Advanced Pyrrolidine‐Carbamate Self‐Immolative Spacer with Tertiary Amine Handle Induces Superfast Cyclative Drug Release. (14th June 2022)

• Record Type: Journal Article
• Authors: Dal Corso, Alberto; Frigoli, Margaux; Prevosti, Martina; Mason, Mattia; Bucci, Raffaella; Belvisi, Laura; Pignataro, Luca; Gennari, Cesare
• Is Part Of: ChemMedChem. Volume 17:Number 15(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-06-14
• Subjects: cascade reactions -- disassembly -- drug delivery -- prodrugs -- self-immolative spacers; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202200279
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: 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 p K a calculations suggest a plausible mechanism for the superior efficacy of the advanced SI spacer compared to state‐of‐art analogues. Abstract : The functionalization of a pyrrolidine‐carbamate self‐immolative spacer with a tertiary amine handle leads to a highly reactive construct, showing fast carbamate cleavage and release of OH‐bearing drugs.