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

Chembiochem. 2024 Feb 28:e202400174. doi: 10.1002/cbic.202400174. Online ahead of print.ABSTRACTSelf-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.PMID:38415320 | DOI:10.1002/cbic.202400174
Source: Chembiochem - Category: Biochemistry Authors: Source Type: research