Novel l-amino acid ester prodrugs of azacitidine: Design, enzymatic synthesis and the investigation of release behavior

• A facile, enzymatic synthesis protocol of l-amino acid ester prodrugs of azacitidine was developed.
• A series of Boc-protected amino acid-azacitidine conjugates were prepared in good regioselectivity and yield.
• Various factors which influence the catalytic efficiency were systematically investigated.
• In vitro hydrolysis of prodrugs showed that the amino acid ester prodrugs had sustained release characteristic.

A facile, enzymatic synthesis protocol of l-amino acid ester prodrugs of azacitidine was developed. Firstly, transesterification of azacitidine with Boc protected vinyl aminocarboxylates was performed under the catalysis of subtilisin in anhydrous pyridine at 50 °C. A series of Boc-protected amino acid-azacitidine conjugates were prepared in good regioselectivity and yield. Various factors which influence the catalytic efficiency were systematically investigated. And then, the obtained azacitidine derivatives were subjected to a deprotection process to give l-amino acid ester prodrugs of azacitidine. In vitro hydrolysis of prodrugs showed that the amino acid ester prodrugs had obvious sustained release characteristic. These characteristics will have potential value for clinic application.

A facile, enzymatic synthesis protocol of l-amino acid ester prodrugs of azacitidine, which displayed sustained release characteristics, was successfully developed with good regioselectivity and yields.Figure optionsDownload as PowerPoint slide