posted on 2021-08-30, 14:37authored byGuiyang Yao, Caroline H. Knittel, Simone Kosol, Marius T. Wenz, Bettina G. Keller, Hendrik Gruß, Alexandra C. Braun, Christian Lutz, Torsten Hechler, Andreas Pahl, Roderich D. Süssmuth
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 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.