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Advanced Pyrrolidine‐Carbamate Self‐Immolative Spacer with Tertiary Amine Handle Induces Superfast Cyclative Drug Release

Amine‐carbamate self‐immolative (SI) spacers represent practical and versatile tools in targeted prodrugs, but their slow degradation mechanism limits drug activation at the site of disease. We engineered a pyrrolidine‐carbamate SI spacer with a tertiary amine handle which strongly accelerates the s...

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Detalles Bibliográficos
Autores principales: Dal Corso, Alberto, Frigoli, Margaux, Prevosti, Martina, Mason, Mattia, Bucci, Raffaella, Belvisi, Laura, Pignataro, Luca, Gennari, Cesare
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9544318/
https://www.ncbi.nlm.nih.gov/pubmed/35620983
http://dx.doi.org/10.1002/cmdc.202200279
Descripción
Sumario:Amine‐carbamate self‐immolative (SI) spacers represent practical and versatile tools in targeted prodrugs, but their slow degradation mechanism limits drug activation at the site of disease. We engineered a pyrrolidine‐carbamate SI spacer with a tertiary amine handle which strongly accelerates the spacer cyclization to give a bicyclic urea and the free hydroxy groups of either cytotoxic (Camptothecin) or immunostimulatory (Resiquimod) drugs. In silico conformational analysis and pK (a) calculations suggest a plausible mechanism for the superior efficacy of the advanced SI spacer compared to state‐of‐art analogues.