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.

Keywords: cleavable linkers; click chemistry; iodolactonization; pyridazine elimination; trans-cyclooctene.