Chemo-enzymatic synthesis of ester-linked docetaxel-monosaccharide conjugates as water-soluble prodrugs

Molecules. 2011 Aug 9;16(8):6769-77. doi: 10.3390/molecules16086769.

Abstract

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.

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Chromatography, High Pressure Liquid
  • Docetaxel
  • Esters / chemistry*
  • Esters / pharmacology
  • Female
  • Fungal Proteins / metabolism*
  • Glycoconjugates / chemistry*
  • Glycoconjugates / pharmacology
  • Glycosylation
  • Humans
  • Hydrolysis
  • Lactase / metabolism
  • Magnetic Resonance Spectroscopy
  • Monosaccharides / metabolism
  • Prodrugs / chemistry*
  • Prodrugs / pharmacology
  • Solubility
  • Taxoids / chemistry*
  • Taxoids / pharmacology
  • Water
  • Xylosidases / metabolism
  • beta-Galactosidase / metabolism

Substances

  • Antineoplastic Agents
  • Esters
  • Fungal Proteins
  • Glycoconjugates
  • Monosaccharides
  • Prodrugs
  • Taxoids
  • Water
  • Docetaxel
  • Xylosidases
  • Lactase
  • beta-Galactosidase
  • exo-1,4-beta-D-xylosidase