4.7 Article

Tetrazine-induced activation of a trimethyl lock as a click-to-release system for protected doxorubicin

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CHEMICAL COMMUNICATIONS
卷 59, 期 48, 页码 7451-7454

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ROYAL SOC CHEMISTRY
DOI: 10.1039/d3cc01334k

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We describe a chemically triggered click-to-release system that combines the trimethyl lock (TML) lactonization with the bioorthogonal inverse electron demand Diels-Alder (IEDDA) reaction of a vinyl ether and a tetrazine. The IEDDA reaction was found to be rate-limiting in the three-step sequence. The reaction rates could be enhanced by increasing the electrophilicity of the tetrazine, while maintaining reactivity and stability. The system was successfully demonstrated with the release of an anticancer drug from a vinyl-modified TML.
We herein report a novel chemically triggered click-to-release system, that combines the trimethyl lock (TML) lactonization with the bioorthogonal inverse electron demand Diels-Alder (IEDDA) reaction of a vinyl ether and a tetrazine. Kinetic studies were carried out on a vinyl phenol model system with six tetrazines using NMR and UV/Vis spectroscopy, revealing that within the three step sequence the IEDDA reaction was rate-limiting. The reaction rates were enhanced by increasing the electrophilicity of the tetrazine, while balancing reactivity and stability of the tetrazines. The anticancer drug doxorubicin was conjugated to a vinyl-modified TML. Its subsequent liberation from vinyl-TML was triggered by dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate and followed quantitatively by NMR, thereby providing a proof-of-concept for the tetrazine/TML click-to-release system. In addition the applicability of the reaction under physiolgoical conditions could be shown.

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