Comparative Anti-Retrovirus and Anti-Hepadnavirus Activity of Three Different Classes of Nucleoside Phosphonate Derivatives

Balzarini, Jan; Kruining, J.; Heijtink, R. A.; Clercq, Erik De

doi:10.1177/095632029400500602

Cited by 13 publications

(3 citation statements)

References 19 publications

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“…and 17 have potent anti-retroviral activity (Holy, 1993;Balzarini et al, 1994); 4 and 5 have anti-DNA virus activity (Holy, 1993). Compound 11 showed some PIV inhibitory activity with SI of 30 to >333 by CPE inhibition assay, but failed to inhibit virus in a virus yield assay.The compound also inhibited other strains and clinical isolates of PIV, but only weakly.…”

Section: Discussionmentioning

confidence: 99%

Acyclic Phosphonomethylether Nucleoside Inhibitors of Respiratory Viruses

Barnard

Bischofberger

Kim

et al. 1997

Antivir Chem Chemother

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SummaryA series of acyclic phosphonomethylether nucleosides were synthesized and then evaluated for inhibitory activity against respiratory viruses of clinical significance using CPE inhibition, neutral red uptake and virus yield reduction assays. Of the 20 compounds synthesized, none significantly inhibited influenza A or B viruses or respiratory syncytial virus strains A2, Long or 18537; the selective indices (51) were less than 10. A new compound, G5-2128 (2R, 5R-9-[2,5-dihydro-5-(phosphonomethoxy)-2-furanyl]adenine; D4API), selectively inhibited adenovirus 5 (51)10) as did G5-0577 (9-(3-hydroxy-2-phosphonylmethoxypropyl)-adenine; HPMPA) and G5-0504 [(S)-1-[3-hydroxy-2-(phosphonylmethoxypropyl)]-cytosine; HPMPC]. The 50% effective concentrations (EC so) ranged from 8-100 I1g mL-l and 50% cell inhibitory concentrations (CC so )from 40-1000 I1g ml.", All three compounds were also found to be active against laboratory strains and clinical isolates of adenovirus types 1, 2, 8 and 41 with EC so values ranging from 0.2 to 10 I1g ml,". Two compounds, G5-438 (9-(2-phosphonylmethoxyethyl)guanine, PMEG) and G5-2542 (9-[3-phosphonomethoxy)methoxymethyl]guanine) inhibited parainfluenza virus 3 strain C243, with 51 of 52 and >333, respectively. PMEG also inhibited measles virus strains CC, Halonen and Chicago with EC so values ranging from 0.03-9119 ml,". These data suggest that these compounds should be considered for possible development as therapeutic agents for respiratory virus infections.

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Section: Discussionmentioning

confidence: 99%

Acyclic Phosphonomethylether Nucleoside Inhibitors of Respiratory Viruses

Barnard

Bischofberger

Kim

et al. 1997

Antivir Chem Chemother

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“…Also, diseases caused by other related mammalian retrovirusesmurine acquired immunodeficiency disease, FIV and FeLV, Visna virus, and simian immunodeficiency virus 3b,7 were successfully treated with this drug. The in vitro activity against HIV-1 and HIV-2 as well as the expected therapeutic effect in AIDS-related viral diseases 8 predetermined this compound [Adefovir] 9 and its bis(pivaloyloxymethyl) ester [Bis-(POM)-PMEA, Adefovir dipivoxil, Preveon] with an increased oral absorption and increased transport into the cell 10 for clinical studies against AIDS 11 and hepatitis B . Molecular biological investigation 13 demonstrated phosphorylation of PMEA to its mono- and diphosphate (analogues of nucleoside di- and triphosphates) catalyzed by nucleotide kinases 14 or 5-phosphoribosyl 1-pyrophosphate synthetase; the diphosphate (PMEApp) is inhibitory to cellular DNA polymerases .…”

