2',3',5'-Triacetyl-5-Azacytidine as A Potential Prodrug of Azacitidine
Ziemba A, et al. Chemotherapy research and practice, 2011, 2011.
Myelodysplastic syndromes (MDS) are a group of incurable stem cell malignancies that are primarily treated with supportive care. Azacitidine and decitabine are two FDA-approved DNA methyltransferase (DNMT) inhibitors that improve overall response. The study evaluated 2,3,5-triacetyl-5-azacytidine (TAC) as a potential prodrug of azacitidine. The prodrug exhibits significant pharmacokinetic improvements in bioavailability, solubility, and stability compared to the parent compound.
Synthesis of 2,3,5-Triacetyl-5-Azacytidine
· 2 ,3 ,5-triacetyl-5-azacytidine was prepared through condensation of trimethylsilylated-5-azacytosine and 1,2,3,5-tetra-O-acetyl-β-Dribofuranose.
· In a 150 mL, 3-necked flask, a mixture of 5-azacytosine, hexamethyldisilazane, and ammonium sulfate was heated at reflux for 2 hours. A fresh amount of ammonium sulfate was added, and the reflux was continued for 6 hours.
· The excess hexamethyldisilazane was removed under reduced vacuum to afford trimethylsilylated 5- azacytosine as an off-white residue.
· Trimethylsilylated 5-azacytosine and 1,2,3,5-Tetra-Oacetyl-β-D-ribofuranose were dissolved in acetonitrile, and the mixture was cooled at 0◦C in an ice-water bath.
· Trimethylsilyl trifluoromethanesulfonate (TMSOTf) was added slowly at 0°C then stirred at room temperature for 3 hours. The reaction mixture was extracted, washed, dried and recrystallized to obtain the final product.