Synthesis and antiviral activity of the carbocyclic analogs of 5-ethyl-2'-deoxyuridine and of 5-ethynyl-2'-deoxyuridine

Yf, Shealy; Ca, O'Dell; Arnett, G.; Wm, Shannon

doi:10.1021/jm00151a013

Cited by 29 publications

(8 citation statements)

References 1 publication

(1 reference statement)

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“…(()-Carba-T was reported to have in vitro antiherpetic activity in the CPE inhibition assay. 17,18 The EC 50 values for (()-carba-T measured by this method were 0.8 µg/mL (HSV-1) and 7.0 µg/mL (HSV-2) in primary rabbit kidney cells 17 and 24 µg/mL (HSV-1) and 57 µg/mL (HSV-2) in Vero cells. 18 Later, (+)-carba-T was synthesized and reported to have EC 50 values of 0.2 µg/mL (HSV-1) and 2 µg/mL (HSV-2) in the same system.…”

Section: Antiviral Activitymentioning

confidence: 87%

Nucleosides with a Twist. Can Fixed Forms of Sugar Ring Pucker Influence Biological Activity in Nucleosides and Oligonucleotides?

et al. 1996

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The sugar moiety of nucleosides in solution is known to exist in a rapid dynamic equilibrium between extreme Northern and Southern conformations as defined in the pseudorotational cycle. In the present work, we describe how the bicyclo[3.1.0]hexane template fixes the ring pucker of 2'-deoxy-methanocarba-nucleosides 1-5 and 12 to values corresponding to either one of these two extreme conformations that are typical of nucleosides. The syntheses of the fixed Northern conformers 1-5 were performed by Mitsunobu coupling of the heterocyclic bases with the chiral carbocyclic alcohol 6 [(1R,2S,4R,5S)-1-[(benzyloxy)methyl]-2-(tert-butyloxy)-4-hydrox ybicyclo[3.1.0]hexane], while the synthesis of the Southern conformer, (S)-methanocarba-T (12), was reported earlier. Carbocyclic thymidine (carba-T, 13) was used as a reference, flexible carbocyclic nucleoside. Antiviral evaluation of these compounds revealed a very potent antiherpetic activity associated with the Northern thymidine analogue 2, which was more powerful than the reference standard acyclovir against both HSV-1 and HSV-2. (N)-Methanocarba-T (2) was further evaluated as a component of a short oligodeoxynucleotide (ODN) phosphorothioate (5'-CTTCATTTTTTCTTC-3') where all thymidines were replaced by 2. The expected thermodynamic stability resulting from the preorganization of the pseudosugar rings into a Northern conformation, typical of A-DNA, was evident by the increase in Tm of the corresponding DNA/RNA heteroduplex. However, the rigid A-tract ODN caused loss of RNase H recruitment. A detailed conformational analysis of (N)-methanocarba-T (2) and (S)-methanocarba-T (12), as representative examples of conformationally rigid pseudorotational antipodes, revealed that in addition to their different forms of ring pucker, (S)-methanocarba-T appears to be a rather stiff molecule with fewer low-energy conformational states available compared to (N)-methanocarba-T. The syn/anti-energy barrier for these nucleoside analogues is 5-6 kcal/mol higher than for common nucleosides.

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Section: Antiviral Activitymentioning

confidence: 87%

Nucleosides with a Twist. Can Fixed Forms of Sugar Ring Pucker Influence Biological Activity in Nucleosides and Oligonucleotides?

et al. 1996

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“…This study has revealed clearly that EdU is a strong cytotoxic Figure 1 , Figure 5 , Figure 6 and Figure 8 and genotoxic agent ( Figure 2 , Figure 3 , Figure 4 , Figure 7 and Figure 8 ). Interestingly, EdU and its derived halogenated analogs were originally used for inactivation of particular viral strains [ 28 ]. A concentration of 0.039 µM EdU induced total Herpes Simplex Virus inactivation [ 7 ].…”

Section: Discussionmentioning

confidence: 99%

Evaluating the Genotoxic and Cytotoxic Effects of Thymidine Analogs, 5-Ethynyl-2′-Deoxyuridine and 5-Bromo-2′-Deoxyurdine to Mammalian Cells

Haskins

Maeda

et al. 2020

IJMS

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BrdU (bromodeoxyuridine) and EdU (ethynyldeoxyuridine) have been largely utilized as the means of monitoring DNA replication and cellular division. Although BrdU induces gene and chromosomal mutations and induces sensitization to photons, EdU‘s effects have not been extensively studied yet. Therefore, we investigated EdU’s potential cytotoxic and mutagenic effects and its related underlying mechanisms when administered to Chinese hamster ovary (CHO) wild type and DNA repair-deficient cells. EdU treatment displayed a higher cytotoxicity and genotoxicity than BrdU treatment. Cells with defective homologous recombination repair displayed a greater growth delay and severe inhibition of clonogenicity with EdU compared to wild type and other DNA repair-deficient cells. Inductions of sister chromatid exchange and hypoxanthine phosphorybosyl transferase (HPRT) mutation were observed in EdU-incorporated cells as well. Interestingly, on the other hand, EdU did not induce sensitization to photons to the same degree as BrdU. Our results demonstrate that elevated concentrations (similar to manufacturers suggested concentration; >5–10 μM) of EdU treatment were toxic to the cell cultures, particularly in cells with a defect in homologous recombination repair. Therefore, EdU should be administered with additional precautions.

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“…It was found that EdU has an anti-HSV-1 and HSV-2 (Herpes simplex virus) effect and also an impact against the vaccinia virus or cytomegalovirus. Concurrently, the effective concentration proves to be too toxic for non-infectious cells [ 79 , 80 , 81 , 82 ]. In 2007, EdU was successfully tested as a possible inhibitor of the cell growth of human breast cancer cells [ 83 ].…”

Section: Click Chemistry and Its Use In Dna Replication Researchmentioning

confidence: 99%

DNA Replication: From Radioisotopes to Click Chemistry

Ligasová

Koberna

2018

Molecules

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The replication of nuclear and mitochondrial DNA are basic processes assuring the doubling of the genetic information of eukaryotic cells. In research of the basic principles of DNA replication, and also in the studies focused on the cell cycle, an important role is played by artificially-prepared nucleoside and nucleotide analogues that serve as markers of newly synthesized DNA. These analogues are incorporated into the DNA during DNA replication, and are subsequently visualized. Several methods are used for their detection, including the highly popular click chemistry. This review aims to provide the readers with basic information about the various possibilities of the detection of replication activity using nucleoside and nucleotide analogues, and to show the strengths and weaknesses of those different detection systems, including click chemistry for microscopic studies.

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Synthesis and antiviral activity of the carbocyclic analogs of 5-ethyl-2'-deoxyuridine and of 5-ethynyl-2'-deoxyuridine

Cited by 29 publications

References 1 publication

Nucleosides with a Twist. Can Fixed Forms of Sugar Ring Pucker Influence Biological Activity in Nucleosides and Oligonucleotides?

Nucleosides with a Twist. Can Fixed Forms of Sugar Ring Pucker Influence Biological Activity in Nucleosides and Oligonucleotides?

Evaluating the Genotoxic and Cytotoxic Effects of Thymidine Analogs, 5-Ethynyl-2′-Deoxyuridine and 5-Bromo-2′-Deoxyurdine to Mammalian Cells

DNA Replication: From Radioisotopes to Click Chemistry

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