NEW ACTIVE PACLITAXEL AMINO-ACIDS DERIVATIVES WITH IMPROVED WATER SOLUBILITY

Paclitaxel shows interesting clinical activity against sever al tumors . However, its poor solubility is an important limitation: Cremophor E L used for intravenous administration is responsible for hypersensitiv ity reactions. In order to improve solubility while preserving the act ivity, we have synthesized new paclitaxel amino acid derivatives subst ituted with a glutaryl group at the 2' position followed by the reacti on of a peptide link between the carboxyl and the amino terminal group of the amino acid. The derivatives were cytotoxic in vitro against ma ny sensitive cell lines. They also increased G(2)+M phase arrest Moreo ver these derivatives were stable for over a year and showed a better solubility in water than the parent compound. The ester linkage is hyd rolysed in slightly acid lysosomal conditions to free paclitaxel which binds to tubulin.