The design, synthesis, and evaluation of two universal doxorubicin-linkers: Preparation of conjugates that retain topoisomerase II activity

The design, synthesis, and evaluation of two N-alkylmaleimide aldehydes have been achieved, which upon reductive alkylation with the C3′-amino group of doxorubicin (DOX) permits the preparation of DOX conjugates via Michael addition of thiol-containing vectors. This method enables the mild, facile, and high-throughput preparation of DOX conjugates that retain the basic C3′-nitrogen, a pre-requisite for topoisomerase II inhibition. Seven DOX–amino acid conjugates were prepared, each displaying similar inhibitory activity as the parent drug.

Graphical abstractTwo universal DOX-linkers were synthesized, which in turn allowed the parallel preparation of DOX conjugates that retain topoisomerase II activity.Figure optionsDownload full-size imageDownload as PowerPoint slide