Comparison of the Antiviral Activities of Alkoxyalkyl and Alkyl Esters of Cidofovir against Human and Murine Cytomegalovirus Replication In Vitro

Abstract

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.Cidofovir (CDV), an acyclic phosphonate analog of dCMP, is an antiviral agent that is active against all double-stranded DNA viruses including herpes simplex, cytomegalovirus (CMV), orthopoxviruses, adenovirus, Epstein-Barr virus, polyomavirus, and papillomavirus (9). CDV is not orally active but is effective when administered intravenously for CMV retinitis in patients with AIDS (8,19). Esterification of CDV with certain alkoxyalkanols dramatically increases the antiviral activity and selectivity of CDV in vitro (2, 11, 13, 15) and confers oral bioavailability (4,5,6,14,20). Hexadecyloxypropyl-CDV (HDP-CDV) and various other alkoxyalkyl CDV esters are orally active in three lethal challenge models of poxvirus disease (5, 20) and in animal models of CMV disease (4, 14).The alkyl chain length of these CDV analogs is related to solubility and the ability of the compounds to associate with biomembranes. To examine the effect of structure on antiviral activity and selectivity of alkoxyalkanol-CDV analogs against CMV, we synthesized a family of alkoxypropylCDVs and -cyclic CDVs (cCDVs) varying in overall chain length from 8 to 24 atoms. The nature of the linker group is also important because it may strongly affect the rate of cellular metabolic conversion to CDV. We synthesized several representative analogs having propanediol, ethandiol, or glycerol linkers to assess the effect of the linker structure. Finally, we also synthesized and evaluated a series of alkylCDVs lacking the linker.The various CDV and cCDV analogs were tested...

Alkoxyalkyl Esters of ( S )-9-[3-Hydroxy-2-(Phosphonomethoxy)Propyl]Adenine Are Potent Inhibitors of the Replication of Wild-Type and Drug-Resistant Human Immunodeficiency Virus Type 1 In Vitro

“…Alkoxyalkyl esters of (S)-HPMPA were more cytotoxic than unmodified (S)-HPMPA. This is consistent with the results obtained previously with alkoxyalkyl esters of CDV, which also exhibited greater cytotoxicity and greater selectivity than CDV (4,16,20).…”

“…Our group reported previously that conversion of acyclic nucleoside phosphonates to alkoxyalkyl or alkyl esters greatly increases their antiviral activity (4,16), and structure-activity studies have established that the optimal length of the alkoxyalkyl ester is about 20 atoms (20). Alkoxyalkyl esters of cidofovir (CDV) are orally active in lethal infection models with ectromelia (6) and cowpox and vaccinia (18).…”

Enhanced antiproliferative effects of alkoxyalkyl esters of cidofovir in human cervical cancer cells in vitro

“…Purity was assessed at >98%. The proton nuclear magnetic resonance and mass spectrometry data for these compounds have been reported previously (5,8). The structures of cidofovir and OLE-CDV are shown in Fig.…”

“…Cidofovir Analogues HDP-CDV, ODE-CDV, and OLE-CDV were synthesized, purified, and characterized as previously described (5,8). Briefly, a mixture of cyclic cidofovir, hexadecyloxypropanol, octadecyloxyethanol, or oleyloxypropanol and triphenylphosphine was treated with diisopropylazodicarboxylate to give the cyclic ester.…”

Management of multidrug‐resistant viruses in the immunocompromised host

“…Hexadecyloxypropyl CDV (HDP-CDV or CMX001) and octadecyloxyethyl CDV (ODE-CDV) exhibit enhanced in vitro activity against all human herpesviruses and retain activity in many drug-resistant isolates (Quenelle et al, 2010). For example, they show activity in drug-resistant CMV isolates that have mutations in UL97 and UL54 genes including those with GCV resistance (Wan et al, 2005).…”