Acyclovir Analogues Research Articles

Unusual Tritylation Reactions of Tricyclic Analogues of Acyclovir and an Attempt to Elucidate Their Mechanism

Unusual Tritylation Reactions of Tricyclic Analogues of Acyclovir and an Attempt to Elucidate Their Mechanism

Synthesis and antiviral properties of 9-[(2-methyleneaminoxyethoxy)methyl]guanine derivatives as novel Acyclovir analogues

This paper reports the synthesis and the antiviral properties of a series of 9-[(2-methyleneaminoxyethoxy)methyl]guanine derivatives, which can be viewed as analogues of the antiherpes drug Acyclovir (ACV) from which they differ in the replacement of its hydroxy group with variously substituted methyleneaminoxy moieties. Some of the newly synthesized compounds proved to possess a certain activity against HSV-1, albeit lower than that of ACV.

Aqueous Solubilities, Infinite Dilution Activity Coefficients and Octanol-Water Partition Coefficients of Tricyclic Analogs of Acyclovir*

Solubilities of tricyclic analogs of acyclovir have been determined in water at 25, 35, and 45°C and in octanol, water-saturated octanol, and octanol-saturated water at 25°C. Octanol-water partition coefficients were determined at 25°C. Melting temperatures and molar enthalpies of fusion were measured. Activity coefficients in water, octanol, and in aqueous octanol solutions were determined and are discussed. The effect of hydrophilic and hydrophobic substituents in the tricyclic analogs on their thermodynamic properties are discussed. The standard Gibbs energy of transfer between the saturated phases were found to correlate with known values of the melting point of the solvents and the solubilities of the solute. For a number of the compounds examined, correlations between the minimum inhibitory concentration against the herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), varicella-zoster virus (VZV), thymidine kinase-deficient (TK−) strains of VZV and \(\Delta G_{{\text{W}} \to {\text{0}}}^0 ;\Delta G_{{\text{tr}}}^0\) were established. Detailed conclusions have been derived concerning the relationships between the structure and the thermodynamic parameters of the compounds examined.

Chemistry and anti-herpes simplex virus type 1 evaluation of cycloSal-nucleotides of acyclic nucleoside analogues.

The synthesis of different cycloSal-phosphotriesters of the acyclic nucleoside analogues acyclovir (ACV), penciclovir (PCV) and T-penciclovir (T-PCV) as potential new lipophilic, membrane-soluble pronucleotides is described. The introduction of the cycloSal moiety was achieved by using reactive cyclic chlorophosphane reagents. In addition to the cycloSal-PCV monophosphate (MP) phosphotriesters, a second derivative bearing an acetyl group at the second primary alcohol function was prepared. In hydrolysis studies the cycloSal-ACVMPs showed the expected range of hydrolytic stability dependent on the substituent in the masking group (8-17 h). In contrast, the cycloSal-PCVMP derivatives exhibited a 11- to 15-fold increase in hydrolytic lability as compared to the corresponding cycloSal-ACVMP derivatives. We demonstrated that the free primary alcohol group is responsible for this rate acceleration because cycloSal-OAc-PCVMP, in which the hydroxyl group was blocked by acetylation, did not show the aforementioned acceleration. Unexpectedly, the hydrolysis product was not PCVMP but according to NMR and mass spectrometry it was cycloPCVMP (cPCVMP). The title compounds were evaluated in vitro for their ability to inhibit herpes simplex virus type 1 (HSV-1) and thymidine kinase-negative (TK-) HSV-1 replication in Vero cells. The cycloSal-ACVMP compounds exhibited high antiviral activity in HSV-1-infected cells. More importantly, one derivative retained all activity from the wild-type virus strain in HSV-1/TK(-)-infected Vero cells. The PCV derivatives were markedly less active. The reason for the failure of the cycloSal-PCVMPs seems to be due to the formation of cPCVMP instead of the desired PCVMP.

ChemInform Abstract: A Case of Unusual Sterically Driven C‐Tritylation Reaction of Tricyclic Analogues of Acyclovir.