Section: Introductionmentioning

confidence: 99%

Structure−Antiviral Activity Relationship in the Series of Pyrimidine and Purine N-[2-(2-Phosphonomethoxy)ethyl] Nucleotide Analogues. 1. Derivatives Substituted at the Carbon Atoms of the Base

et al. 1999

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A series of dialkyl esters of purine and pyrimidine N-[2-(phosphonomethoxy)ethyl] derivatives substituted at position 2, 6, or 8 of the purine base or position 2, 4, or 5 of the pyrimidine base were prepared by alkylation of the appropriate heterocyclic base with 2-chloroethoxymethylphosphonate diester in the presence of sodium hydride, cesium carbonate, or 1,8-diazabicyclo[5,4, 0]undec-7-ene (DBU) in dimethylformamide. Additional derivatives were obtained by the transformations of the bases in the suitably modified intermediates bearing reactive functions at the base moiety. The diesters were converted to the corresponding monoesters by sodium azide treatment, while the free acids were obtained from the diester by successive treatment with bromotrimethylsilane and hydrolysis. None of the PME derivatives in the pyrimidine series, their 6-aza or 3-deaza analogues, exhibited any activity against DNA viruses or retroviruses tested, except for the 5-bromocytosine derivative. Substitution of the adenine ring in PMEA at position 2 by Cl, F, or OH group decreased the activity against all DNA viruses tested. PMEDAP was highly active against HSV-1, HSV-2, and VZV in the concentration range (EC50) of 0.07-2 microg/mL. Also the 2-amino-6-chloropurine derivative was strongly active (EC50 = 0.1-0. 4 microg/mL) against herpes simplex viruses and (EC50 = 0.006-0.3 microg/mL) against CMV and VZV. PMEG was the most active compound of the whole series against DNA viruses (EC50 approximately 0.01-0.02 microg/mL), though it exhibited significant toxicity against the host cells. The base-modified compounds did not show any appreciable activity against DNA viruses except for 7-deazaPMEA (IC50 approximately 7.5 microg/mL) against HIV-1 and MSV. The neutral (diisopropyl, diisooctyl) diesters of PMEA were active against CMV and VZV, while the corresponding monoesters were inactive. The diisopropyl ester of the 2-chloroadenine analogue of PMEA showed substantially (10-100x) higher activity against CMV and VZV than the parent phosphonate. Also, the diisopropyl and diisooctyl ester of PMEDAP inhibited CMV and VZV, but esterification of the phosphonate residue did not improve the activity against either MSV or HIV.

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“…In the acyclic nucleoside phosphonates, the oxygen atom at the β-position to the phosphonate is vital for the antiviral activities and replacement by an alkyl side chain (15) abolishes all antiviral activities [64,65]. Insertion of an extra oxygen atom between the nucleobase and side chain (16) substantially reduces the anti-HBV activity of adefovir [66]. (S)-HPMPA (17) shows good anti-HBV activity, with an EC 50 around 0.4 µM in HB 611 cell line, whereas its congener (S)-HPMPC (18, cidofovir) has a potency about 20 folds lower [67].…”

Section: Structure-activity Relationship Of Adefovir Analogsmentioning

confidence: 98%

Nucleoside Analogs as Anti-HBV Agents

Zhou¹,

Littler

2006

CTMC

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Chronic hepatitis B virus (HBV) infection affects about 400 million people worldwide. The development of nucleoside analogs that inhibit HBV polymerase provides an important approach for treating HBV infection. The approval of lamivudine, adefovir and entecavir represents a cornerstone of hepatitis B therapy. However, the challenges from the resistance and the off-therapy viral rebound are still unmet, and there is a need of developing new therapeutic agents. This review will discuss the structure-activity relationship of the most significant anti-HBV nucleoside analogs and the latest development in the field.

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Comparative Anti-Retrovirus and Anti-Hepadnavirus Activity of Three Different Classes of Nucleoside Phosphonate Derivatives

Cited by 13 publications

References 19 publications

Acyclic Phosphonomethylether Nucleoside Inhibitors of Respiratory Viruses

Acyclic Phosphonomethylether Nucleoside Inhibitors of Respiratory Viruses

Structure−Antiviral Activity Relationship in the Series of Pyrimidine and Purine N-[2-(2-Phosphonomethoxy)ethyl] Nucleotide Analogues. 1. Derivatives Substituted at the Carbon Atoms of the Base

Nucleoside Analogs as Anti-HBV Agents

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