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Expedited access to polyunsaturated fatty acids and biofunctional analogues by full solid-phase synthesis

Nature Chemistry volume 17, pages 1391–1400 (2025)Cite this article

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Abstract

Polyunsaturated fatty acids (PUFAs) represent a fundamental and essential class of lipids that exhibit versatile biofunctions. Lipidomic analysis has identified a growing number of lipid species, including PUFAs with diverse structural variations and biofunctions, yet their structure–function relationships are still largely unknown. In this context, an efficient synthesis of PUFAs would be highly desirable. However, no practical methodology exists for their preparation, in contrast to peptides and nucleic acids, for which diverse molecules are accessible through a well-established solid-phase synthesis. To address this, we have developed an efficient and expedited method to access a wide array of PUFAs by full solid-phase synthesis. The method allows the synthesis of various PUFAs and analogues through rapid and facile operations. Moreover, within our PUFA library, we have discovered an artificial fatty acid, antiefin, that has a high anti-inflammatory effect in vivo. Therefore, our practical synthetic pathway to PUFAs, a crucial class of lipids, is expected to make an important contribution to lipid science.

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Fig. 1: Overview of this study.
Fig. 2: Elongation reaction using copper acetylides and solid-phase synthesis of Trp(Boc)-tagged EPA.
Fig. 3: FFAR1 activation by the synthesized PUFAs in the TGFα shedding assay.
Fig. 4: Anti-inflammatory effect of the furanyl PUFA 1r.

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Data availability

The data supporting the findings of this study are available within the Article and its Supplementary Information files. Source data for the assays and measurements are available via the UTokyo Repository at https://repository.dl.itc.u-tokyo.ac.jp/records/2010704 (ref. 44).

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Acknowledgements

This work was performed in part at the One-stop Sharing Facility Center for Future Drug Discoveries in the Graduate School of Pharmaceutical Sciences, The University of Tokyo. We thank K. Nozaki, T. Iwasaki and X. Jin (The University of Tokyo) for fruitful discussions and support with GC measurements. The atomic absorption measurements were performed at the Common Facilities of the Analytical Chemistry Laboratory, Department of Applied Chemistry, School of Engineering, The University of Tokyo. We thank T. Yamagishi (The University of Tokyo) for fruitful discussions and support with the atomic absorption measurements. This research was supported by JSPS KAKENHI (grant nos. JP22K14780 (to Y. Saito) and JP22KJ1101 (to M.A.)), AMED (grant no. JP233fa727001 (to Y. Saito and J.K.)), the Toyota Riken Scholar Program (to Y. Saito), the Mizuho Foundation for the Promotion of Sciences (to Y. Saito), KONICA MINOLTA Award in Synthetic Organic Chemistry, Japan (to Y. Saito) and JST-CREST (grant no. JPMJCR21N5 (to S.S.)).

Author information

Author notes

  1. Azusa Saika

    Present address: Institute of Molecular and Cell Biology, Agency for Science Technology and Research, Singapore, Singapore

  2. Takahiro Nagatake

    Present address: Laboratory of Functional Anatomy, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan

  3. These authors contributed equally: Yutaro Saito, Mayuko Akita, Azusa Saika.

Authors and Affiliations

  1. Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan

    Yutaro Saito, Mayuko Akita, Yusuke Sano, Jumpei Morimoto & Shinsuke Sando

  2. Laboratory of Vaccine Materials, Laboratory of Gut Environmental System, Microbial Research Center for Health and Medicine, National Institutes of Biomedical Innovation, Health and Nutrition (NIBN), Osaka, Japan

    Azusa Saika, Masashi Hotta, Takahiro Nagatake & Jun Kunisawa

  3. Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

    Akiharu Uwamizu & Junken Aoki

  4. Department of Microbiology and Immunology, Kobe University Graduate School of Medicine, Hyogo, Japan

    Jun Kunisawa

  5. International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Jun Kunisawa

  6. Graduate School of Medicine, Graduate School of Dentistry, Graduate School of Pharmaceutical Sciences, Department of Science, The University of Osaka, Osaka, Japan

    Jun Kunisawa

  7. Research Organization for Nano and Life Innovation, Waseda University, Tokyo, Japan

    Jun Kunisawa

  8. Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan

    Shinsuke Sando

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Contributions

Y. Saito, J.K. and S.S. conceived and designed the project. Y. Saito, M.A. and Y. Sano performed the synthetic experiments with the help of J.M. and S.S. Y. Saito, M.A., A.S., M.H. and T.N. performed the cellular experiments with the help of A.U., J.A., J.K. and S.S. A.S., M.H. and T.N. performed the animal experiments with the help of J.K. Finally, Y. Saito, M.A. and S.S wrote the paper, which was edited by all of the co-authors.

Corresponding authors

Correspondence to Yutaro Saito, Jun Kunisawa or Shinsuke Sando.

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Competing interests

Y. Saito, M.A., Y. Sano and S.S. have filed a patent application related to the preparation method of polyunsaturated fatty acids on a solid phase (patent applicant: The University of Tokyo; inventors: Y. Saito, S.S., M.A., Y. Sano and Yaohong Shi; international Patent application number: PCT/JP2025/011856; current application status: pending). All other authors declare no competing interests.

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Supplementary Materials and Methods, Figs. 1–4, Tables 1–6, NMR spectra and HPLC, LC–MS and GC chromatograms.

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Saito, Y., Akita, M., Saika, A. et al. Expedited access to polyunsaturated fatty acids and biofunctional analogues by full solid-phase synthesis. Nat. Chem. 17, 1391–1400 (2025). https://doi.org/10.1038/s41557-025-01853-5

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