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.