Design, Synthesis, and Biochemical Evaluation of Alpha-Amanitin Derivatives Containing Analogs of the trans-Hydroxyproline Residue for Potential Use in Antibody-Drug Conjugates.

Kaveh Matinkhoo, Antonio A W L Wong, Chido M Hambira, Brandon Kato, Charlie Wei, Christoph Müller, Torsten Hechler, Alexandra Braun, Francesca Gallo, Andreas Pahl, David M Perrin

Chemistry (Weinheim an der Bergstrasse, Germany) 2021 Jul 16

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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. © 2021 Wiley-VCH GmbH.

Citation

Kaveh Matinkhoo, Antonio A W L Wong, Chido M Hambira, Brandon Kato, Charlie Wei, Christoph Müller, Torsten Hechler, Alexandra Braun, Francesca Gallo, Andreas Pahl, David M Perrin. Design, Synthesis, and Biochemical Evaluation of Alpha-Amanitin Derivatives Containing Analogs of the trans-Hydroxyproline Residue for Potential Use in Antibody-Drug Conjugates. Chemistry (Weinheim an der Bergstrasse, Germany). 2021 Jul 16;27(40):10282-10292