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Isolation, synthesis and bioactivity studies of phomactin terpenoids


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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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

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.

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

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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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.