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Application of the highly sensitive labeling reagent to the structural confirmation of readily isomerizable peptides

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Abstract

Thioamycolamide A (1) is a biosynthetically unique cytotoxic cyclic microbial lipopeptide that bears a d-configured thiazoline, a thioether bridge, a fatty acid side chain, and a reduced C-terminus. It has gained attention for its unique structure, and very recently we reported the total synthesis of 1 via a biomimetic route. The NMR spectra of synthetic 1 agreed with those of natural 1. However, structural identity between peptidic natural and synthetic compounds is often difficult to confirm by comparison of NMR spectra because their NMR spectra vary depending on the conditions in the NMR tube, which often result in the structural misassignment of peptidic compounds. Especially, our total synthesis based on the putative biomimetic route potentially gives 1 as a diastereomixture at the final step. The problem is that the diastereomers of peptidic mid-sized molecules often exhibit similar properties (such as NMR spectra and bioactivities), and their separation procedures are often laborious. Herein we report the structural confirmation of synthetic 1 by the LC–MS-based chromatographic comparison with the use of our highly sensitive labeling reagent l-FDVDA; the highly sensitive-advanced Marfey’s method (HS-advanced Marfey’s method). This work demonstrated the utility of our highly sensitive labeling reagent for the structural determination of not only scarce natural products but also readily isomerizable synthetic compounds.

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Acknowledgments

This work was financially supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan [17H06401 (H.K.), 18K14396 (T.K.), and 19H02840 (H.K.)], and the Platform Project for Supporting Drug Discovery and Life Science Research from the Japan Agency for Medical Research and Development (AMED), Japan. Contributions from the SUNBOR GRANT, the Daiichi-Sankyo Award in The Society of Synthetic Organic Chemistry Japan, the Takeda Science Foundation, and The Tokyo Biochemical Research Foundation to T.K. are also greatly appreciated.

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Correspondence to Takefumi Kuranaga or Hideaki Kakeya.

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Pan, C., Kuranaga, T. & Kakeya, H. Application of the highly sensitive labeling reagent to the structural confirmation of readily isomerizable peptides. J Nat Med 75, 339–343 (2021). https://doi.org/10.1007/s11418-020-01472-z

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