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

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.

PNA-Based Dynamic Combinatorial Libraries (PDCL) and screening of lectins.

Selections from dynamic combinatorial libraries (DCL) benefit from the dynamic nature of the library that can change constitution upon addition of a selection pressure, such as ligands binding to a protein. This technology has been predominantly used with small molecules interacting with each other through reversible covalent interaction. However, application of this technology in biomedical research and drug discovery has been limited by the reversibility of covalent exchange and the analytical deconvolution of small molecule fragments.