scholarly journals Ether Lipid‐Ester Prodrugs of Acyclic Nucleoside Phosphonates: Activity against Adenovirus Replication In Vitro

2005 ◽  
Vol 191 (3) ◽  
pp. 396-399 ◽  
Author(s):  
Caroll B. Hartline ◽  
Kortney M. Gustin ◽  
William B. Wan ◽  
Stephanie L. Ciesla ◽  
James R. Beadle ◽  
...  
Keyword(s):  
Ether Lipid ◽  
Acyclic Nucleoside Phosphonates ◽  
Lipid Ester ◽  
Acyclic Nucleoside ◽  
Adenovirus Replication ◽  
Ester Prodrugs

scholarly journals Oral Treatment of Murine Cytomegalovirus Infections with Ether Lipid Esters of Cidofovir

2004 ◽  
Vol 48 (9) ◽  
pp. 3516-3522 ◽  
Author(s):  
Earl R. Kern ◽  
Deborah J. Collins ◽  
W. Brad Wan ◽  
James R. Beadle ◽  
Karl Y. Hostetler ◽  
...  
Keyword(s):  
Oral Treatment ◽  
Ether Lipid ◽  
Murine Cytomegalovirus ◽  
Significant Protection ◽  
Mcmv Infection ◽  
Lipid Ester ◽  
Human Cmv ◽  
Cytomegalovirus Infections ◽  
Ester Prodrugs

ABSTRACT To improve the oral bioavailability of cidofovir (CDV), a series of ether lipid ester prodrugs were synthesized and evaluated for activity against murine cytomegalovirus (MCMV) infection. Four of these analogs, hexadecyloxypropyl (HDP)-CDV, octadecyloxyethyl (ODE)-CDV, oleyloxyethyl (OLE)-CDV, and oleyloxypropyl (OLP)-CDV, were found to have greater activity than CDV against human CMV and MCMV in vitro. The efficacy of oral treatment with these compounds against MCMV infections in BALB/c mice was then determined. Treatment with HDP-CDV, ODE-CDV, OLE-CDV, or OLP-CDV at 2.0 to 6.7 mg/kg of body weight provided significant protection when daily treatments were initiated 24 to 48 h after viral inoculation. Additionally, HDP-CDV or ODE-CDV administered twice weekly or as a single dose of 1.25 to 10 mg/kg was effective in reducing mortality when treatment was initiated at 24 h, 48 h, or, in some cases, 72 h after viral inoculation. In animals treated daily with HDP-CDV or ODE-CDV, virus titers in lung, liver, spleen, kidney, pancreas, salivary gland, and blood were reduced 3 to 5 log10-fold, which was comparable to CDV given intraperitoneally. These results indicated that HDP-CDV or ODE-CDV given orally was as effective as parenteral CDV for the treatment of experimental MCMV infection and suggest that further evaluation for use in CMV infections in humans is warranted.

scholarly journals Antischistosomal Activity of Hexadecyloxypropyl Cyclic 9-(S)-[3-Hydroxy-2-(Phosphonomethoxy)Propyl]Adenine and Other Alkoxyalkyl Esters of Acyclic Nucleoside Phosphonates Assessed by Schistosome Worm Killing In Vitro

2009 ◽  
Vol 53 (12) ◽  
pp. 5284-5287 ◽  
Author(s):  
Sanaa S. Botros ◽  
Samia William ◽  
James R. Beadle ◽  
Nadejda Valiaeva ◽  
Karl Y. Hostetler
Keyword(s):  
Animal Models ◽  
Schistosoma Mansoni ◽  
Ether Lipid ◽  
Antischistosomal Activity ◽  
Acyclic Nucleoside Phosphonates ◽  
Acyclic Nucleoside

ABSTRACT 9-(S)-[3-Hydroxy-2-(phosphonomethoxy)propyl]adenine [(S)-HPMPA] has been reported to have antischistosomal activity. Ether lipid esters of (S)-HPMPA and cidofovir (CDV) have greatly increased activities in antiviral assays and in lethal animal models of poxvirus diseases. To see if ether lipid esters of CDV and (S)-HPMPA enhance antischistosomal activity, we tested their alkoxyalkyl esters using Schistosoma mansoni worm killing in vitro. Hexadecyloxypropyl (HDP)-cyclic-(S)-HPMPA and HDP-cyclic-CDV exhibited significant in vitro antischistosomal activities and may offer promise alone or in combination with praziquantel.

