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1.
Abstract

The synthesis of 9-[2-(phosphonomethoxy)allyl]guanine (1) and 9-[2-(phosphonomethoxy)allyl]-8-aza-guanine (2), two new unsaturated acyclic phosphonate nucleosides analogues of the anti-HIV agents PMPG and 8-aza-PMPG, is described. Compounds 1 and 2 were evaluated for activity against human immunodeficiency virus (HIV-1 and HIV-2) and herpes simplex virus (HSV-1 and HSV-2).  相似文献   

2.
Abstract

Abstract. A number of 5-substituted constrained acyclic analogs of cytidine and uridine have been prepared in which the glycosyl torsion angle is constrained in the anti conformation. Compounds 2a-c, 3a-c, 4, 5 and 6 were tested for activity against HCMV and HSV-1. Compounds 2a and 2b showed moderate activity against HCMV. Compound 2c exhibited a weak inhibitory activity against HSV-1. Compounds 2a, 3a, 4, 5, 6, 8, and 9 were screened for their anti-HIV or antitumor activity. None of them were active against HIV. However, compound 9 showed a 50% inhibition on MDA-MB-231/ATTC breast cancer cell growth at a concentration of 0.15 μM.  相似文献   

3.
Analogs of (E)-5-(2-bromovinyl)-2 ′-deoxycytidine (BrVdCyd) (1) by substitution at N4 were synthesized to impart resistance against deamination. The anti-HSV-1 activity and solution conformation of these analogs were determined. N4-Acetyl-BrVdCyd (2) was a potent inhibitor of HSV-1 replication whereas N4-propanoyl-BrVdCyd (3) had good activity and N4-Butanoyl-BrVdCyd (4) had only low activity against HSV-1 replication. N4-Methyl-BrVdCyd (5) was devoid of activity against HSV-1.  相似文献   

4.
Abstract

Geminal difluorocyclopropane analogues of nucleosides 7a7e were synthesized. Compounds 7a and 7c7e were obtained by alkylation of nucleic acid bases or their appropriate precursors with (cis)-1-benzyloxymethyl-2-bromomethyl-3,3-difluorocyclopropane (8). Analogue 7b was prepared by hydrolysis of 2-amino-6-chloropurine derivative 7e. Compounds 7a7d did not exhibit any antiviral activity against HCMV, HSV-1, HSV-2, EBV, VZV, HBV and HIV-1 or antitumor effects against murine leukemia L1210, mouse tumors PO3 or C38 and human tumor H15.  相似文献   

5.

The Z- and E-thymine and cytosine pronucleotides 3d, 4d, 3e, and 4e of methylenecyclopropane nucleosides analogues were synthesized, evaluated for their antiviral activity against human cytomegalovirus (HCMV), herpes simplex virus 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), human immunodeficiency virus type 1 (HSV-1), and hepatitis B virus (HBV) and their potency was compared with the parent compounds 1d, 2d, 1e, and 2e. Prodrugs 3d and 4d were obtained by phosphorylation of parent analogues 1d or 2d with reagent 8. A similar phosphorylation of N4-benzoylcytosine methylenecyclopropanes 9a and 9b gave intermediates 11a and 11b. Deprotection with hydrazine in pyridine–acetic acid gave pronucleotides 3e and 4e. The Z-cytosine analogue 3e was active against HCMV and EBV. The cytosine E-isomer 4e was moderately effective against EBV.  相似文献   

6.
Abstract

Cyclopropyl carbocyclic nucleosides have been synthesized from the key intermediate 2 which was converted to the mesylated cyclopropyl methyl alcohol 3. Condensation of compound 3 with various purine and pyrimidine bases gave the desired nucleosides. All synthesized nucleosides were evaluated for antiviral activity and cellular toxicity. Among them adenine 22 and guanine 23 derivatives showed moderate antiviral activity against HIV-1 and HBV. None of the other compounds showed any significant antiviral activities against HIV-1, HBV, HSV-1 and HSV-2 in vitro up to 100μM.  相似文献   

7.

Novel acyclic nucleoside analogues were designed and synthesized as open-chain analogues of neplanocin A. The coupling of the allylic bromide with purine bases using cesium carbonate afforded a series of novel acyclic nucleosides. The synthesized compounds Ia II were evaluated for their antiviral activity against various viruses such as HIV, HSV-1, HSV-2, and ECMV.  相似文献   

8.
АBSTRACT

Esters of the antiherpetic drugs ganciclovir, penciclovir with the bile acids (cholic, chenodeoxycholic and deoxycholic) and amino acid esters of acyclovir were generated and evaluated for their in vitro antiviral activity against herpes simplex viruses type 1 and type 2 (HSV-1, HSV-2). The antiviral assays demonstrated that modified analogs of ACV and PCV are less active compared to the initial substances against HSV-1and HSV-2. CC50 for ganciclovir-deoxycholate corresponded to the CC50 of the other analogs and its activity is lower than ganciclovir. Obtained results show that tested modification do not improve bioavailability of nucleoside analogs in cells.  相似文献   

