The Design And Synthesis Of Water-soluble Derivatives Of Taxanes And Their Preliminary Research Of Biological Activity

At present, plant alkaloids and other natural plant drugs probably hasoccupied the largest market share in our country. Among them, thepaclitaxel and docetaxel are the first-line clinical chemotherapy drugs.Paclitaxel and Docetaxel can only been applied in the clinic by injectionsfor the bad oral administration caused by the bad water-solublity. Manyresearchers have attempted to solve this problem by the improvement offormulation and structure. But the ideal results were few. In this research, afew low-toxic, water-soluble ligands were used to synthesize thewater-soluble prodrugs of paclitaxel or docetaxel. Eight water-solublederivatives were obtained and characterized by MS and NMR. Accordingthe results of the water solubility and release of original drug in vitro,2’-(2-(N, N-diethyl) glycine) docetaxel ester hydrochloride was selectedto carry out the preliminary pharmacokinetic and pharmacodynamicexperiments.Result: Pharmacokinetic results show that: intravenous injection2’-(2-(N, N-diethyl) glycine) docetaxel ester hydrochloride in rats,2’-(2-(N, N-diethyl) glycine) docetaxel ester hydrochloride and metabolites （docetaxel）can be simultaneously detected in the plasma. Docetaxelderivative assumes the double-phase elimination in vivo,2hours later theelimination slows down, AUC0-tis446±172ng h/ml, The half-life ofterminal elimination (t1/2) is7.45±3.40h. Plasma clearance rate is high, to8.55+2.66L/h/kg. Concentration of metabolite in plasma reaches thepeak rapidly, after administration of first sampling point time (5min),AUC0-tis258±20ng h/ml, equivalent of57.8%of docetaxel.Pharmacodynamic experiments in vitro had been investigated, including,the effects of the prodrugs on cell strain increment and survival by CCK-8method in vitro, the effect on cell lines cycle determined by flow cytometryanalysis, and the effect on the sensitivity of tumor cell detected byATP-TCA method. And the results show that: the selected docetaxelderivative has antitum or activity. The preliminary experiments in vivoshowed the docetaxel derivative(23.74mg/kg) has obvious inhibition on thetumor growth.Conclusion：Water-soluble derivatives of paclitaxel and docetaxel aresynthesized in this paper. The secreened derivative,2’-(2-(N, N-diethyl) glycine) docetaxel ester hydrochloride, has higherwater-solubility, stronger anti-tumor activity, and lower toxicity thanreference drugs.