- A Bioorthogonal Chemical Reporter of Viral Infection
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Pathogen-selective labeling was achieved by using the novel gemcitabine metabolite analogue 2′-deoxy-2′,2′-difluoro-5-ethynyluridine (dF-EdU) and click chemistry. Cells infected with Herpes Simplex Virus-1 (HSV-1), but not uninfected cells, exhibit nuclear staining upon the addition of dF-EdU and a fluorescent azide. The incorporation of the dF-EdU into DNA depends on its phosphorylation by a herpes virus thymidine kinase (TK). Crystallographic analyses revealed how dF-EdU is well accommodated in the active site of HSV-1 TK, but steric clashes prevent dF-EdU from binding human TK. These results provide the first example of pathogen-enzyme-dependent incorporation and labeling of bioorthogonal functional groups in human cells.
- Neef, Anne B.,Pernot, Lucile,Schreier, Verena N.,Scapozza, Leonardo,Luedtke, Nathan W.
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- Influence of 4′-Substitution on the Activity of Gemcitabine and Its ProTide against VZV and SARS-CoV-2
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In addition to its therapeutic value as a chemotherapy drug, gemcitabine is of ongoing interest to the scientific community for its broad-spectrum antiviral activity. Herein the synthesis of 4′-methoxy- and 4′-fluoro-substituted gemcitabine analogues along with their phosphoramidate prodrugs is described. Among these derivatives, 4′-fluorogemcitabine proved to be active against varicella zoster virus (VZV, TK+ strain) with an EC50 of 0.042 μM and produced significant cytotoxicity (CC50 = 0.11 μM). Upon derivatization of this trifluoro nucleoside as its prodrug, decreased anti-VZV activity was observed, but with a concomitantly improved selectivity index (SI = 36). When this prodrug was tested against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), its antiviral activity (EC50 = 0.73 μM) was comparable to or slightly lower than its cytotoxic concentration in measurements of cell growth and cell morphology, respectively.
- Zheng, Zihua,Groaz, Elisabetta,Snoeck, Robert,De Jonghe, Steven,Herdewijn, Piet,Andrei, Graciela
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supporting information
p. 88 - 92
(2020/12/21)
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- Novel derivatives of nucleosides
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PURPOSE: A novel nucleoside derivative and a method for synthesizing the same are provided to ensure excellent bioavailability and to enable oral administration. CONSTITUTION: A novel nucleoside derivative is a compound of chemical formula 2. A method for preparing the compound of chemical formula 2 comprise a step of adding NaOMe or hydrogen ion to a compound of chemical formula 10. The compound of chemical formula 10 is prepared by adding LiN_3 to a compound of chemical formula 9.
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Paragraph 0095-0097
(2017/12/27)
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- SUBSTITUTED NUCLEOSIDES, NUCLEOTIDES AND ANALOGS THEREOF
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Disclosed herein are nucleosides, nucleotides and nucleotide analogs, methods of synthesizing the same and methods of treating diseases and/or conditions such as a Picornavirus and/or Flaviviridae infection with one or more nucleosides, nucleotides and nucleotide analogs.
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Paragraph 0676; 1030; 1311
(2015/04/21)
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- SUBSTITUTED NUCLEOSIDES, NUCLEOTIDES AND ANALOGS THEREOF
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Disclosed herein are nucleosides, nucleotide analogs, methods of synthesizing nucleotide analogs and methods of treating diseases and/or conditions such as a Filoviridae virus infection with one or more nucleosides and/or nucleotide analogs.
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Paragraph 0543; 0546
(2016/03/11)
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- Discovery of 4′-chloromethyl-2′-deoxy-3′,5′-di- O -isobutyryl-2′-fluorocytidine (ALS-8176), A first-in-class RSV polymerase inhibitor for treatment of human respiratory syncytial virus infection
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Respiratory syncytial virus (RSV) is a leading pathogen of childhood and is associated with significant morbidity and mortality. To date, ribavirin is the only approved small molecule drug, which has limited use. The only other RSV drug is palivizumab, a monoclonal antibody, which is used for RSV prophylaxis. Clearly, there is an urgent need for small molecule RSV drugs. This article reports the design, synthesis, anti-RSV activity, metabolism, and pharmacokinetics of a series of 4′-substituted cytidine nucleosides. Among tested compounds 4′-chloromethyl-2′-deoxy-2′-fluorocytidine (2c) exhibited the most promising activity in the RSV replicon assay with an EC50 of 0.15 μM. The 5′-triphosphate of 2c (2c-TP) inhibited RSV polymerase with an IC50 of 0.02 μM without appreciable inhibition of human DNA and RNA polymerases at 100 μM. ALS-8176 (71), the 3′,5′-di-O-isobutyryl prodrug of 2c, demonstrated good oral bioavailability and a high level of 2c-TP in vivo. Compound 71 is a first-in-class nucleoside RSV polymerase inhibitor that demonstrated excellent anti-RSV efficacy and safety in a phase 2 clinical RSV challenge study.
