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

Abstract

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

Keywords

• docetaxel
• chemo-enzymatic synthesis
• glycoside
• ester-linker
• prodrug
• cytotoxicity