scholarly journals Ether Lipid Ester Derivatives of Cidofovir Inhibit Polyomavirus BK Replication In Vitro

2006 ◽  
Vol 50 (4) ◽  
pp. 1564-1566 ◽  
Author(s):  
Parmjeet Randhawa ◽  
Noush Afarin Farasati ◽  
Ron Shapiro ◽  
Karl Y. Hostetler
Keyword(s):  
Virus Replication ◽  
Ether Lipid ◽  
Bk Virus ◽  
Effective Concentration ◽  
Selectivity Index ◽  
Transplant Recipients ◽  
Polyomavirus Bk ◽  
Lipid Ester ◽  
Derivatives Of

ABSTRACT Polyomavirus BK is a significant pathogen in transplant recipients, but no effective antiviral therapy is available. We show that cidofovir can inhibit BK virus replication in vitro. Esterification of cidofovir with hexadecyloxypropyl, octadecyloxyethyl, and oleyloxyethyl groups results in up to a 3-log lowering of the 50% effective concentration and an increased selectivity index.

scholarly journals Evaluation of Nucleoside Phosphonates and Their Analogs and Prodrugs for Inhibition of Orthopoxvirus Replication

2003 ◽  
Vol 47 (7) ◽  
pp. 2193-2198 ◽  
Author(s):  
Kathy A. Keith ◽  
Michael J. M. Hitchcock ◽  
William A. Lee ◽  
Antonin Holý ◽  
Earl R. Kern
Keyword(s):  
Vaccinia Virus ◽  
Cowpox Virus ◽  
Active Compounds ◽  
Culture Cells ◽  
Tissue Culture Cells ◽  
B Virus ◽  
Immunodeficiency Virus ◽  
Acyclic Nucleoside Phosphonates ◽  
Acyclic Nucleoside

ABSTRACT In the event of a bioterrorism attack using smallpox virus, there currently is no approved drug for the treatment of infections with this virus. We have reported previously that (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (HPMPC) (also known as cidofovir [CDV]) has good activity against poxvirus infections; however, a major limitation is the requirement for intravenous administration. Two related acyclic nucleoside phosphonates (ANPs), adefovir (PMEA) and tenofovir (PMPA), are active against human immunodeficiency virus or hepatitis B virus but do not have activity against the orthopoxviruses. Therefore, we have evaluated a number of analogs and potential oral prodrugs of these three compounds for their ability to inhibit the replication of vaccinia virus or cowpox virus in tissue culture cells. The most-active compounds within the CDV series were (S)-HPMPA and (butyl l-alaninyl) cyclic HPMPC, with 50% effective concentrations (EC50s) from 4 to 8 μM, compared with 33 to 43 μM for CDV. Although PMEA itself was not active, adefovir dipivoxil {bis[(pivaloyl)oxymethyl] PMEA} and bis(butyl l-alaninyl) PMEA were active against both viruses, and bis(butyl l-alaninyl) PME-N6-(cyclopropyl)DAP and (isopropyl l-alaninyl)phenyl PME-N6-(cyclopropyl)DAP were the most active compounds tested, with EC50s of 0.1 to 2.6 μM. In the PMPA series, none of the analogs tested had significantly better activity than PMPA itself. These data indicate that a number of these ANP derivatives have activity against vaccinia virus and cowpox virus in vitro and should be evaluated for their efficacies in animal models.

New in vitro method for evaluating antiviral activity of acyclic nucleoside phosphonates against plant viruses

2010 ◽  
Vol 88 (3) ◽  
pp. 296-303 ◽  
Author(s):  
J. Špak ◽  
A. Holý ◽  
D. Pavingerová ◽  
I. Votruba ◽  
V. Špaková ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Plant Viruses ◽  
In Vitro Method ◽  
Acyclic Nucleoside Phosphonates ◽  
Acyclic Nucleoside

scholarly journals Inhibition of Herpesvirus Replication by Hexadecyloxypropyl Esters of Purine- and Pyrimidine-Based Phosphonomethoxyethyl Nucleoside Phosphonates

2008 ◽  
Vol 52 (12) ◽  
pp. 4326-4330 ◽  
Author(s):  
Mark N. Prichard ◽  
Caroll B. Hartline ◽  
Emma A. Harden ◽  
Shannon L. Daily ◽  
James R. Beadle ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Epstein Barr Virus ◽  
Hiv Infections ◽  
Barr Virus ◽  
Immunodeficiency Virus ◽  
Acyclic Nucleoside Phosphonates ◽  
Acyclic Nucleoside ◽  
Epstein Barr ◽  
Simplex Virus ◽  
Ester Prodrugs

