A double-triggered self-immolative spacer for increased selectivity of molecular release

Huvelle, Steve; Saux, Thomas Le; Jullien, Ludovic

doi:10.1039/d1ob02124a

Org. Biomol. Chem.

2022

DOI: 10.1039/d1ob02124a

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A double-triggered self-immolative spacer for increased selectivity of molecular release

Steve Huvelle

Thomas Le Saux

Ludovic Jullien

Abstract: A self-immolative spacer based on disymetrical N,N’ bis carbamate aniline is introduced to liberate a substrate from a precursor after dual activation. The proof of principle of its exclusive selectivity...

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Cited by 2 publications

References 27 publications

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

Mason,

Bisbal Lopez,

Bashiri

et al. 2024

ChemBioChem

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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.

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

Mason,

Bisbal Lopez,

Bashiri

et al. 2024

ChemBioChem

View full text Add to dashboard Cite

show abstract

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

et al. 2022

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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.

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A double-triggered self-immolative spacer for increased selectivity of molecular release

Abstract: A self-immolative spacer based on disymetrical N,N’ bis carbamate aniline is introduced to liberate a substrate from a precursor after dual activation. The proof of principle of its exclusive selectivity...

Cited by 2 publications

References 27 publications

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

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

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

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