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Use of a biosynthetic intermediate to explore the chemical diversity of pseudo-natural fungal polyketides

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Abstract

The structural complexity and diversity of natural products make them attractive sources for potential drug discovery, with their characteristics being derived from the multi-step combination of enzymatic and non-enzymatic conversions of intermediates in each biosynthetic pathway. Intermediates that exhibit multipotent behaviour have great potential for use as starting points in diversity-oriented synthesis. Inspired by the biosynthetic pathways that form complex metabolites from simple intermediates, we developed a semi-synthetic process that combines heterologous biosynthesis and artificial diversification. The heterologous biosynthesis of fungal polyketide intermediates led to the isolation of novel oligomers and provided evidence for ortho-quinonemethide equivalency in their isochromene form. The intrinsic reactivity of the isochromene polyketide enabled us to access various new chemical entities by modifying and remodelling the polyketide core and through coupling with indole molecules. We thus succeeded in generating exceptionally diverse pseudo-natural polyketides through this process and demonstrated an advanced method of using biosynthetic intermediates.

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Figure 1: Introducing the concept of diversity-oriented semi-synthesis.
Figure 2: Structural diversity of natural and pseudo-natural polyketides based on fungal NR-PKS pathways.
Figure 3: Proposed polyketide oligomerization scheme through o-QMs.
Figure 4: Chemical diversification of 2 and 5 to polyketide oligomers 1119 and azaphilone-type compounds 3444.
Figure 5: Synthesis of indole–polyketide hybrid compounds.

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References

  1. Butler, M. S. The evolving role of natural products in drug discovery. Nature Rev. 4, 206–220 (2005).

    Google Scholar 

  2. Newman, D. J. & Cragg, G. M. Natural products as source of new drugs over the 30 years from 1981 to 2010. J. Nat. Prod. 75, 311–335 (2012).

    Article  CAS  Google Scholar 

  3. Cragg, G. M. & Newman, D. J. Natural products: a continuing source of novel drug leads. Biochim. Biophys. Acta 1830, 3670–3695 (2013).

    Article  CAS  Google Scholar 

  4. Ortholand, J. Y. & Ganesan, A. Natural products and combinatorial chemistry: back to the future. Curr. Opin. Chem. Biol. 8, 271–280 (2004).

    Article  CAS  Google Scholar 

  5. Rosén, J., Gottfries, J., Muresan, S., Backlund, A. & Oprea, T. I. Novel chemical space exploration via natural products. J. Med. Chem. 52, 1953–1962 (2009).

    Article  Google Scholar 

  6. Eichner, S. et al. The interplay between mutasynthesis and semisynthesis: generation and evaluation of an ansamitocin library. Angew. Chem. Int. Ed. 51, 752–757 (2012).

    Article  CAS  Google Scholar 

  7. Kirschning, A. & Hahn, F. Merging chemical synthesis and biosynthesis: a new chapter in the total synthesis of natural products and natural product libraries. Angew. Chem. Int. Ed. 51, 4012–4022 (2012).

    Article  CAS  Google Scholar 

  8. Goss, R. J. M., Shankar, S. & Fayad, A. A. The generation of ‘unnatural’ products: synthetic biology meets synthetic chemistry. Nat. Prod. Rep. 29, 870–889 (2012).

    Article  CAS  Google Scholar 

  9. Steinmetz, H. et al. Precursor-directed syntheses and biological evaluation of new elansolide derivatives. ChemBioChem 13, 1813–1817 (2012).

    Article  CAS  Google Scholar 

  10. Yan, Y. et al. Multiplexing of combinatorial chemistry in antimycin biosynthesis: expression of molecular diversity and utility. Angew. Chem. Int. Ed. 52, 12308–12312 (2013).

    Article  CAS  Google Scholar 

  11. Altmann, K. H., Gaugaz, F. Z. & Schiess, R. Diversity through semisynthesis: the chemistry and biological activity of semisynthetic epothilone derivatives. Mol. Divers. 15, 383–399 (2011).

    Article  CAS  Google Scholar 

  12. Dupuis, S. N. et al. Synthetic diversification of natural products: semi-synthesis and evaluation of triazole jadomycins. Chem. Sci. 3, 1640–1644 (2012).

    Article  CAS  Google Scholar 

  13. Ignatenko, V. A., Han, Y. & Tochtrop, G. P. Molecular library synthesis using complex substrates: expanding the framework of triterpenoids. J. Org. Chem. 78, 410–418 (2013).