9.
Abstract

We have reported previously that purine methylenecyclopropane analogs are potent agents against cytomegaloviruses. In an attempt to extend the activity of these compounds, the 2-amino-6-cyclopropylaminopurine analog, QYL-1064, was selected for further study by modifying the purine 6 substituent. A total of 22 analogs were tested against herpes simplex virus types 1 and 2 (HSV-1, HSV-2), varicella zoster virus (VZV), human cytomegalovirus (HCMV), murine cytomegalovirus (MCMV), Epstein-Barr virus (EBV), human herpesvirus type 6 (HHV-6) and human herpesvirus type 8 (HHV-8). Ten of the analogs had activity against at least one of the viruses tested. One compound had moderate activity against HSV-1 and six had activity against VZV. All but one compound was active against HCMV with a mean EC50 of 2.1 ± 0.6 µM, compared with a mean EC50 of 3.9 ± 0.8 µM for ganciclovir. Of special interest was the fact that eight of the ten compounds were active against both HHV-6A and HHV-6B with mean EC50 values of 6.0 ± 5.2 µM and <2.4 ± 1.5 µM, respectively. Only two compounds had activity against EBV, whereas all but one compound was active against HHV-8 with a mean EC50 of 3.1 ± 1.7 µM. These results indicate that members of this series of methylenecyclopropane analogs are highly active against HCMV, HHV-6, and HHV-8 but are less active against HSV, VZV, and EBV.  相似文献   

10.
Novel syntheses of 4′-modified cyclopentenyl pyrimidine C-nucleosides were performed via C-C bond formation using SN2 alkylation via the key intermediate mesylates 6 and 16, which were prepared from acyclic ketone derivatives. When antiviral evaluation of synthesized compound was performed against various viruses such as HIV-1, HSV-1 and HSV-2, isocytidine analogue 20 showed moderate anti-HIV activity in CEM cell line (EC50 = 13.1 μmol).7  相似文献   

11.
Abstract

A series of 2′,3′-dideoxy-2′-fluoro-L-threo-pentofuranosyl nucleosides has been synthesized as potential antiviral agents. The synthesized compounds were evaluated against HIV-1, HBV, HSV-1, and HSV-2. Among the synthesized analogues, only the cytosine derivative showed moderate antiviral activity against HIV and HBV.  相似文献   

12.
Novel 1-(1,3-disubstituted-imidazolidyn-2-ylidene)-3-ethoxycarbonylmethylurea derivatives (3a3j) were obtained from appropriate 1-aryl-3-arylsulfonyl-1H-imidazolidine-2-imines (1a–1j) and ethyl isocyanatoacetate (2), which were subjected to condensation. Seven compounds were tested for their antiviral activity against HSV-1 and CVB3 viruses. Among the tested compounds, 3c was found to be active against HSV-1, proving that 4-methoxy substituent as R and 4-methyl substituent as R1 are most beneficial for activity against this virus. Furthermore, 3e and 3g were active against CVB3, which demonstrated that both 4-methyl and 4-chloro substitution is tolerated as R1, whereas 4-chloro and 2-methoxy substituents are best as R. It was also shown that the active compounds are characterized by relatively big surface area, small ovality, and greatest HOMO and LUMO energies in comparison to the rest of the compounds.  相似文献   

13.
Abstract

Synthesis of Z- and E-methylenecyclopropane analogues of adenosine 3 and 4 by alkylation of adenine with novel alkylating agent 5 is described. The E-isomer 4 is a substrate for adenosine deaminase. Compounds 3 and 4 were tested for antiviral activity against HCMV, HSV-1, HSV-2, EBV, VZV, HBV and HIV-1.  相似文献   

14.
The synthesis of dideoxy-6-azathymidine 4′-thionucleoside 1-(2,3-dideoxy-4-thio-β-D-erythro-pentofuranosyl)-(6-azathymidine) (2), and the L-nucleoside, 1-(4-thio-β-L-erythro-pentofuranosyl)-(6-azathymidine) (3) and their evaluation against a wide panel of antiviral assays are described. The L-thionucleoside (3) was devoid of antiviral activity. The dideoxy-thionucleoside (2) was moderately active against vaccinia virus (VV) and the herpes simplex virus strains HSV-1 (strain KOS) and HSV-2 (strain G) (MIC 12 μM) and retained inhibitory activity vs a thymidine kinase-deficient strain HSV-1/TK, suggesting that (2) is not dependent on viral TK-catalysed phosphorylation for antiviral activity and/or may use an alternative metabolic activation pathway.  相似文献   

