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

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, a...

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Bibliographic Details
Published in:Chemistry : a European journal 2023-08, Vol.29 (45), p.e202300755-n/a
Main Authors: Liu, Bing, Hoeve, Wolter, Versteegen, Ron M., Rossin, Raffaella, Kleijn, Laurens H. J., Robillard, Marc S.
Format: Article
Language:English
Subjects:
Antibodies
Chemistry
cleavable linkers
click chemistry
Drug delivery
iodolactonization
pyridazine elimination
Stereoselectivity
trans-cyclooctene
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Summary: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. Intramolecular iodolactonization was employed for the efficient and stereoselective conversion of an sTCO click‐conjugation precursor to a highly reactive and stable click‐cleavable sTCO antibody conjugate linker.
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.202300755