Synthesis and antiviral evaluation of alkoxyalkyl derivatives of 9-(S)-(3-hydroxy-2-phosphonomethoxypropyl)adenine against cytomegalovirus and orthopoxviruses.
9-(S)-(3-Hydroxy-2-phosphonomethoxypropyl)adenine [(S)-HPMPA] was one of the first acyclic nucleoside phosphonates described and has been reported to have good antiviral activity against most double-stranded DNA viruses, including the herpes group viruses and the orthopoxviruses. However, (S)-HPMPA is not orally bioavailable and has not been developed for clinical use. We have prepared orally bioavailable lipid esters of (S)-HPMPA and report their synthesis and antiviral evaluation against cytomegalovirus and orthopoxviruses. These esters were evaluated in vitro in cells infected with human cytomegalovirus (HCMV), murine cytomegalovirus (MCMV), vaccinia (VV), and cowpox viruses (CV). The most active compound, oleyloxyethyl-(S)-HPMPA, was found to have EC50 value of 0.003 microM against HCMV vs 1.4 microM for unmodified HPMPA. In cells infected with VV and CV, octadecyloxyethyl-(S)-HPMPA had EC50 values of 0.01-0.02 microM versus 2.7-4.0 microM for unmodified HPMPA. When compared with the alkoxyalkyl esters of cidofovir, the corresponding alkoxyalkyl esters of (S)-HPMPA were equally active against HCMV and MCMV but were 15-20-fold more active against VV and CV in vitro. The alkoxyalkyl esters of (S)-HPMPA are promising new compounds worthy of further investigation for treatment of infections caused by herpes viruses and orthopoxviruses.
Beadle
James R
JR
Department of Medicine, VA San Diego Healthcare System and the University of California, San Diego, La Jolla, California 92093-0676, USA.
Wan
William B
WB
Ciesla
Stephanie L
SL
Keith
Kathy A
KA
Hartline
Caroll
C
Kern
Earl R
ER
Hostetler
Karl Y
KY
D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects*; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018155:Orthopoxvirus / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D004952:Esters; D063065:Organophosphonates; C050127:9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine; D000225:Adenine