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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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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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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