ABSTRACT Patients infected with human immunodeficiency virus (HIV) often suffer from herpesvirus infections as a result of immunosuppression. These infections can occur while patients are receiving antiretroviral therapy, and additional drugs required to treat their infection can adversely affect compliance. It would be useful to have antivirals with a broader spectrum of activity that included both HIV and the herpesviruses. We reported previously that alkoxyalkyl ester prodrugs of cidofovir are up to 3 orders of magnitude more active against herpesvirus replication and may be less toxic than the unmodified drug. To determine if this strategy would be effective for certain phosphonomethoxyethyl nucleoside phosphonates which are also active against HIV infections, the hexadecyloxypropyl (HDP) esters of 1-(phosphonomethoxyethyl)-cytosine, 1-(phosphonomethoxyethyl)-5-bromo-cytosine (PME-5BrC), 1-(phosphonomethoxyethyl)-5-fluoro-cytosine, 9-(phosphonomethoxyethyl)-2,6-diaminopurine (PME-DAP), and 9-(phosphonomethoxyethyl)-2-amino-6-cyclopropylaminopurine (PME-cPrDAP) were evaluated for activity against herpesvirus replication. The HDP esters were substantially more active than the unmodified acyclic nucleoside phosphonates, indicating that esterification with alkoxyalkyl groups increases the antiviral activity of many acyclic nucleoside phosphonates. The most interesting compounds included HDP-PME-cPrDAP and HDP-PME-DAP, which were 12- to 43-fold more active than the parent nucleoside phosphonates against herpes simplex virus and cytomegalovirus, and HDP-PME-cPrDAP and HDP-PME-5BrC which were especially active against Epstein-Barr virus. The results presented here indicate that HDP-esterified acyclic nucleoside phosphonates with antiviral activity against HIV also inhibit the replication of some herpesviruses and can extend the spectrum of activity for these compounds.

scholarly journals Antiretrovirus Activity of a Novel Class of Acyclic Pyrimidine Nucleoside Phosphonates

2002 ◽  
Vol 46 (7) ◽  
pp. 2185-2193 ◽  
Author(s):  
J. Balzarini ◽  
C. Pannecouque ◽  
E. De Clercq ◽  
S. Aquaro ◽  
C.-F. Perno ◽  
...  
Keyword(s):  
Pyrimidine Nucleotide ◽  
Immunodeficiency Virus ◽  
Murine Sarcoma Virus ◽  
Acyclic Nucleoside Phosphonates ◽  
Sarcoma Virus ◽  
Acyclic Nucleoside ◽  
Murine Sarcoma ◽  
Antiretroviral Activity

ABSTRACT A novel class of acyclic nucleoside phosphonates has been discovered in which the base consists of a pyrimidine preferably containing an amino group at C-2 and C-4 and a 2-(phosphonomethoxy)ethoxy (PMEO) or a 2-(phosphonomethoxy)propoxy (PMPO) group at C-6. The 6-PMEO 2,4-diaminopyrimidine (compound 1) and 6-PMPO 2,4-diaminopyrimidine (compound 11) derivatives showed potent activity against human immunodeficiency virus (HIV) in the laboratory (i.e., CEM and MT-4 cells) and in primary (i.e., peripheral blood lymphocyte and monocyte/macrophage) cell cultures and pronounced activity against Moloney murine sarcoma virus in newborn NMRI mice. Their in vitro and in vivo antiretroviral activity was comparable to that of reference compounds 9-[(2-phosphonomethoxy)ethyl]adenine (adefovir) and (R)-9-[(2-phosphonomethoxy)-propyl]adenine (tenofovir), and the enantiospecificity of (R)- and (S)-PMPO pyrimidine derivatives as regards their antiretroviral activity was identical to that of the classical (R)- and (S)-9-(2-phosphonomethoxy)propyl purine derivatives. The prototype PMEO and PMPO pyrimidine analogues were relatively nontoxic in cell culture and did not markedly interfere with host cell macromolecular (i.e., DNA, RNA, or protein) synthesis. Compounds 1 and 11 should be considered attractive novel pyrimidine nucleotide phosphonate analogues to be further pursued for their potential as antiretroviral agents in the clinical setting.

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