Synthesis and biological evaluation of 2'-carbamate-linked and 2'-carbonate-linked prodrugs of paclitaxel: selective activation by the tumor-associated protease plasmin.
The nontoxic paclitaxel-2'-carbamate prodrugs 2-5 and paclitaxel-2'-carbonate prodrug 6 were synthesized and tested for activation by the tumor-associated enzyme plasmin. A generally applicable method for the synthesis of paclitaxel-2'-carbamates was developed. In buffer solution, prodrug 2, which contained an unsubstituted ethylenediamine spacer, was not stable, whereas prodrugs 3-6 were highly stable. Prodrugs 3-6 showed on average a decrease in cytotoxicity of more than 8000-fold in comparison with the parent drug in seven human tumor cell lines. Prodrugs 5 and 6 are the most nontoxic prodrugs of paclitaxel that yield the free parent drug upon selective activation currently reported. Enzyme hydrolysis and spacer elimination rates were determined by incubation of prodrugs 5 and 6 in the presence of human plasmin. From these results, prodrug 6 was selected as the promising prodrug for further in vivo studies.
de Groot
F M
FM
Department of Organic Chemistry, NSR-Center for Molecular Structure, Design and Synthesis, University of Nijmegen, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands.
van Berkom
L W
LW
Scheeren
H W
HW
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005341:Fibrinolysin / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D043823:Taxoids; D014407:Tumor Cells, Cultured
C412820:2'-(valyl-leucyl-lysyl-PABC)paclitaxel; D000970:Antineoplastic Agents; D009842:Oligopeptides; D011355:Prodrugs; D043823:Taxoids; D005341:Fibrinolysin; D017239:Paclitaxel