title: Antiviral activities of novel 5-phosphono-pent-2-en-1-yl nucleosides and their alkoxyalkyl phosphonoesters.
abstract: Three acyclic nucleoside phosphonates are currently approved for clinical use against infections caused by cytomegalovirus (Vistide), hepatitis B virus (Hepsera), and human immunodeficiency virus type 1 (Viread). This important antiviral class inhibits viral polymerases after cellular uptake and conversion to their diphosphates, bypassing the first phosphorylation, which is required for conventional nucleoside antivirals. Small chemical alterations in the acyclic side chain lead to marked differences in antiviral activity and the spectrum of activity of acyclic nucleoside phosphonates against various classes of viral agents. We synthesized a new class of acyclic nucleoside phosphonates based on a 5-phosphono-pent-2-en-1-yl base motif in which the oxygen heteroatom usually present in acyclic nucleoside phosphonates has been replaced with a double bond. Since the intrinsic phosphonate moiety leads to low oral bioavailability and impaired cellular penetration, we also prepared the hexadecyloxypropyl esters of the 5-phosphono-pent-2-en-1-yl nucleosides. Our earlier work showed that this markedly increases antiviral activity and oral bioavailability. Although the 5-phosphono-pent-2-en-1-yl nucleosides themselves were not active, the hexadecyloxypropyl esters were active against DNA viruses and hepatitis B virus, in vitro. Notably, the hexadecyloxypropyl ester of 9-(5-phosphono-pent-2-en-1-yl)-adenine was active against hepatitis B virus mutants resistant to lamivudine, emtricitabine, and adefovir.
authors.affiliation: Department of Medicine (0676), University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0676, USA.
authors.forename: Hyunah
authors.initials: H
authors.lastname: Choo
authors.forename: James R
authors.initials: JR
authors.lastname: Beadle
authors.forename: Earl R
authors.initials: ER
authors.lastname: Kern
authors.forename: Mark N
authors.initials: MN
authors.lastname: Prichard
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Keith
authors.forename: Caroll B
authors.initials: CB
authors.lastname: Hartline
authors.forename: Julissa
authors.initials: J
authors.lastname: Trahan
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Aldern
authors.forename: Brent E
authors.initials: BE
authors.lastname: Korba
authors.forename: Karl Y
authors.initials: KY
authors.lastname: Hostetler
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003587:Cytomegalovirus / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects; D006515:Hepatitis B virus / Q000187:drug effects; D006801:Humans; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D009705:Nucleosides; D009943:Organophosphorus Compounds