UNIT 15.2 Synthesis of Cidofovir and (S)-HPMPA Ether Lipid Prodrugs
Published Online: 1 JUN 2007
Copyright © 2007 by John Wiley and Sons, Inc.
Lab Protocol Title
Current Protocols in Nucleic Acid Chemistry
How to Cite
Beadle, J. R. 2007. Synthesis of Cidofovir and (S)-HPMPA Ether Lipid Prodrugs. Current Protocols in Nucleic Acid Chemistry. 29:15.2.1–15.2.16.
- Published Online: 1 JUN 2007
- Published Print: JUN 2007
Cidofovir [(S)-1-(3-hydroxy-2-phosphonomethoxypropyl)cytosine] and (S)-HPMPA [(S)-9-(3-hydroxy-2-phosphonomethoxypropyl)adenine] are potent nucleoside phosphonate antiviral agents that are not orally bioavailable unless one or both of their negative charges are masked. This unit describes the synthesis of hexadecyloxypropyl esters of cidofovir and (S)-HPMPA. These prodrugs are readily absorbed after oral administration and are converted intracellularly to the corresponding diphosphates. The hexadecyloxypropyl esters of cidofovir and (S)-HPMPA are orally active in animal models of viral infection. Two synthetic strategies are employed. In the first, cyclic cidofovir is coupled to 3-hexadecyloxy-1-propanol using the Mitsunobu reaction (triphenylphosphine, DIAD), followed by basic hydrolysis of the cyclic ester. In the second, the lipid moiety is incorporated into a phosphonate synthon and a stepwise approach is used to assemble the (S)-HPMPA analog.
- acyclic nucleoside phosphonates;
- ether lipid prodrugs;