Development of Protein-Binding Bifunctional Linkers for a New Generation of Dual-Acting Prodrugs

摘要

The aim of this work was to develop a new bifunctional maleimide linker for the development of dual-acting prodrugs that incorporate two pharmaceutically different anticancer agents independently bound by enzymatically cleavable substrates.The linker consists of a carboxyl group in one arm and an activated 1,6-self-immolative para-aminobenzyloxycarbonyl spacer together with a cathepsin B cleavable dipeptide Phe-Lys in the other.Aided with this linker,we have prepared a fhiol-binding prodrug that contains the anticancer drugs doxorubicin and paclitaxel.Bound to the cysteine-34 position of albumin,it was cleaved efficiently by cathepsin B releasing the free drugs.