Development of protein-binding bifunctional linkers for a new generation of dual-acting prodrugs.
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 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.
Abu Ajaj
Khalid
K
Tumor Biology Center, Breisacher Strasse 117, 79106 Freiburg, Germany.
Biniossek
Martin L
ML
Kratz
Felix
F
D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism; D002401:Cathepsin B / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D004317:Doxorubicin / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D008301:Maleimides / Q000737:chemistry; D017239:Paclitaxel / Q000737:chemistry / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism*; D012709:Serum Albumin / Q000378:metabolism
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D008301:Maleimides; D011355:Prodrugs; D011506:Proteins; D012709:Serum Albumin; C043592:maleimide; D004317:Doxorubicin; D002401:Cathepsin B; D017239:Paclitaxel