title: Synthesis and antiviral evaluation of alkoxyalkyl esters of phosphonopropoxymethyl-guanine and phosphonopropoxymethyl-diaminopurine.
abstract: Phosphonopropoxymethyl-guanine is the methylene phosphonate analogue of acyclovir. Although not highly active against HSV, 4-38 microM of phosphonopropoxymethyl-guanine has been reported to be active against human and murine cytomegalovirus. Recently we found that cidofovir, when esterified with alkoxyalkyl moieties, showed greatly increased antiviral activity against cytomegalovirus, herpes simplex virus and orthopoxviruses, in vitro. The alkoxyalkyl esters of cidofovir are orally active in murine models of human and murine cytomegalovirus and orthopoxviruses in vivo. To see if the antiviral activity of phosphonopropoxymethyl-guanine, phosphonopropoxymethyl-diaminopurine and phosphonopropoxymethyl-N6-cyclopropyl-diaminopurine could be increased by this approach, we synthesized their hexadecyloxypropyl- and octadecyloxyethyl- esters and evaluated antiviral activity and cytotoxicity in cells infected with HSV-1 and HCMV, in vitro. Marked increases in antiviral activity were noted in the alkoxyalkyl esters of phosphonopropoxymethyl-guanine. Alkoxyalkyl esters of diaminopurine and N6-cyclopropyl-diaminopurine showed slight increases in activity against HSV-1 and marked increases in activity against HCMV. The results suggest that esterification with alkoxyalkyl moieties may be a generally useful way to increase antiviral activity of nucleoside phosphonates.
authors.affiliation: Department of Medicine, Division of Infectious Disease, University of California, San Diego, CA, USA.
authors.forename: Jacqueline C
authors.initials: JC
authors.lastname: Ruiz
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Aldern
authors.forename: James R
authors.initials: JR
authors.lastname: Beadle
authors.forename: Caroll B
authors.initials: CB
authors.lastname: Hartline
authors.forename: Earl R
authors.initials: ER
authors.lastname: Kern
authors.forename: Karl Y
authors.initials: KY
authors.lastname: Hostetler
mesh_terms: D015075:2-Aminopurine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000187:drug effects / Q000254:growth & development; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000254:growth & development; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D010948:Viral Plaque Assay
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; D015075:2-Aminopurine; D006147:Guanine