RESUMEN
(S)-9-[3-Hydroxy-2-(phosphonomethoxy)propyl]adenine [(S)-HPMPA], is an effective broad-spectrum antiviral against many DNA viruses but has been reported to be inactive against human immunodeficiency virus (HIV). We synthesized several alkoxyalkyl esters of (S)-HPMPA and now report that hexadecyloxypropyl-(S)-HPMPA [HDP-(S)-HPMPA] and octadecyloxyethyl-(S)-HPMPA [ODE-(S)-HPMPA]had 50% effective concentrations of 0.4 to 7.0 nanomolar and were nearly fully active against HIV variants having reverse transcriptase mutations M184V and K103N and against a zidovudine-resistant variant with mutations D67N, K70R, T215Y, and K219Q. Resistance to HDP-(S)-HPMPA and ODE-(S)-HPMPA was noted for a mutant with mutation K65R. HDP-(S)-HPMPA is also active against herpes simplex virus type 1, human cytomegalovirus, hepatitis B virus, adenoviruses, and orthopoxviruses and is worthy of further evaluation as a possibly therapy for HIV infection.
Asunto(s)
Adenina/análogos & derivados , Antivirales/farmacología , VIH-1/efectos de los fármacos , VIH-1/fisiología , Organofosfonatos/farmacología , Replicación Viral/efectos de los fármacos , Adenina/síntesis química , Adenina/química , Adenina/farmacología , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Antivirales/síntesis química , Antivirales/química , Recuento de Células , Línea Celular , Supervivencia Celular/efectos de los fármacos , ADN Viral/genética , ADN Viral/metabolismo , Farmacorresistencia Viral/genética , Ésteres/síntesis química , Ésteres/química , Ésteres/farmacología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Variación Genética , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Humanos , Técnicas In Vitro , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Mutación , Organofosfonatos/síntesis química , Organofosfonatos/químicaRESUMEN
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.
Asunto(s)
Adenina/análogos & derivados , Antivirales/síntesis química , Citomegalovirus/efectos de los fármacos , Organofosfonatos/síntesis química , Orthopoxvirus/efectos de los fármacos , Adenina/síntesis química , Adenina/química , Adenina/farmacología , Antivirales/química , Antivirales/farmacología , Línea Celular , Ésteres/síntesis química , Ésteres/química , Ésteres/farmacología , Humanos , Organofosfonatos/química , Organofosfonatos/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Alkoxyalkyl esters of cidofovir (CDV) have substantially greater antiviral activity and selectivity than unmodified CDV against herpesviruses and orthopoxviruses in vitro. Enhancement of antiviral activity was also noted when cyclic CDV was esterified with alkoxyalkanols. In vitro antiviral activity of the most active analogs against human cytomegalovirus (HCMV) and orthopoxviruses was increased relative to CDV up to 1,000- or 200-fold, respectively. Alkyl chain length and linker structure are important potential modifiers of antiviral activity and selectivity. In this study, we synthesized a series of alkoxyalkyl esters of CDV or cyclic CDV with alkyl chains from 8 to 24 atoms and having linker moieties of glycerol, propanediol, and ethanediol. We also synthesized alkyl esters of CDV which lack the linker to determine if the alkoxyalkyl linker moiety is required for activity. The new compounds were evaluated in vitro against HCMV and murine CMV (MCMV). CDV or cyclic CDV analogs both with and without linker moieties were highly active against HCMV and MCMV, and their activities were strongly dependent on chain length. The most active compounds had 20 atoms esterified to the phosphonate of CDV. Both alkoxypropyl and alkyl esters of CDV provided enhanced antiviral activities against CMV in vitro. Thus, the oxypropyl linker moiety is not required for enhanced activity. CDV analogs having alkyl ethers linked to glycerol or ethanediol linker groups also demonstrated increased activity against CMV.
Asunto(s)
Fármacos Anti-VIH/farmacología , Citomegalovirus/efectos de los fármacos , Citomegalovirus/fisiología , Citosina/análogos & derivados , Citosina/farmacología , Organofosfonatos/farmacología , Animales , Células Cultivadas , Cidofovir , Colorantes , Ésteres/síntesis química , Ésteres/farmacología , Glicoles de Etileno/química , Glicerol/química , Humanos , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Ratones , Rojo Neutro , Glicoles de Propileno/química , Relación Estructura-Actividad , Ensayo de Placa Viral , Replicación Viral/efectos de los fármacosRESUMEN
The acyclic nucleoside phosphonate cidofovir (CDV) and its closely related analogue (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)-adenine ([S]-HPMPA) have been reported to have activity against many adenovirus (AdV) serotypes. A new series of orally active ether lipid-ester prodrugs of CDV and of (S)-HPMPA that have slight differences in the structure of their lipid esters were evaluated, in tissue-culture cells, for activity against 5 AdV serotypes. The results indicated that, against several AdV serotypes, the most active compounds were 15-2500-fold more active than the unmodified parent compounds and should be evaluated further for their potential to treat AdV infections in humans.
Asunto(s)
Adenovirus Humanos/efectos de los fármacos , Antivirales/farmacología , Citosina/análogos & derivados , Nucleósidos/farmacología , Organofosfonatos/farmacología , Profármacos/farmacología , Replicación Viral/efectos de los fármacos , Adenina/análogos & derivados , Adenina/síntesis química , Adenina/química , Adenina/farmacología , Adenovirus Humanos/fisiología , Antivirales/síntesis química , Células Cultivadas , Cidofovir , Citosina/síntesis química , Citosina/química , Citosina/farmacología , Ésteres/química , Éter/química , Humanos , Lípidos/química , Pruebas de Sensibilidad Microbiana/métodos , Nucleósidos/química , Organofosfonatos/síntesis química , Organofosfonatos/química , Profármacos/síntesis química , Profármacos/químicaRESUMEN
A new series of ether lipid esters of cidofovir (CDV) were evaluated against vaccinia and cowpox viruses. Activity was dependent on number of atoms in the alkyl or alkoxyalkyl chain, the linker moiety, and the presence of a double bond in the alkoxyalkyl chains linked to the phosphonate moiety of CDV.