New active paclitaxel amino acids derivatives with improved water solubility.
Paclitaxel shows interesting clinical activity against several tumors. However, its poor solubility is an important limitation: Cremophor EL used for intravenous administration is responsible for hypersensitivity reactions. In order to improve solubility while preserving the activity, we have synthesized new paclitaxel amino acid derivatives substituted with a glutaryl group at the 2' position followed by the reaction of a peptide link between the carboxyl and the amino terminal group of the amino acid. The derivatives were cytotoxic in vitro against many sensitive cell lines. They also increased G2+M phase arrest. Moreover, these derivatives were stable for over a year and showed a better solubility in water than the parent compound. The ester linkage is hydrolysed in slightly acid lysosomal conditions to free paclitaxel which binds to tubulin.
Department of Biochemistry, Faculty of Medicine, Université Laval, Sie-Foy, Québec, Canada.
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D000596:Amino Acids; D000818:Animals; D001216:Asparagine; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D015195:Drug Design; D005260:Female; D005973:Glutamine; D005990:Glycerol / Q000031:analogs & derivatives; D005998:Glycine; D006801:Humans; D008546:Melanoma, Experimental; D051379:Mice; D015394:Molecular Structure; D010051:Ovarian Neoplasms; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D012694:Serine; D012995:Solubility; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014867:Water
D000596:Amino Acids; D014867:Water; D005973:Glutamine; D012694:Serine; C000515:cremophor EL; D001216:Asparagine; D017239:Paclitaxel; D005990:Glycerol; D005998:Glycine