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Iodine-mediated tryptathionine formation facilitates the synthesis of novel amanitines

G. Yao, C.H. Knittel, S. Kosol, M. Wenz, B.G. Keller, H. Gruß, A. Braun, C. Lutz, T. Hechler, A. Pahl, R.D. Süssmuth ``' – 2021

Synthetic methods on the macrocyclization of peptides are of high interest since they facilitate the synthesis of various types of potentially bioactive compounds, e.g. addressing targets like protein-protein-interactions. Herein, we report on an efficient method to construct tryptathioninecrosslinks in peptides between the amino acids Trp and Cys. This reaction not only is the basis for the total synthesis of the death cap toxin α-amanitin but also provides rapid access to various new amanitin analogues. This study for the first time presents a systematic compilation of structure activity relations (SAR) of amatoxins with regard to RNA polymerase II inhibition and cytotoxicity with one amanitin derivative of superior RNAP II inhibition. The present approach paves the way for the synthesis of structurally diverse amatoxins as future payloads for antibody-toxin-conjugates in cancer therapy.

Title
Iodine-mediated tryptathionine formation facilitates the synthesis of novel amanitines
Author
G. Yao, C.H. Knittel, S. Kosol, M. Wenz, B.G. Keller, H. Gruß, A. Braun, C. Lutz, T. Hechler, A. Pahl, R.D. Süssmuth ``'
Date
2021
Citation
J. Am. Chem. Soc. (accepted)
Type
Text