2-Aryl-2-hydroxyethylamine substituted 4-oxo-4,7-dihydrothieno[2,3-b]pyridines as broad-spectrum inhibitors of human herpesvirus polymerases

Schnute, Mark E.; Anderson, David J.; Brideau, Roger J.; Ciske, Fred L.; Collier, Sarah; Cudahy, Michele M.; Eggen, MariJean; Génin, Michaël; Hopkins, Todd A.; Judge, Thomas M.; Kim, Euibong J.; Knechtel, Mary L.; Nair, Sajiv K.; Nieman, James A.; Oien, Nancee L.; Scott, Allen; Tanis, Steven P.; Vaillancourt, Valerie; Wathen, Michael W.; Wieber, Janet L.

doi:10.1016/j.bmcl.2007.03.102

Cited by 47 publications

(25 citation statements)

References 18 publications

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“…The results of these studies are shown in Table 1. In similarity to previously reported values (11,56,71,86), we found that ACV has an IC 50 for WT EBV of 4.1 M (0.92 g/ml), while GCV is more potent, with an IC 50 of 1.5 M (0.39 g/ml). In contrast, we found that ACV has an IC 50 of 36.4 M (8.19 g/ml) for the PKmut virus, and GCV has an IC 50 of 19.6 M (5 g/ml).…”

Section: Vol 84 2010 Ebv-pk Mutant Is Resistant To Ganciclovir/acycsupporting

confidence: 91%

“…We found that the IC 50 of ACV for WT EBV was 4.1 M, while the IC 50 of GCV was 1.5 M. Previous studies using Southern blot methods to measure the amount of lytic EBV viral replication also reported that the IC 50 of ACV for WT EBV is considerably higher (7 to 10 M) (71,86) than the IC 50 of GCV (found to be 1.0 M) (11,56). The definition of in vitro resistance of HSV isolates to ACV has varied in the literature from 4.4 to 13.2 M, according to the method selected and various other factors (14,22,23).…”

Section: Discussionsupporting

confidence: 45%

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The Epstein-Barr Virus (EBV)-Encoded Protein Kinase, EBV-PK, but Not the Thymidine Kinase (EBV-TK), Is Required for Ganciclovir and Acyclovir Inhibition of Lytic Viral Production

Qiao¹,

Hagemeier²,

Fingeroth

et al. 2010

J Virol

142

122

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Ganciclovir (GCV) and acyclovir (ACV) are guanine nucleoside analogues that inhibit lytic herpesvirus replication. GCV and ACV must be monophosphorylated by virally encoded enzymes to be converted into nucleotides and incorporated into viral DNA. However, whether GCV and/or ACV phosphorylation in EpsteinBarr virus (EBV)-infected cells is mediated primarily by the EBV-encoded protein kinase (EBV-PK), the EBV-encoded thymidine kinase (EBV-TK), or both is controversial. To examine this question, we constructed EBV mutants containing stop codons in either the EBV-PK or EBV-TK open reading frame and selected for stable 293T clones latently infected with wild-type EBV or each of the mutant viruses. Cells were induced to the lytic form of viral replication with a BZLF1 expression vector in the presence and absence of various doses of GCV and ACV, and infectious viral titers were determined by a green Raji cell assay. As expected, virus production in wild-type EBV-infected Epstein-Barr virus (EBV) is a human herpesvirus that causes infectious mononucleosis and is associated with a variety of different human tumors (1,47,81). Like all herpesviruses, EBV can infect cells in either the latent or lytic form (13). The lytic form of infection is required for horizontal spread of the virus from cell to cell and from host to host. During the lytic form of viral replication, EBV uses a virally encoded DNA polymerase and the oriLyt replication origin to duplicate its genome (24, 36, 51). The lytic form of EBV replication can be effectively inhibited in vitro by the guanine nucleoside analogues, acyclovir (ACV) and ganciclovir (GCV) (11,16,50,56). Since acyclovir is significantly less toxic than ganciclovir in patients, acyclovir is generally used to treat diseases associated with lytic EBV infection, such as oral hairy leukoplakia (3).GCV and ACV cannot be incorporated into viral or cellular DNA unless they are phosphorylated and converted into nucleotides (17,29). Work in other herpesvirus systems has demonstrated that the first step in GCV or ACV phosphorylation is not performed efficiently by cellular nucleoside kinases but can be carried out by virally encoded enzymes in cells infected with various herpesviruses (6,17,20,25,29,75). Human herpes simplex virus 1 (HSV-1) and HSV-2 encode a viral thymidine kinase (TK) which mediates the first step in GCV and ACV phosphorylation in virally infected cells (20,21,73), and ACV-and GCV-resistant HSV mutants isolated from patients commonly have mutations in the viral thymidine kinase gene (5,14,46,64) and less commonly within the viral DNA polymerase gene (61). In contrast, the human cytomegalovirus (HCMV) does not encode a viral thymidine kinase protein.Instead, in HCMV-infected cells, the virally encoded protein kinase (UL97) mediates the first step of GCV phosphorylation (53, 75) and (albeit much less efficiently) ACV phosphorylation (76). Once made, the triphosphorylated form of ACV (and to a lesser extent GCV) is a much better substrate for herpesvirus-encoded DNA polymerases than...

