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Fluorescent Isoindole Crosslink (FlICk) Chemistry: A Rapid, User‐friendly Stapling Reaction
Author(s) -
Todorovic Mihajlo,
Schwab Katerina D.,
Zeisler Jutta,
Zhang Chengcheng,
Bénard Francois,
Perrin David M.
Publication year - 2019
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201906514
Subject(s) - isoindole , chemistry , bicyclic molecule , peptide , fluorescence , combinatorial chemistry , stereochemistry , indole test , biochemistry , physics , quantum mechanics
The stabilization of peptide secondary structure via stapling is a ubiquitous goal for creating new probes, imaging agents, and drugs. Inspired by indole‐derived crosslinks found in natural peptide toxins, we employed ortho ‐phthalaldehydes to create isoindole staples, thus transforming inactive linear and monocyclic precursors into bioactive monocyclic and bicyclic products. Mild, metal‐free conditions give an array of macrocyclic α‐melanocyte‐stimulating hormone (α‐MSH) derivatives, of which several isoindole‐stapled α‐MSH analogues ( K i ≈1 n m ) are found to be as potent as α‐MSH. Analogously, late‐stage intra‐annular isoindole stapling furnished a bicyclic peptide mimic of α‐amanitin that is cytotoxic to CHO cells (IC 50 =70 μ m ). Given its user‐friendliness, we have termed this approach FlICk (fluorescent isoindole crosslink) chemistry.