Amine-Carbamate Self-Immolative Spacers Counterintuitively Release 3° Alcohol at Much Faster Rates than 1° Alcohol Payloads.

Autor: Mason M; Dipartimento di Chimica, Università degli Studi di Milano, Via C. Golgi, 19, I, -20133, Milan, Italy., Bisbal Lopez L; Dipartimento di Chimica, Università degli Studi di Milano, Via C. Golgi, 19, I, -20133, Milan, Italy., Bashiri F; Dipartimento di Chimica, Università degli Studi di Milano, Via C. Golgi, 19, I, -20133, Milan, Italy., Herrero A; Dipartimento di Chimica, Università degli Studi di Milano, Via C. Golgi, 19, I, -20133, Milan, Italy., Baron A; Dipartimento di Chimica, Università degli Studi di Milano, Via C. Golgi, 19, I, -20133, Milan, Italy., Bucci R; Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, via G. Venezian 21, 20133, Milan, Italy., Pignataro L; Dipartimento di Chimica, Università degli Studi di Milano, Via C. Golgi, 19, I, -20133, Milan, Italy., Gennari C; Dipartimento di Chimica, Università degli Studi di Milano, Via C. Golgi, 19, I, -20133, Milan, Italy., Dal Corso A; Dipartimento di Chimica, Università degli Studi di Milano, Via C. Golgi, 19, I, -20133, Milan, Italy.
Jazyk: angličtina
Zdroj: Chembiochem : a European journal of chemical biology [Chembiochem] 2024 Apr 16; Vol. 25 (8), pp. e202400174. Date of Electronic Publication: 2024 Mar 14.
DOI: 10.1002/cbic.202400174
Abstrakt: Self-immolative (SI) spacers are degradable chemical connectors widely used in prodrugs and drug conjugates to release pharmaceutical ingredients in response to specific stimuli. Amine-carbamate SI spacers are particularly versatile, as they have been used to release different hydroxy cargos, ranging from 2° and 3° alcohols to phenols and oximes. In this work, we describe the ability of three amine-carbamate SI spacers to release three structurally similar imidazoquinoline payloads, bearing either a 1°, a 2° or a 3° alcohol as the leaving group. While the spacers showed comparable efficacy at releasing the 2° and 3° alcohols, the liberation of the 1° alcohol was much slower, unveiling a counterintuitive trend in nucleophilic acyl substitutions. The release of the 1° alcohol payload was only possible using a SI spacer bearing a pyrrolidine ring and a tertiary amine handle, which opens the way to future applications in drug delivery systems.
(© 2024 Wiley‐VCH GmbH.)
Databáze: MEDLINE
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