Synthesis of Phosphoramidate Prodrugs: ProTide Approach

AbstractThe ProTide (pronucleotide) approach is a prodrug strategy elaborated to deliver nucleoside monophosphate into the cell, circumventing the first and inefficient rate‐limiting phosphorylation step of nucleosides and improving the cellular penetration of nucleotides. The ProTide of a nucleoside phosphate is a phosphoramidate prodrug consisting of an amino acid ester promoiety linked via P‐N bond to a nucleoside aryl phosphate. Such prodrugs have increased lipophilicity and thus are capable of altering cell and tissue distribution. The ProTide technology was successfully and extensively applied to a wide variety of nucleoside phosphates, endowed with antiviral and anticancer activity. This unit describes two different synthetic strategies allowing the preparation of phosphoramidates of 6‐O‐methyl‐2′−β‐C‐methylguanosine as model compounds for nucleosides having only the 5′‐OH as reactive hydroxyl group, and phosphoramidates of 2′−β‐D‐arabinouridine (AraU) as model compounds for nucleosides containing two or more reactive hydroxyl groups. Curr. Protoc. Nucleic Acid Chem. 53:15.5.1‐15.5.15. © 2013 by John Wiley & Sons, Inc.