Iodine-Mediated Tryptathionine Formation Facilitates the Synthesis of Amanitins

Autor:	Bettina G. Keller, Hendrik Gruß, Guiyang Yao, Andreas Pahl, Marius T. Wenz, Simone Kosol, Caroline H. Knittel, Torsten Hechler, Alexandra Braun, Roderich D. Süssmuth, Christian Lutz
Rok vydání:	2021
Předmět:	chemistry.chemical_classification biology Toxin Chemistry Cancer therapy Total synthesis RNA polymerase II General Chemistry medicine.disease_cause Biochemistry Catalysis Amino acid Colloid and Surface Chemistry medicine Rapid access biology.protein Cytotoxicity Amanitin
Zdroj:	Journal of the American Chemical Society. 143:14322-14331
ISSN:	1520-5126 0002-7863
DOI:	10.1021/jacs.1c06565
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9ea3c528059bc7ff978e0918406aab84 https://doi.org/10.1021/jacs.1c06565 Zobrazit plný text záznamu