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Readily Accessible Strained Difunctionalized trans-Cyclooctenes with Fast Click and Release Capabilities.

Daan SondagLuuk MaartenseHeleen de JongFrank F J de KleijneKimberly M BongerDennis W P M LöwikThomas J BoltjeJan DommerholtPaul B WhiteDaniel Blanco-AniaFloris P J T Rutjes
Published in: Chemistry (Weinheim an der Bergstrasse, Germany) (2022)
The click reaction between a functionalized trans-cyclooctene (TCO) and a tetrazine (Tz) is a compelling method for bioorthogonal conjugation in combination with payload releasing capabilities. However, the synthesis of difunctionalized TCOs remains challenging. As a result, these compounds are poorly accessible, which impedes the development of novel applications. In this work, the scalable and accessible synthesis of a new bioorthogonal difunctionalized TCO is reported in only four single selective high yielding steps starting from commercially available compounds. The TCO-Tz click reaction was assessed and revealed excellent kinetic rates and subsequently payload release was shown with various functionalized derivatives. Tetrazine triggered release of carbonate and carbamate payloads was demonstrated up to 100 % release efficiency and local drug release was shown in a cellular toxicity study which revealed a >20-fold increase in cytotoxicity.
Keyphrases
  • drug release
  • drug delivery
  • single cell
  • oxidative stress
  • molecularly imprinted