- Wang, Guangyi,Deval, Jerome,Hong, Jin,Dyatkina, Natalia,Prhavc, Marija,Taylor, Joshua,Fung, Amy,Jin, Zhinan,Stevens, Sarah K.,Serebryany, Vladimir,Liu, Jyanwei,Zhang, Qingling,Tam, Yuen,Chanda, Sushmita M.,Smith, David B.,Symons, Julian A.,Blatt, Lawrence M.,Beigelman, Leo
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p. 1862 - 1878
(2015/04/22)
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- SUBSTITUTED NUCLEOSIDES, NUCLEOTIDES AND ANALOGS THEREOF
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Disclosed herein are nucleosides, nucleotides and nucleotide analogs, methods of synthesizing the same and methods of treating diseases and/or conditions such as a Coronaviridae virus, a Togaviridae virus, a Hepeviridae virus and/or a Bunyaviridae virus infection with one or more nucleosides, nucleotides and nucleotide analogs.
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Paragraph 0594; 0597
(2016/03/08)
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- SUBSTITUTED NUCLEOSIDES, NUCLEOTIDES AND ANALOGS THEREOF
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Disclosed herein are nucleosides, nucleotides and analogs thereof, pharmaceutical compositions that include one or more of nucleosides, nucleotides and analogs thereof, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a disease and/or a condition, including an infection from a norovirus, with a nucleoside, a nucleotide and an analog thereof.
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Paragraph 0298
(2015/01/16)
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- SUBSTITUTED NUCLEOSIDES, NUCLEOTIDES AND ANALOGS THEREOF
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Disclosed herein are nucleosides, nucleotides and analogs thereof, pharmaceutical compositions that include one or more of nucleosides, nucleotides and analogs thereof, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a disease and/or a condition, including an infection from a paramyxovirus and/or an orthomyxovirus, with a nucleoside, a nucleotide and an analog thereof.
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Paragraph 0420; 0421
(2013/07/05)
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- Degradation chemistry of gemcitabine hydrochloride, a new antitumor agent
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The anti-tumor agent gemcitabine hydrochloride, a β-difluoronucleoside, is remarkably stable in the solid state. In 0.1 N HCl solution at 40 °C, deamination of gemcitabine occurs, yielding its uridine analogue. Approximately 86% of the initial gemcitabine remains after 4 weeks under these conditions. Cleavage of the N-glycosidic bond of gemcitabine or conversion to its α-anomer in 0.1 N HCl solution is not observed over a 4- week period. However, this work has shown that gemcitabine hydrochloride anomerizes in 0.1 N NaOH at 40 °C. Approximately 72% of the initial gemcitabine remains after 4 weeks under the basic conditions used. Uridine hydrolysis products are also formed under these conditions. The anomerization reaction, which is unusual under basic conditions, has been confirmed by characterization of the chromatographically isolated α-anomer by NMR and mass spectrometry. A mechanism involving an acyclic intermediate is proposed.
- Anliker,McClure,Britton,Stephan,Maple,Cooke
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p. 716 - 719
(2007/10/02)
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- Stereospecific synthesis of 2-deoxy-2,2-difluororibonolactone and its use in the preparation of 2'-deoxy-2',2'-difluoro-β-D-ribofuranosyl pyrimidine nucleosides: The key role of selective crystallization
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A stereospecific synthesis of 2'-deoxy-2',2'-difluorocytidine (gemcitabine), a potential anticancer agent, is described. The stereoselectivity was accomplished via two diastereoselective crystallizations, i.e. the crystallization of the key intermediate, difluororibonolactone 2a, and the crystallization of the hydrochloride salt of gemcitabine 16b from the anomeric mixture. Because of the availability of 2a in large quantities, other 2'-deoxy-2',2'-difluoropyrimidine nucleosides such as 2'-deoxy-2',2'-difluorouridine (19) were synthesized for structure-activity relationship studies.
- Chou,Heath,Patterson,Poteet,Lakin,Hunt
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p. 565 - 570
(2007/10/02)
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