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Section: Vol 84 2010 Ebv-pk Mutant Is Resistant To Ganciclovir/acycsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 45%

The Epstein-Barr Virus (EBV)-Encoded Protein Kinase, EBV-PK, but Not the Thymidine Kinase (EBV-TK), Is Required for Ganciclovir and Acyclovir Inhibition of Lytic Viral Production

Qiao¹,

Hagemeier²,

Fingeroth

et al. 2010

J Virol

142

122

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“…(1.86 g, 5 mmol), the appropriate acetylacetone, ethyl acetoacetate, ethyl cyanoacetate, malononitrile, benzoylacetonitrile, (5 mmol) and ammonium acetate (0.38 g, 5 mmol), was heated in acetic acid (10 mL) under reflux for 3 h. on cooling, the separated solid was filtered, washed with water and crystallized from the proper solvent afforded 10-14, respectively. (10). Beige crystals, Yield: 84%, melting point: 160-162 °C (acetic acid).…”

Section: -(5-bromobenzofuran-2-yl)pyrido[3'2':45]thieno[32-d]pyrimentioning

confidence: 99%

“…The thieno [2,3-b]pyridine derivatives occupy special place and have attracted considerable attention because of their broad pharmacological activities, including anticancer [1][2][3][4][5][6][7][8][9], antiviral [10][11][12][13], anti-inflammatory [14][15][16][17], antimicrobial [18,19], antidiabetic [20][21][22][23], antihypertensive [24][25][26] and osteogenic [27,28] activities, in addition to treatment of CNS disorders [29][30][31]. Also, pyridine derivatives of different heterocyclic nucleus have shown potent pharmacological properties like antifungal [32,33], antitubercular [34], antibacterial [35], antimicrobial [36], insecticida [37].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of some new Thieno[2,3-b]pyridines, Pyrimidino[4',5':4,5]thieno[2,3-b]pyridine and Pyridines Incorporating 5-Bromobenzofuran-2-yl Moiety

2015

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2-Sulfanyl-6-(2-thienyl)pyridine-3-carbonitrile, 1-Amino-6-(5-bromo-benzofuran-2-yl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile, thieno [2,3-b]pyridins, pyrimidino[4',5':4,5] thieno [2,3-b]pyridine, quinazoline and carbamate derivatives were synthesized from sodium 3-(5-bromobenzofuran-2-yl)-3-oxoprop-1-en-1-olate with. The newly synthesized compounds were elucidated by elemental analysis, spectral data, and alternative synthesis whenever possible and chemical transportation.

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“…1,2 Some of them proved to possess antiviral, 3,4 anti-diabetic, 5 antimicrobial, 6,7 anti-inflammatory, 8 antitumor, 9 antiparasitic 10 and neurotropic activities. 11 Also, thienopyrimidine derivatives have been the subject of several chemical and biological studies on account of their wide spectrum of biological activity.…”

Section: Introductionmentioning

confidence: 99%

Fused thieno[2,3-b]pyridines: synthesis and characterization of new condensed pyridothienopyrimidines

Bakhite¹,

Abeed²,

Ahmed³

2017

Arkivoc

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2-Aryl-2-hydroxyethylamine substituted 4-oxo-4,7-dihydrothieno[2,3-b]pyridines as broad-spectrum inhibitors of human herpesvirus polymerases

Cited by 47 publications

References 18 publications

The Epstein-Barr Virus (EBV)-Encoded Protein Kinase, EBV-PK, but Not the Thymidine Kinase (EBV-TK), Is Required for Ganciclovir and Acyclovir Inhibition of Lytic Viral Production

The Epstein-Barr Virus (EBV)-Encoded Protein Kinase, EBV-PK, but Not the Thymidine Kinase (EBV-TK), Is Required for Ganciclovir and Acyclovir Inhibition of Lytic Viral Production

Synthesis of some new Thieno[2,3-b]pyridines, Pyrimidino[4',5':4,5]thieno[2,3-b]pyridine and Pyridines Incorporating 5-Bromobenzofuran-2-yl Moiety

Fused thieno[2,3-b]pyridines: synthesis and characterization of new condensed pyridothienopyrimidines

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