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Antimicrobial Agents and Chemotherapy Sep 1981Trifluorothymidine (TFT) was tested for antiviral activity against mouse cytomegalovirus (MCMV) and human cytomegalovirus (HCMV) in one-step replication assays. The TFT...
Trifluorothymidine (TFT) was tested for antiviral activity against mouse cytomegalovirus (MCMV) and human cytomegalovirus (HCMV) in one-step replication assays. The TFT concentration required to reduce virus yield by 50% (ID50) was 0.22 microM for MCMV and 0.012 microM for HCMV. The antiviral activity of TFT against MCMV was reversed by addition of equimolar thymidine, and no antiviral activity was demonstrable in a host cell line lacking thymidine kinase. Thus, TFT's anti-MCMV activity is dependent on a host cell TK since this herpesvirus lacks thymidine kinase. A continuous subcutaneous infusion of TFT achieving a serum concentration of 1 microM failed to protect mice from lethal MCMV infection, perhaps because serum levels of thymidine were comparable to the drug level. Comparison of the ID50 against HCMV and the ID50 against human bone marrow progenitor cells resulted in an in vitro therapeutic ratio of 108, suggesting that TFT might offer some promise as a clinically useful anti-HCMV agent.
Topics: Animals; Bone Marrow Cells; Cells, Cultured; Colony-Forming Units Assay; Cytomegalovirus; Humans; Mice; Mice, Inbred ICR; Thymidine; Trifluridine; Virus Replication
PubMed: 6272627
DOI: 10.1128/AAC.20.3.286 -
Angewandte Chemie (International Ed. in... May 2013[Image: see text] The 5-(2’-Deoxyuridinyl) methyl radical is a key intermediate in the thymine oxidative reaction mediated by reactive oxygen species. Evidence is...
[Image: see text] The 5-(2’-Deoxyuridinyl) methyl radical is a key intermediate in the thymine oxidative reaction mediated by reactive oxygen species. Evidence is presented that is prone to both oxidation and reduction reactions at the absence of O. These results question the current paradigm and suggest that the redox chemistry of , which has been largely overlooked in the past, may play a major role in determining the fate of .
Topics: Anaerobiosis; Chromatography, High Pressure Liquid; Deoxyuridine; Molecular Structure; Oxidation-Reduction; Photolysis
PubMed: 23589226
DOI: 10.1002/anie.201209454 -
Acta Crystallographica. Section C,... May 2021β-2'-Deoxyribonucleosides are the constituents of nucleic acids, whereas their anomeric α-analogues are rarely found in nature. Moreover, not much information is...
β-2'-Deoxyribonucleosides are the constituents of nucleic acids, whereas their anomeric α-analogues are rarely found in nature. Moreover, not much information is available on the structural and conformational parameters of α-2'-deoxyribonucleosides. This study reports on the single-crystal X-ray structure of α-2'-deoxycytidine, CHNO (1), and the conformational parameters characterizing 1 were determined. The conformation at the glycosylic bond is anti, with χ = 173.4 (2)°, and the sugar residue adopts an almost symmetrical C2'-endo-C3'-exo twist (T; S-type), with P = 179.7°. Both values lie outside the conformational range usually preferred by α-nucleosides. In addition, the amino group at the nucleobase shows partial double-bond character. This is supported by two separated signals for the amino protons in the H NMR spectrum, indicating a hindered rotation around the C4-N4 bond and a relatively short C-N bond in the solid state. Crystal packing is controlled by N-H...O and O-H...O contacts between the nucleobase and sugar moieties. Moreover, two weak C-H...N contacts (C1'-H1' and C3'-H3'A) are observed. A Hirshfeld surface analysis was carried out and the results support the intermolecular interactions observed by the X-ray analysis.
Topics: Crystallography, X-Ray; Deoxycytidine; Deoxyribonucleosides; Hydrogen Bonding; Molecular Conformation; Nucleic Acids
PubMed: 33949335
DOI: 10.1107/S2053229621003430 -
Medical Hypotheses Sep 2020The recent global pandemic created by the Coronavirus SARS-CoV-2, started in Wuhan, China in December 2019, has generated panic, both in term of human death (4-5% of...
The recent global pandemic created by the Coronavirus SARS-CoV-2, started in Wuhan, China in December 2019, has generated panic, both in term of human death (4-5% of infected patients identified through testing) and the global economy. Human sufferings seem to be continuing, and it is not clear how long this will continue and how much more destruction it is going to cause until complete control is achieved. One of the most disturbing issues is Covid-19 treatment; although a large number of medications, previously used successfully with other viruses (including Chinese herbal medicines and anti-malaria drugs), are under consideration, there remain questions as to whether they can play a satisfactory role for this disease. Global attempts are ongoing to find the drugs for the treatment of this virus but none of the antiviral drugs used for treatment of other human viral infection is working and hence attempts to find new drugs are continuing. Here the author is proposing that 5-Fluorouracil (5-FU) which when used on its own is failing as an antiviral agent due to the removal of this compound by proof reading ability exceptionally found in Coronaviruses. The author here is proposing to test 5-FU in combination with a number of deoxynucleosides on animal models infected with this Covid-19. Should encouraging results ensue, therapies could then be tried on patients.
