Synthesis of novel paclitaxel prodrugs designed for bioreductive activation in hypoxic tumour tissue.
The syntheses and preliminary evaluation of the first potential bioreductive paclitaxel prodrugs are described. These prodrugs were designed as potential candidates in more selective chemotherapy by targeting hypoxic tumour tissue. Aromatic nitro and azide groups were used as the bioreductive trigger. Generation of paclitaxel occurs after reduction and subsequent 1,6-elimination or 1,8-elimination. All prodrugs are stable in buffer and indeed give paclitaxel after chemical reduction of the aromatic nitro or azide functionality. In aerobic cytotoxicity assays several prodrugs exhibit diminished cytotoxicity. These compounds are interesting candidates for further biological evaluation.
Damen
Eric W P
EW
Department of Organic Chemistry, NSR Center for Molecular Structure, Design and Synthesis, University of Nijmegen, Toernooiveld, 6525 ED, Nijmegen, The Netherlands.
Nevalainen
Tapio J
TJ
van den Bergh
Toine J M
TJ
de Groot
Franciscus M H
FM
Scheeren
Hans W
HW
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D002455:Cell Division / Q000187:drug effects; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D010084:Oxidation-Reduction; D017239:Paclitaxel / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D013057:Spectrum Analysis; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D011355:Prodrugs; D017239:Paclitaxel