  16. Search for Roberto G. S. Berlinck in:

  17. Search for Richmond Sarpong in:

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.

Competing interests

The authors declare no competing interests.

Corresponding authors

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

Supplementary information

  1. Supplementary Information

    Supplementary experimental details and compound characterization data

  2. Reporting Summary

  3. Crystallographic data

    CIF for compound 3; CCDC reference: 1830519

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/s41557-018-0084-x