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Synthesis of branched arabinogalactans up to a 140-mer from Panax notoginseng and their anti-pancreatic-cancer activity

Nature Synthesis volume 3, pages 245–255 (2024)Cite this article

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Abstract

RN1, a highly branched arabinogalactan isolated from the flower of Panax notoginseng, possesses a potent ability to inhibit the development of pancreatic cancer. Due to the structural complexity and heterogeneity of RN1, it is difficult to extract homogeneous RN1 from natural sources. The structure–activity relationship is ambiguous, particularly the correlation between molecular size and function. We report the total synthesis of the RN1 glycan featuring 140 monosaccharide units via an efficient iterative preactivation-based one-pot glycosylation strategy, providing an intact complex polysaccharide, allowing investigation of its structure–activity relationship. Using this glycosylation strategy, a glycan library comprising nine molecules was constructed, ranging from 5-mer to 140-mer. Finally, all compounds in the library were screened for anti-pancreatic-cancer activity via detection of cell proliferation, apoptosis and cell cycle. The active structural domain of RN1 was revealed to be a decasaccharide fragment that exhibited superior performance compared to gemcitabine, a frequently used anti-pancreatic-cancer drug.

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Fig. 1: The structure of highly branched arabinogalactan RN1 and the retrosynthetic analysis by an iterative preactivation-based one-pot glycan assembly protocol.
Fig. 2: Synthesis of two repeating 10-mer units.
Fig. 3: Synthesis of 40-mer donor 2 and 100-mer acceptor 3.
Fig. 4: Assembly of protected 140-mer 26 and its full deprotection to 1 (RN1).
Fig. 5: Synthesis of a glycan library ranging from 5-mer to 70-mer.
Fig. 6: Structural characterization of protected and deprotected glycans.
Fig. 7: Anti-pancreatic-cancer activity evaluation of synthetic glycans.

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Data availability

All data supporting the results and conclusions are available within the article and its Supplementary Information. Synthetic experimental procedures, compound characterization, NMR and mass spectrometer results are available in the Supplementary Information. Requests for materials should be addressed to X.-S.Y. Source data are provided with this paper.

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Acknowledgements

This work was financially supported by grants from the National Natural Science Foundation of China (22237001, 81821004), the National Key Research and Development Program of China (2022YFC3400800) and the Beijing Outstanding Young Scientist Program (BJJWZYJH01201910001001). We thank Q. Li, F. Liu, L. Zhong, X. Shi, X. Liu, W. Zhou and S. Di at Peking University for their helpful assistance in analysis of glycan structures. We thank C. Ju at the Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, for her assistance in analysis of biological results. We thank K. Ding at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, for his discussion about the structure of RN1.

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Authors and Affiliations

  1. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, and Chemical Biology Center, Peking University, Beijing, China

    Xianjin Qin, Chenghao Xu, Mingli Liu, Fansheng Zeng, Wenlong Yao, Yi Deng, Tianfu Xu, Shengyuan Sun, Dongyue Sun, Juan Mo & Xin-Shan Ye

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Contributions

X.-S.Y. conceived the research. X.Q. and X.-S.Y. designed the experiments. X.Q. performed most of the synthetic experiments. X.Q., C.X. and J.M. performed biological evaluation experiments. M.L., F.Z., W.Y., Y.D., T.X., S.S. and D.S. synthesized some monosaccharide and disaccharide building blocks. X.Q. and X.-S.Y. analysed the data. X.Q. and X.-S.Y. wrote the manuscript. X.-S.Y. supervised the project.

Corresponding author

Correspondence to Xin-Shan Ye.

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X.-S.Y. and X.Q. are applying for a Chinese patent filed by Peking University. The remaining authors declare no competing interests.

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Nature Synthesis thanks Kan Ding, Chi-Huey Wong and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information

General Methods and Materials (pages 2–3); Experimental Procedures and Characterization of Compounds (Supplementary Schemes 1–13 and Tables 1–4); Construction of Glycan Library (Supplementary Schemes 14–18 and Table 5); Structural Characterization (Supplementary Figs. 1–4); NMR and Mass Spectra (pages 89–366); Repeating units of RN1 (Supplementary Fig. 5, page 370).

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Unprocessed optical density value for the viability test and unprocessed cell cycle results.

Source Data Fig. 7

Unprocessed cell apoptosis and cell cycle results.

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Qin, X., Xu, C., Liu, M. et al. Synthesis of branched arabinogalactans up to a 140-mer from Panax notoginseng and their anti-pancreatic-cancer activity. Nat. Synth 3, 245–255 (2024). https://doi.org/10.1038/s44160-023-00428-x

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