    Article  CAS  Google Scholar 

  14. Balthaser, B. R., Maloney, M. C., Beeler, A. B., Porco, J. A. & Snyder, J. K. Remodeling of the natural product fumagillol employing a reaction discovery approach. Nature Chem. 3, 969–973 (2011).

    Article  CAS  Google Scholar 

  15. Huigens, R. W. et al. A ring-distortion strategy to construct stereochemically complex and structurally diverse compounds from natural products. Nature Chem. 5, 195–202 (2013).

    Article  CAS  Google Scholar 

  16. Keller, N. P., Turner, G. & Bennett, J. W. Fungal secondary metabolism from biochemistry to genomics. Nature Rev. Immunol. 3, 937–947 (2005).

    CAS  Google Scholar 

  17. Kharwar, R. N., Mishra, A., Gond, S. K., Stierle, A. & Stierle, D. Anticancer compounds derived from fungal endophytes: their importance and future challenges. Nat. Prod. Rep. 28, 1208–1228 (2011).

    Article  CAS  Google Scholar 

  18. Brakhage, A. A. & Schroeckh, V. Fungal secondary metabolites—strategies to activate silent gene clusters. Fungal Genet. Biol. 48, 15–22 (2011).

    Article  CAS  Google Scholar 

  19. Scherlach, K. & Hertweck, C. Triggering cryptic natural product biosynthesis in microorganisms. Org. Biomol. Chem. 7, 1753–1760 (2009).

    Article  CAS  Google Scholar 

  20. Fisch, K. M. et al. Chemical induction of silent biosynthetic pathway transcription in Aspergillus niger. J. Ind. Microbiol. Biotechnol. 36, 1199–1213 (2009).

    Article  CAS  Google Scholar 

  21. Khaldi, N. et al. SMURF: genomic mapping of fungal secondary metabolite clusters. Fungal Genet. Biol. 47, 736–741 (2010).

    Article  CAS  Google Scholar 

  22. Tagami, K. et al. Reconstitution of biosynthetic machinery for indole–diterpene paxilline in Aspergillus oryzae. J. Am. Chem. Soc. 135, 1260–1263 (2013).

    Article  CAS  Google Scholar 

  23. Chiang, Y. M. et al. An efficient system for heterologous expression of secondary metabolite genes in Aspergillus nidulans. J. Am. Chem. Soc. 135, 7720–7731 (2013).

    Article  CAS  Google Scholar 

  24. Asai, T. et al. Structurally diverse chaetophenol productions induced by chemically mediated epigenetic manipulation of fungal gene expression. Org. Lett. 15, 3346–3349 (2013).

    Article  CAS  Google Scholar 

  25. Asai, T., Taniguchi, T., Yamamoto, T., Monde, K. & Oshima, Y. Structures of spiroindicumides A and B, unprecedented carbon skeletal spirolactones, and determination of the absolute configuration by vibrational circular dichroism exciton approach. Org. Lett. 15, 4320–4323 (2013).

    Article  CAS  Google Scholar 

  26. Asai, T., Yamamoto, T. & Oshima, Y. Aromatic polyketide production in Cordyceps indigotica, an entomopathogenic fungus, induced by exposure to a histone deacetylase inhibitor. Org. Lett. 14, 2006–2009 (2012).

    Article  CAS  Google Scholar 

  27. Hashimoto, M. et al. Product identification of non-reducing polyketide synthases with C-terminus methyltransferase domain from Talaromyces stipitatus using Aspergillus oryzae heterologous expression. Bioorg. Med. Chem. Lett. 25, 1381–1384 (2015).

    Article  CAS  Google Scholar 

  28. Liao, D., Li, H. & Lei, X. Efficient generation of ortho-quinone methide: application to the biomimetic syntheses of (±)-schefflone and tocopherol trimers. Org. Lett. 14, 18–21 (2012).

    Article  CAS  Google Scholar 

  29. Steinhagen, H. & Corey, E. J. A convenient and versatile route to hydroquinolines by inter- and intramolecular aza-Diels–Alder pathways. Angew. Chem. Int. Ed. 38, 1928–1931 (1999).

    Article  CAS  Google Scholar 

  30. O'Connor, S. E. & Maresh, J. J. Chemistry and biology of monoterpene indole alkaloid biosynthesis. Nat. Prod. Rep. 23, 532–547 (2006).

