A Concise Synthetic Approach to Highly Reactive Click-to-Release Trans-Cyclooctene Linkers

Bing Liu; Wolter ten Hoeve; Ron M. Versteegen; Raffaella Rossin; Laurens H.J. Kleijn; Marc S. Robillard

doi:10.1002/chem.202300755

A Concise Synthetic Approach to Highly Reactive Click-to-Release Trans-Cyclooctene Linkers

Bing Liu, Wolter ten Hoeve, Ron M. Versteegen, Raffaella Rossin, Laurens H.J. Kleijn, Marc S. Robillard (Corresponding author)

Research output: Contribution to journal › Article › Academic › peer-review

8 Citations (Scopus)

Abstract

An increase in the click-to-release reaction rate between cleavable trans-cyclooctenes (TCO) and tetrazines would be beneficial for drug delivery applications. In this work, we have developed a short and stereoselective synthesis route towards highly reactive sTCOs that serve as cleavable linkers, affording quantitative tetrazine-triggered payload release. In addition, the fivefold more reactive sTCO exhibited the same in vivo stability as current TCO linkers when used as antibody linkers in circulation in mice.

Original language	English
Article number	e202300755
Number of pages	5
Journal	Chemistry - A European Journal
Volume	29
Issue number	45
DOIs	https://doi.org/10.1002/chem.202300755
Publication status	Published - 10 Aug 2023
Externally published	Yes

Funding

Lieke Wouters (Tagworks Pharmaceuticals) is kindly acknowledged for her contribution to in vitro stability evaluations.

Keywords

cleavable linkers
click chemistry
iodolactonization
pyridazine elimination
trans-cyclooctene
Animals
Cyclooctanes/chemistry
Mice
Drug Delivery Systems

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10.1002/chem.202300755

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title = "A Concise Synthetic Approach to Highly Reactive Click-to-Release Trans-Cyclooctene Linkers",

abstract = "An increase in the click-to-release reaction rate between cleavable trans-cyclooctenes (TCO) and tetrazines would be beneficial for drug delivery applications. In this work, we have developed a short and stereoselective synthesis route towards highly reactive sTCOs that serve as cleavable linkers, affording quantitative tetrazine-triggered payload release. In addition, the fivefold more reactive sTCO exhibited the same in vivo stability as current TCO linkers when used as antibody linkers in circulation in mice.",

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AU - Rossin, Raffaella

AU - Kleijn, Laurens H.J.

AU - Robillard, Marc S.

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AB - An increase in the click-to-release reaction rate between cleavable trans-cyclooctenes (TCO) and tetrazines would be beneficial for drug delivery applications. In this work, we have developed a short and stereoselective synthesis route towards highly reactive sTCOs that serve as cleavable linkers, affording quantitative tetrazine-triggered payload release. In addition, the fivefold more reactive sTCO exhibited the same in vivo stability as current TCO linkers when used as antibody linkers in circulation in mice.

KW - cleavable linkers

KW - click chemistry

KW - iodolactonization

KW - pyridazine elimination

KW - trans-cyclooctene

KW - Animals

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KW - Drug Delivery Systems

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A Concise Synthetic Approach to Highly Reactive Click-to-Release Trans-Cyclooctene Linkers

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