15.
Abstract

Reactions of α, α′-dichloroazo compounds 2 with SbCl5 gave 1-(chloroalkyl)-1-aza-2-azoniaallene salts 3 as reactive intermediates. Cycloadditions of 3 with the ribofuranosyl cyanide 4 afforded the β-D-ribofuranosyl-1,2,4-triazolium salts 5, which rearranged spontaneously to salts 6. Hydrolysis of 6 gave the 1,2,4-triazole C-nucleosides 7, which yielded the free nucleosides 8 after deblocking. Analogously, 12 was prepared from the cycloaddition of 4 with the α-chloroazo compound 10 in the presence of SbCl5. Deblocking of 12 with sodium methoxide afforded 13. Compounds 8a,b,e,f and 13 were tested against HIV-1, HIV-2, HSV-1 and HSV-2 and were found to be inactive.  相似文献   

16.
Abstract

Eight phosphonic acid analogs of acyclovir (ACV) or ganciclovir (DHPG) inhibited human cytomegalovirus in vitro. Therapeutic indices were: phosphonate diacid of DHPG: 500; DHPG: 500; phosphonate monoethylester of DHPG: 258; phosphonate monoethylester of ACV: 94; cyclic phosphonate of DHPG: 64; ACV: 60; phosphonate monobutylester of ACV: 1.5; phosphonate monoethylester of deoxy DHPG: 4.6; 8-bromo ACV phosphonate monoethylester: >2; phosphonate monoethylester heptyl of ACV: 1. Types 1 and 2 herpesvirus (HSV-1, HSV-2) and varicella zoster virus (VZV) were poorly inhibited by these new compounds, suggesting highly specific anti-HCMV activity. None exhibited significant cytotoxic effects as measured by uptake of [3H]thymidine, [3H]uridine and [3H]leucine.  相似文献   

17.
Electronic parameters of 1′,3 ′-oxygen play significant roles in steering the conformation of nucleoside phosphonic acid analogues. To investigate the relationship of two oxygen atoms with antiviral enhancement, novel 1′,3 ′-dioxolane 5 ′-deoxyphosphonic acid purine analogues were synthesized via de novo acyclic stereoselective route from acrolein and glycolic acid. The synthesized nucleoside phosphonic acid analogues 14 and 19 were subjected to antiviral screening against several viruses, such as HIV-1, HSV-1, HSV-2, and HCMV. The guanine analogue 19 exhibits in vitro anti-HIV-1 activity similar to that of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) in MT-4 cells.  相似文献   

18.
The first synthesis of a 4′-methylated carbocyclic C-nucleoside 16 was achieved via the mesylate intermediate 10, which was prepared using ring-closing metathesis and SN2 alkylation from acetol 5. When antiviral evaluation of synthesized compound 16 was performed against various viruses such as HIV, HSV-1, HSV-2, and HCMV, it showed moderate anti-HIV activity in MT-4 cell line (EC50 = 14.7 μmol).  相似文献   

19.
Background aimsDendritic cells (DCs) are the most potent antigen presenting cells of the immune system and have been under intense study with regard to their use in immunotherapy against cancer and infectious disease agents. In the present study, DCs were employed to assess their value in protection against live virus challenge in an experimental model using lethal and latent herpes simplex virus (HSV) infection in Balb/c mice.MethodsDCs obtained ex vivo in the presence of granulocyte-macrophage colony-stimulating factor and interleukin-4 were loaded with HSV-1 proteins (DC/HSV-1 vaccine). Groups of mice were vaccinated twice, 7 days apart, via subcutaneous, intraperitoneal or intramuscular routes with DC/HSV-1 and with mock (DC without virus protein) and positive (alum adjuvanted HSV-1 proteins [HSV-1/ALH]) control vaccines. After measuring anti-HSV-1 antibody levels in blood samples, mice were given live HSV-1 intraperitoneally or via ear pinna to assess the protection level of the vaccines with respect to lethal or latent infection challenge.ResultsIntramuscular, but not subcutaneous or intraperitoneal, administration of DC/HSV-1 vaccine provided complete protection against lethal challenge and establishment of latent infection as assessed by death and virus recovery from the trigeminal ganglia. It was also shown that the immunity was not associated with antibody production because DC/HSV-1 vaccine, as opposed to HSV-1/ALH vaccine, produced very little, if any, HSV-1-specific antibody.ConclusionsOverall, our results may have some impact on the design of vaccines against genital HSV as well as chronic viral infections such as hepatitis B virus, hepatitis C virus and human immunodeficiency virus.  相似文献   

20.
Abstract

Several 5-(4-substituted benzyl)-6-azauracils have been synthesized from the corresponding benzaldehydes. The 5-benzyl-6-azauracils were silylated with hexamethyldisilazane and then glycosylated with aliphatic halides, e.g., (2-acetoxyethoxy)methyl bromide and 1,3-dibenzyloxy-2-chloromethoxypropane, to give protected acyclic nucleosides which were deprotected to afford acyclonucleosides of 5-(4-substituted benzyl)-6-azauracils. None of the compounds exhibited significant antiviral activity against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in vitro.  相似文献   

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