    Article  CAS  Google Scholar 

  31. Xu, Z., Baunach, M., Ding, L. & Hertweck, C. Bacterial synthesis of diverse indole terpene alkaloids by an unparalleled cyclization sequence. Angew. Chem. Int. Ed. 51, 10293–10297 (2012).

    Article  CAS  Google Scholar 

  32. Boettger, D. & Hertweck, C. Molecular diversity sculpted by fungal PKS–NRPS hybrids. ChemBioChem 14, 28–42 (2013).

    Article  CAS  Google Scholar 

  33. Zi, W., Xie, W. & Ma, D. Total synthesis of akuammiline alkaloid (–)-vincorine via intramolecular oxidative coupling. J. Am. Chem. Soc. 134, 9126–9129 (2012).

    Article  CAS  Google Scholar 

  34. Sandkovsky, U., Vargas, L. & Florescu, D. F. Adenovirus: current epidemiology and emerging approaches to prevention and treatment. Curr. Infect. Dis. Rep. 16, 416–423 (2014).

    Article  Google Scholar 

  35. Naesens, L. et al. Antiadenovirus activities of several classes of nucleoside and nucleotide analogues. Antimicrob. Agents Chemother. 49, 1010–1016 (2005).

    Article  CAS  Google Scholar 

  36. Diaconu, I. et al. Human adenovirus replication in immunocompetent Syrian hamsters can be attenuated with chlorpromazine or cidofovir. J. Gene. Med. 12, 435–445 (2010).

    Article  CAS  Google Scholar 

  37. Morita, H. et al. Synthesis of unnatural alkaloid scaffolds by exploiting plant polyketide synthase. Proc. Natl Acad. Sci. USA 108, 13504–13509 (2013).

    Article  Google Scholar 

  38. Xu, Y. et al. Diversity-oriented combinatorial biosynthesis of benzenediol lactone scaffolds by subunit shuffling of fungal polyketide synthase. Proc. Natl Acad. Sci. USA 111, 12354–12359 (2014).

    Article  CAS  Google Scholar 

  39. Hansen, D. A. et al. Biocatalytic synthesis of pikromycin, methymycin, neomethymycin, novamethymycin, and ketomethymycin. J. Am. Chem. Soc. 135, 11232–11238 (2013).

    Article  CAS  Google Scholar 

  40. Newman, A. G., Vagstad, A. L., Storm, P. A. & Townsend, C. A. Systematic domain swaps of iterative, nonreducing polyketide synthases provide a mechanistic understanding and rationale for catalytic reprogramming. J. Am. Chem. Soc. 136, 7348–7362 (2014).

    Article  CAS  Google Scholar 

  41. Harvey, C. J. B., Puglisi, J. D., Pande, V. S., Cane, D. E. & Khosla, C. Precursor directed biosynthesis of an orthogonally functional erythromycin analogue: selectivity in the ribosome macrolide binding pocket. J. Am. Chem. Soc. 134, 12259–12265 (2012).

    Article  CAS  Google Scholar 

  42. Liu, T., Chiang, Y. M., Somoza, A. D., Oakley, B. R. & Wang, C. C. C. Engineering of an ‘unnatural’ natural product by swapping polyketide synthase domains in Aspergillus nidulans. J. Am. Chem. Soc. 133, 13314–13316 (2011).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by JSPS KAKENHI (grant no. 25108702 to T.A. and 25293022 to Y.O.) from the Japan Society for the Promotion of Science (JSPS) and in part by the Platform for Drug Discovery, Informatics and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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Authors

Contributions

T.A. conceived and designed the experiments, and carried out the experimental work, analysed the experimental results and wrote the manuscript. K.T., S.I. and N.S. performed the experimental work. K.G., M.H. and I.F. discussed the heterologous expression experiment. K.N. and E.K. examined the biological screening. Y.O. discussed all the results and provided oversight.

Corresponding authors

Correspondence to Teigo Asai or Yoshiteru Oshima.

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The authors declare no competing financial interests.

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Asai, T., Tsukada, K., Ise, S. et al. Use of a biosynthetic intermediate to explore the chemical diversity of pseudo-natural fungal polyketides. Nature Chem 7, 737–743 (2015). https://doi.org/10.1038/nchem.2308

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