Synthesis of cidofovir and (S)-HPMPA ether lipid prodrugs.
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.
Beadle
James R
JR
University of California, San Diego, La Jolla, California, USA.
D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D000998:Antiviral Agents / Q000138:chemical synthesis*; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D009682:Magnetic Resonance Spectroscopy; D063065:Organophosphonates / Q000138:chemical synthesis*; D021241:Spectrometry, Mass, Electrospray Ionization
D000998:Antiviral Agents; D063065:Organophosphonates; D003596:Cytosine; C050127:9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine; D000225:Adenine; D000077404:Cidofovir