title: Synthesis, transport and antiviral activity of Ala-Ser and Val-Ser prodrugs of cidofovir.
abstract: We report the synthesis and biological evaluation of Ala-(Val-)l-Ser-CO(2)R prodrugs of 1, where a dipeptide promoiety is conjugated to the P(OH)(2) group of cidofovir (1) via esterification by the Ser side chain hydroxyl group and an ethyl group (4 and 5) or alone (6 and 7). In a murine model, oral administration of 4 or 5 did not significantly increase total cidofovir species in the plasma compared to 1 or 2, but 7 resulted in a 15-fold increase in a rat model and had an in vitro EC(50) value against human cytomegalovirus comparable to 1. Neither 6 nor 7 exhibited toxicity up to 100 μM in KB or HFF cells.
authors.affiliation: Department of Chemistry, University of Southern California, Los Angeles, CA 90089-0744, USA.
authors.forename: Larryn W
authors.initials: LW
authors.lastname: Peterson
authors.forename: Jae-Seung
authors.initials: JS
authors.lastname: Kim
authors.forename: Paul
authors.initials: P
authors.lastname: Kijek
authors.forename: Stefanie
authors.initials: S
authors.lastname: Mitchell
authors.forename: John
authors.initials: J
authors.lastname: Hilfinger
authors.forename: Julie
authors.initials: J
authors.lastname: Breitenbach
authors.forename: Kathy
authors.initials: K
authors.lastname: Borysko
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: D000284:Administration, Oral; D000409:Alanine / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D002478:Cells, Cultured; D000077404:Cidofovir; D003587:Cytomegalovirus / Q000187:drug effects*; D003596:Cytosine / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D063065:Organophosphonates / Q000097:blood / Q000737:chemistry*; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D012694:Serine / Q000737:chemistry / Q000494:pharmacology; D014633:Valine / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; D010455:Peptides; D011355:Prodrugs; D012694:Serine; D003596:Cytosine; D014633:Valine; D000077404:Cidofovir; D000409:Alanine