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A case of unusual sterically driven C-tritylation reaction of tricyclic analogues of acyclovir

3,9-Dihydro-3-[(2-hydroxyethoxy)methyl]-6-methyl-9-oxo-5 H-imidazo[1,2- a]purine ( 1) and its silylated derivative ( 2) when tritylated under conditions suitable for regioselective N-5 alkylation underwent instead C-substitution to give 7-trityl ( 12, 3) and 7-(4-benzhydrylphenyl) ( 13, 4) derivatives as major and minor products, respectively. Substrates lacking 6-Me group ( 5, 6) yielded 5-tritylated ( 10, 7) and 5,7-ditritylated ( 11, 8) major products and 7-tritylated ( 9) minor product. The regioselectivity of the reaction seems to be driven mainly by steric hindrance of the 6-Me substituent.

Antiviral drug susceptibility of human herpesvirus 8.

We studied the susceptibility of human herpesvirus 8 (HHV-8) to a number of antiherpesvirus agents. The acyclic nucleoside phosphonate (ANP) analogs cidofovir and HPMPA [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)adenine] effected potent inhibition of HHV-8 DNA synthesis, with 50% effective concentrations (EC50) of 6.3 and 0.6 microM, respectively. Adefovir, an ANP with both antiretrovirus and antiherpesvirus activity, blocked HHV-8 DNA replication at a fourfold-lower concentration than did foscarnet (EC50 of 39 and 177 microM, respectively). The most potent inhibitory effect was obtained with the N-7-substituted nucleoside analog S2242 (EC50, 0.11 microM). The nucleoside analogs acyclovir, penciclovir, H2G ((R)-9-[4-hydroxy-2-(hydroxymethyl) butyl]guanine), and brivudine had weak to moderate effects (EC50 of > or =75, 43, 42, and 24 microM, respectively, and EC90 of > or =75 microM), whereas ganciclovir elicited pronounced anti-HHV-8 activity (EC50, 8.9 microM).

The Pronucleotide Approach. III. Synthesis, Anti-HBV Activity and Stability Studies of the Bis(S-pivaloyl-2-thioethyl) Phosphotriester Derivative of Acyclovir

The nucleoside analog Acyclovir (ACV) is used in the treatment of herpes simplex (HSV) and varicella-zoster (VZV) diseases. The possibility to extend the application field of ACV by using the bis[SATE] pronucleotide approach in order to deliver ACVMP inside the cell was investigated. And actually, the title compound has potent anti-hepatitis B activity in cell culture experiments. Here, we also report its synthesis and stability in various media.

Ganciclovir.

Ganciclovir is a nucleoside analogue of guanosine, a homologue of acyclovir, and the first antiviral drug to be effective in the treatment of cytomegalovirus (CMV) disease in humans.14 It inhibits not only all the herpesviruses but also the transformation of normal cord-blood lymphocytes by Epstein–Barr virus.57 In this review, I outline ganciclovir's mechanisms of action and resistance and discuss the clinical effectiveness of intravenous and oral ganciclovir.Mechanism of ActionThe structures of ganciclovir and of its analogue acyclovir are shown in Figure 1. In vivo, ganciclovir is converted to ganciclovir triphosphate, which inhibits viral DNA polymerases, including those . . .

Synthesis and properties of fluorescent analogues of acyclovir: B. Golankiewicz, W. Folkman and T. Ostrowski Institute of Bioorganic Chemistry of the Polish Academy of Sciences. 61-704 Poznań, Poland

Synthesis and properties of fluorescent analogues of acyclovir: B. Golankiewicz, W. Folkman and T. Ostrowski Institute of Bioorganic Chemistry of the Polish Academy of Sciences. 61-704 Poznań, Poland

Regioselective Synthesis of 9‐[(2‐Hydroxyethoxy)Methyl]‐6‐Benzylaminopurine Analogue of Acyclovir

AbstractThe 6‐benzylaminopurine 1 has been alkylated with (2‐acetoxyethoxy)methylbromide 3, using trimethylsilylation and phase transfer catalysis procedures. The influence of the base, the solvent and the catalyst were studied. When the solid‐liquid phase transfer catalysis was conducted in tetrahydrofuran in the presence of the potassium tert‐butoxide and 18‐crown‐6, the reaction was regioselective to give 9‐[(2‐acetoxyethoxy)methyl]‐6‐benzylaminopurine 5 in 80% yield.

Tricyclic analogues of acyclovir and ganciclovir. Influence of substituents in the heterocyclic moiety on the antiviral activity.

