4.8 Article

Iodine-Mediated Tryptathionine Formation Facilitates the Synthesis of Amanitins

Journal

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 143, Issue 35, Pages 14322-14331

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/jacs.1c06565

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Funding

  1. Alexander von Humboldt Foundation
  2. Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [RTG 2473]

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The study presents an efficient method for constructing tryptathionine-cross-links in peptides between tryptophan and cysteine, which is essential for synthesizing alpha-amanitin and new amanitin analogues. It also provides a systematic compilation of structure-activity relations of amatoxins, showing potential for synthesizing structurally diverse amatoxins as future payloads for antibody-toxin conjugates in cancer therapy.
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 tryptathionine-cross-links 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 alpha-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.

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