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Design, Synthesis, and Biochemical Evaluation of Alpha‐Amanitin Derivatives Containing Analogs of the trans ‐Hydroxyproline Residue for Potential Use in Antibody‐Drug Conjugates
Author(s) -
Matinkhoo Kaveh,
Wong Antonio A. W. L.,
Hambira Chido M.,
Kato Brandon,
Wei Charlie,
Müller Christoph,
Hechler Torsten,
Braun Alexandra,
Gallo Francesca,
Pahl Andreas,
Perrin David M.
Publication year - 2021
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202101373
Subject(s) - amanita phalloides , chemistry , stereochemistry , allosteric regulation , residue (chemistry) , biochemistry , drug , pharmacology , enzyme , biology , botany
Alpha‐amanitin, an extremely toxic bicyclic octapeptide extracted from the death‐cap mushroom, Amanita phalloides , is a highly selective allosteric inhibitor of RNA polymerase II. Following on growing interest in using this toxin as a payload in antibody‐drug conjugates, herein we report the synthesis and biochemical evaluation of several new derivatives of this toxin to probe the role of the trans ‐hydroxyproline (Hyp), which is known to be critical for toxicity. This structure activity relationship (SAR) study represents the first of its kind to use various Hyp‐analogs to alter the conformational and H‐bonding properties of Hyp in amanitin.