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ABSTRACT

 

 

Development of protein-binding bifunctional linkers for a new generation of dual-acting prodrugs

 

Khalid Abu Ajaj, Martin Biniossek, Felix Kratz

 

 

Bioconjugate Chemistry, 2009, 20 (2), 390–396

 

Keywords: combination chemotherapy; albumin-binding prodrug; albumin; cathepsin B; 1,6-self-immolative spacer; doxorubicin; paclitaxel

 

Abstract: The aim of this work was to develop a new bifunctional maleimide linker for the development of dual-acting prodrugs that incorporate two different pharmaceutically 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 thiol-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.

 

 

 

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