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Fast Cyclization of a Proline‐Derived Self‐Immolative Spacer Improves the Efficacy of Carbamate Prodrugs
Author(s) -
Dal Corso Alberto,
Borlandelli Valentina,
Corno Cristina,
Perego Paola,
Belvisi Laura,
Pignataro Luca,
Gennari Cesare
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201916394
Subject(s) - prodrug , chemistry , carbamate , combinatorial chemistry , in vitro , stereochemistry , cleavage (geology) , drug delivery , pyrrolidine , protease , organic chemistry , enzyme , biochemistry , geotechnical engineering , fracture (geology) , engineering
Abstract Self‐immolative (SI) spacers are sophisticated chemical constructs designed for molecular delivery or material degradation. We describe herein a ( S )‐2‐(aminomethyl)pyrrolidine SI spacer that is able to release different types of anticancer drugs (possessing either a phenolic or secondary and tertiary hydroxyl groups) through a fast cyclization mechanism involving carbamate cleavage. The high efficiency of drug release obtained with this spacer was found to be beneficial for the in vitro cytotoxic activity of protease‐sensitive prodrugs, compared with a commonly used spacer of the same class. These findings expand the repertoire of degradation machineries and are instrumental for the future development of highly efficient delivery platforms.