The effect of substitution in the tricyclic moiety of 3,9-dihydro-9-oxo-5H-imidazo[1,2-alpha]purine (1,N-2-ethenoguanine) analogues of acyclovir (1) and ganciclovir (2) on their physical properties and antiherpetic activity was investigated by synthesizing a series of compounds substituted in the 2, 6, or 7 position (6-14). Substitution in the 6-position with phenyl or 4-biphenylyl resulted in fluorescent compounds (7, 9, 13, 14). In general, the substituent in the 6 position potentiated the antiviral activity. The fluorescent 6-phenyl derivatives: 3,9-dihydro-3-[(2-hydroxyethoxy)methyl]-9-oxo-6-phenyl-5H-imidaxo[ 1,2-alpha]purine (7) and its 3-[(1,3-dihydroxy-2-propoxy)methyl] congener (13) were the most potent tricyclic analogues of 1 and 2, respectively. Compound 7 was inhibitory to TK+ HSV-1, TK+ HSV-2, and TK+ VZV within the concentration range of 0.2-2.0 micrograms/mL, well below the cytotoxicity threshold (50 to > 100 micrograms/mL). Compound 13 was inhibitory to TK+ HSV-1 and TK+ HSV-2 within the concentration range of 0.005-0.3 microgram/mL and to TK+ and TK- VZV within the concentration range of 0.4-3 micrograms/mL (cytotoxicity threshold > 200 micrograms/mL). Both 7 and 13 seem to be promising candidate compounds for the noninvasive diagnosis of herpesvirus infections.

Structure-Activity Relationship of Phosphonic Acid Analogs of Acyclovir or Ganciclovir Against Human Cytomegalovirus in MRC-5 Cells

Abstract In vitro anti-HCMV activity of 22 phosphonic acid analogs of acyclovir or ganciclovir (DHPG) was determined in MRC-5 cells to establish structure-activity relationships.

155 Synthesis and antiviral activity of novel tricyclic analogues of acyclovir and ganciclovir: B. Golankiewicz 1, T. Ostrowski 1, G. Andrei 2, R. Snoeck 2 and E. De Clercq 21Institute of Bioorganic Chemistry of the Polish Academy of Sciences, 61–704 Poznań, Poland and 2Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium

155 Synthesis and antiviral activity of novel tricyclic analogues of acyclovir and ganciclovir: B. Golankiewicz 1, T. Ostrowski 1, G. Andrei 2, R. Snoeck 2 and E. De Clercq 21Institute of Bioorganic Chemistry of the Polish Academy of Sciences, 61–704 Poznań, Poland and 2Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium

Optically pure and fluoro substituted acyclovir analogues

1′,2′-Seco-2′-nor-nucleosides carrying a fluorine atom, instead of hydroxyl group, on C-3′ are synthesized in enantiomerically pure form, starting from (2S)-1-fluoro-3-(R)-[(4-methylphenyl)sulfinyl]-2-propanol.

Herpes simplex-1 virus thymidine kinase gene is unable to completely eliminate live, nonimmunogenic tumor cell vaccines.

Recent experiments with genetically engineered tumors have generated renewed interest in active cellular immunotherapy as a cancer treatment modality. In order to consider the use of live tumor cells for immunotherapy in human cancer patients, it will be important to ensure that these cells do not themselves produce morbidity in the event the immune system fails to eliminate them. Toward this end, we have examined a strategy for eliminating genetically manipulated nonimmunogenic tumors in vivo. When B16F10 melanoma cells were transfected with the Herpes simplex virus 1 thymidine kinase (HSV-TK) gene, cells were rendered susceptible to killing by the nucleoside analogs acyclovir (ACV) and ganciclovir (GCV). B16-HSV-TK+ tumors established in C57BL6 mice were successfully "suicided" in vivo when GCV was administered by continuous infusion. However, late recurrences were observed even after 1 month of continuous GCV treatment. In vivo growth kinetics suggested that the recurrences resulted from a tiny number (< 20) of cells that had survived the GCV treatment. Interestingly, recurrent tumors were as sensitive to GCV as the parental B16-HSV-TK+ line. While these results demonstrate potential feasibility of the suicide gene strategy for active immunotherapy with live tumor cells, they also illustrate that approaches dependent on the intracellular generation of cell cycle-dependent toxins may fail to eliminate small numbers of cells that temporarily exit cell cycle or that are pharmacologically sequestered.

