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.
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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