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

• Published in: Chembiochem : a European journal of chemical biology 2024-04, Vol.25 (8), p.e202400174-n/a
• Main Authors: Mason, Mattia, Bisbal Lopez, Lydia, Bashiri, Fazel, Herrero, Aurélie, Baron, Aurélien, Bucci, Raffaella, Pignataro, Luca, Gennari, Cesare, Dal Corso, Alberto
• Format: Article
• Language: English
• Subjects: Alcohols; carbamates; Connectors; Drug delivery; Drug delivery systems; Oximes; Payloads; Phenols; prodrugs; Pyrrolidine; self-immolative spacers; Spacers; TLR agonists
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.202400174

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. The hydroxy groups of structurally‐similar imidazoquinoline payloads are released with different rates from amine‐carbamate self‐immolative (SI) spacers, depending on the extent of C‐α substitution. Unexpectedly, the 2° and 3° alcohol payloads are released with much faster rates than the 1° alcohol, which can be uncaged only by a hyper‐reactive SI spacer.