Chemo-Enzymatic Synthesis of Ester-Linked Docetaxel-Monosaccharide Conjugates as Water-Soluble Prodrugs

Three new docetaxel prodrugs, i.e., 7-propionyldocetaxel 3''-O-β-D-glycopyranosides, which contain ester-linked monosaccharides, were synthesized by a chemo-enzymatic procedure involving enzymatic transglycosylations with lactase, β-galactosidase, or β-xylosidase. The water-solubility of 7-propionyldocetaxel 3''-O-β-D-glucopyranoside was 52-fold higher than that of docetaxel. 7-Propionyldocetaxel 3''-O-β-D-glucopyranoside and 7-propionyldocetaxel 3''-O-β-D-xylopyranoside were effectively hydrolyzed by the relevant enzyme(s) of human cancer cells to release docetaxel, whereas 7-propionyldocetaxel 3''-O-β-D-galactopyranoside was relatively resistant under similar conditions. 7-Propionyldocetaxel 3''-O-β-D-glucopyranoside and 7-propionyldocetaxel 3''-O-β-D-xylopyranoside showed in vitro cytotoxic activity against human cancer cells, whereas 7-propionyldocetaxel 3''-O-β-D-galactopyranoside exerted low cytotoxicity.