Fast Cyclization of a Proline‐Derived Self‐Immolative Spacer Improves the Efficacy of Carbamate Prodrugs. Issue 10 (22nd January 2020)

• Record Type: Journal Article
• Authors: Dal Corso, Alberto; Borlandelli, Valentina; Corno, Cristina; Perego, Paola; Belvisi, Laura; Pignataro, Luca; Gennari, Cesare
• Is Part Of: Angewandte Chemie international edition. Volume 59:Issue 10(2020)
• Page Start: 4176
• Page End: 4181
• Publication Date: 2020-01-22
• Subjects: cascade reactions -- disassembly -- drug delivery -- prodrugs -- self-immolative spacers; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201916394
• Languages: English
• ISSNs: 1433-7851

Abstract

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. Abstract : A matter of time : The fast cyclization of a proline‐derived self‐immolative spacer results in the cleavage of otherwise stable carbamates and leads to the efficient release of hydroxyl‐bearing drugs. This accelerated drug release enhances the in vitro anticancer activity of model prodrugs compared with a commonly used spacer of the same class.