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

Nature Chemistry volume 7, pages 737–743 (2015)Cite this article

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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 11–19 and azaphilone-type compounds 34–44.
Figure 5: Synthesis of indole–polyketide hybrid compounds.

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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 and Affiliations

  1. Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-yama, Aoba-ku, Sendai, Japan

    Teigo Asai, Kento Tsukada, Satomi Ise, Naoki Shirata & Yoshiteru Oshima

  2. School of Pharmacy, Iwate Medical University, Nishitokuta, Yahaba, Iwate, Japan

    Makoto Hashimoto & Isao Fujii

  3. Graduate School of Agricultural Science, Tohoku University, Sendai, Japan

    Katsuya Gomi

  4. Graduate School of Medicine and Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan

    Kosuke Nakagawara & Eiichi N. Kodama

Authors
  1. Teigo Asai
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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.

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Correspondence to Teigo Asai or Yoshiteru Oshima.

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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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