Selective inhibition of proliferation in v-abl- and bcr-abl-transformed cells by a nucleoside analog.

The nucleoside analog acyclovir (9-[2-hydroxy-ethoxy)methyl]guanine or acycloguanosine; ACV) inhibited the in vitro transformation of NIH 3T3 cells by Abelson murine leukemia virus and the proliferation of abl- and bcr-abl-transformed hemopoietic murine cell lines. This effect is selective since ACV at the same concentration had no effect on the src and Ha-ras transformation of NIH 3T3 cells or on the proliferation of hemopoietic cells transformed by those oncogenes. The inhibitory effect on proliferation of abl-transformed cells correlated with the extent of ACV triphosphate formation and incorporation into cellular DNA that was greater than that in normal or other oncogene-transformed cells. The increased ACV triphosphate formation might be due to a higher level of 5'-nucleotidase, the enzyme responsible for trace levels of ACV phosphorylation in uninfected cells.

Synthesis and antiviral activity of 3-substituted derivatives of 3,9-dihydro-9-oxo-5H-imidazo[1,2-a]purines, tricyclic analogues of acyclovir and ganciclovir.

9-[(2-Hydroxyethoxy)methyl]guanine (acyclovir, 1a) and 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (DHPG, ganciclovir, 1b) were transformed to their respective tricyclic derivatives, 3-substituted 3,9-dihydro-9-oxo-5H-imidazo[1,2-a]purines 2b, 3a, and 3b. The 6-methyl-substituted compound 2b was obtained following reaction of 1b with bromoacetone. A two-step approach via 1-(2,2-diethoxyethyl) intermediates 4a,b was the most effective for the preparation of the derivatives unsubstituted in the appended ring (3a,b). The novel acyclonucleosides, in particular ganciclovir derivative 2b, proved markedly active against herpes simplex virus type 1 and 2, varicella-zoster virus, and cytomegalovirus.

A new class of acyclic phosphonate nucleotide analogues: phosphonate isosteres of acyclovir and ganciclovir monophosphates as antiviral agents.

Novel phosphonate isosteres of acyclovir (ACV) and ganciclovir (DHPG) monophosphates were found to be potent and selective antiherpesvirus agents. In the series of phosphonate analogues of ACV monophosphate, only the guanine analogue 20 exhibited activity against herpesviruses, similar to the structure-activity relationship observed for base modification of ACV analogues. The phosphonate isostere of ACV monophosphate (20) was more effective than ACV in the HSV-1 infected mouse model. The 3'-carba analogues of 9-[3-hydroxy-2-(phosphonomethoxy)propyl]purines/pyrimidines (adenine, HPMPA; guanine, HPMPG; cytosine, HPMPC) are devoid of antiherpesvirus activity. This result confirms that the beta-oxygen atom of the phosphonomethyl ether functionality in HPMP-purines/pyrimidines plays a critical role for activity against herpesviruses.

Desciclovir permeation of the human erythrocyte membrane by nonfacilitated diffusion

The mechanism of transport of desciclovir (DCV)—a structural analogue and prodrug of acyclovir (ACV) which provides an improved oral bioavailability of ACV—was investigated in human erythrocytes with a “papaverine-stop” assay. DCV influx was nonconcentrative, linearly dependent on DCV concentration (0.9 μM to 15 mM), insensitive (⩽20% inhibition) to nucleobases, nucleosides, or potent inhibitors of nucleoside transport, and occurred without permeant metabolism. However, DCV was a weak competitive inhibitor of the influx of adenine ( K i = 1.3 mM) and of 5-iodo-2′-deoxyuridine ( K i = 2.9 mM), permeants of the erythrocyte nucleobase and nucleoside carriers, respectively. This indicates that DCV has an affinity for both of these transporters, even though it appears not to be an effective permeant. We conclude that, in contrast to ACV which enters human erythrocytes primarily via the nucleobase carrier, DCV permeates these cells chiefly (⩾80%) by nonfacilitated diffusion. This mechanistic difference in transport between ACV and DCV is attributed to differences in their desolvation energies and suggests an explanation for the differences in the oral bioavailability of ACV which is observed after the administration of these two “acyclic nucleosides”.