title: Synthesis and biological activation of an ethylene glycol-linked amino acid conjugate of cyclic cidofovir.
abstract: Cidofovir (HPMPC) is a broad-spectrum anti-viral agent whose potential, particularly in biodefense scenarios, is limited by its low oral bioavailability. Two prodrugs (3 and 4) created by conjugating ethylene glycol-linked amino acids (L-Val, L-Phe) with the cyclic form of cidofovir (cHPMPC) via a P-O ester bond were synthesized and their pH-dependent stability (3 and 4), potential for in vivo reconversion to drug (3), and oral bioavailability (3) were evaluated. The prodrugs were stable in buffer between pH 3 and 5, but underwent rapid hydrolysis in liver (t(1/2) = 3.7 min), intestinal (t(1/2) = 12.5 min), and Caco-2 cell homogenates (t(1/2) = 20.2 min). In vivo (rat), prodrug 3 was >90% reconverted to cHPMPC. The prodrug was 4x more active than ganciclovir (IC50 value, 0.68 microM vs 3.0 microM) in a HCMV plaque reduction assay. However, its oral bioavailability in a rat model was similar to the parent drug. The contrast between the promising activation properties and unenhanced transport of the prodrug is briefly discussed.
authors.affiliation: Department of Chemistry, University of Southern California, Los Angeles, CA 90089-0744, USA.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Eriksson
authors.forename: John M
authors.initials: JM
authors.lastname: Hilfinger
authors.forename: Jae-Seung
authors.initials: JS
authors.lastname: Kim
authors.forename: Stefanie
authors.initials: S
authors.lastname: Mitchell
authors.forename: Paul
authors.initials: P
authors.lastname: Kijek
authors.forename: Katherine Z
authors.initials: KZ
authors.lastname: Borysko
authors.forename: Julie M
authors.initials: JM
authors.lastname: Breitenbach
authors.forename: John C
authors.initials: JC
authors.lastname: Drach
authors.forename: Boris A
authors.initials: BA
authors.lastname: Kashemirov
authors.forename: Charles E
authors.initials: CE
authors.lastname: McKenna
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000378:metabolism* / Q000493:pharmacokinetics; D001682:Biological Availability; D001711:Biotransformation; D002470:Cell Survival / Q000187:drug effects; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics; D019855:Ethylene Glycol / Q000737:chemistry*; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis; D007624:KB Cells; D009682:Magnetic Resonance Spectroscopy; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000378:metabolism* / Q000493:pharmacokinetics; D000074011:Peptide Transporter 1; D010649:Phenylalanine / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism*; D051381:Rats; D027981:Symporters / Q000378:metabolism; D014633:Valine / Q000737:chemistry; D010948:Viral Plaque Assay
chemical_list: D000596:Amino Acids; D000998:Antiviral Agents; D063065:Organophosphonates; D000074011:Peptide Transporter 1; D011355:Prodrugs; D027981:Symporters; D010649:Phenylalanine; D003596:Cytosine; D019855:Ethylene Glycol; D014633:Valine; D000077404:Cidofovir