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 pKa calculations suggest a plausible mechanism for the superior efficacy of the advanced SI spacer compared to state-of-art analogues.

Advanced Pyrrolidine-Carbamate Self-Immolative Spacer with Tertiary Amine Handle Induces Superfast Cyclative Drug Release / A. Dal Corso, M. Frigoli, M. Prevosti, M. Mason, R. Bucci, L. Belvisi, L. Pignataro, C. Gennari. - In: CHEMMEDCHEM. - ISSN 1860-7187. - (2022). [Epub ahead of print] [10.1002/cmdc.202200279]

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

A. Dal Corso
Primo
;
R. Bucci;L. Belvisi;L. Pignataro
Penultimo
;
C. Gennari
Ultimo
2022

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 pKa calculations suggest a plausible mechanism for the superior efficacy of the advanced SI spacer compared to state-of-art analogues.
cascade reactions; disassembly; drug delivery; prodrugs; self-immolative spacers
Settore CHIM/06 - Chimica Organica
27-mag-2022
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/931626
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