Antiviral activities of novel 5-phosphono-pent-2-en-1-yl nucleosides and their alkoxyalkyl phosphonoesters.
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.
Choo
Hyunah
H
Department of Medicine (0676), University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0676, USA.
Beadle
James R
JR
Kern
Earl R
ER
Prichard
Mark N
MN
Keith
Kathy A
KA
Hartline
Caroll B
CB
Trahan
Julissa
J
Aldern
Kathy A
KA
Korba
Brent E
BE
Hostetler
Karl Y
KY
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*
D000998:Antiviral Agents; D009705:Nucleosides; D009943:Organophosphorus Compounds