Topics: Adenosine Monophosphate; Alanine; Betacoronavirus; COVID-19; Chloroquine; Clinical Trials as Topic; Coronavirus Infections; Deoxyribonucleosides; Deoxyribose; Drug Administration Schedule; Drug Synergism; Fluorouracil; Humans; Inflammation; Models, Theoretical; Pandemics; Pneumonia, Viral; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 32438240
DOI: 10.1016/j.mehy.2020.109754 -
Fungal Cordycepin Biosynthesis Is Coupled with the Production of the Safeguard Molecule Pentostatin.Cell Chemical Biology Dec 2017Cordycepin (COR) and pentostatin (PTN) are adenosine analogs with related bioactivity profiles as both mimic adenosine and can inhibit some of the processes that are...
Cordycepin (COR) and pentostatin (PTN) are adenosine analogs with related bioactivity profiles as both mimic adenosine and can inhibit some of the processes that are adenosine dependent. Both COR and PTN are also natural products and were originally isolated from the fungus Cordyceps militaris and the bacterium Streptomyces antibioticus, respectively. Here, we report that not only is PTN produced by C. militaris but that biosynthesis of COR is coupled with PTN production by a single gene cluster. We also demonstrate that this coupling is an important point of metabolic regulation where PTN safeguards COR from deamination by inhibiting adenosine deaminase (ADA) activity. ADA is not inhibited until COR reaches self-toxic levels, at which point ADA derepression occurs allowing for detoxification of COR to 3'-deoxyinosine. Finally, we show that using our biosynthetic insights, we can engineer C. militaris to produce higher levels of COR and PTN.
Topics: Adenosine Deaminase; Cordyceps; Deoxyadenosines; Pentostatin; Protein Engineering
PubMed: 29056419
DOI: 10.1016/j.chembiol.2017.09.001 -
Antiviral Chemistry & Chemotherapy 2008The antipoxviral activities and phosphorylation of N-methanocarbathymidine ([N]-MCT) and four 5-halo-2'-deoxyuridines, namely 5-fluoro-(FdU), 5-chloro-(CldU),...
BACKGROUND
The antipoxviral activities and phosphorylation of N-methanocarbathymidine ([N]-MCT) and four 5-halo-2'-deoxyuridines, namely 5-fluoro-(FdU), 5-chloro-(CldU), 5-bromo-(BrdU), and 5-iodo-(IdU) derivatives, were explored.
METHODS
Antiviral activities and nucleoside metabolism were determined in C127I mouse, LLC-MK2 monkey, and A549 human cells infected with thymidine-kinase-containing and -deficient (TK+ and TK-) vaccinia (WR strain) viruses.
RESULTS
The antiviral potencies of CldU, BrdU and IdU were increased 16-26-fold in LLC-MK2 cells infected with TK+ compared with TK- virus infections, but enhancement of activity was much less in the other cell lines. (N)-MCT was nearly equally active against TK+ and TK- viruses in the three cell lines. Antiviral activity of FdU was associated with cytotoxicity. Uninfected and infected cells metabolized compounds to mono-, di- and triphosphates. The thymidine, BrdU and IdU triphosphate levels were higher in C127I and LLC-MK2 cells infected with TK+ than with TK- virus. (N)-MCT monophosphate levels were much higher in TK+ virus-infected cells, but without corresponding increases in (N)-MCT triphosphate. Furthermore, TK+ virus infections did not appreciably alter (N)-MCT triphosphate levels in other mouse (L929), monkey (MA-104 and Vero) and human cell lines (A549). Antiviral potency of the compounds was greater in C127I than in LLC-MK2 cells, yet lower intracellular triphosphate levels were found in C127I cells.
CONCLUSION
We conclude that viral TK plays an important role in increasing the antiviral potencies of these compounds in some cell lines, but minimally in others. These findings may have implications in treating infected animals with compounds that are dependent upon poxvirus TK for their activation, because viral TK activity may vary greatly due to cell type.
Topics: Animals; Antiviral Agents; Bromodeoxyuridine; Cell Line, Tumor; Chlorocebus aethiops; Deoxyuridine; Floxuridine; Humans; Idoxuridine; Mice; Phosphorylation; Thymidine; Thymidine Kinase; Vaccinia; Vaccinia virus; Vero Cells; Viral Plaque Assay
PubMed: 18610554
DOI: 10.1177/095632020801900103 -
Nucleic Acids Research Jul 1992We have investigated the conformations of the hexadeoxyribonucleotide, L-d(CGCGCG) composed of L-deoxyribose, the mirror image molecule of natural D-deoxyribose. In this...
We have investigated the conformations of the hexadeoxyribonucleotide, L-d(CGCGCG) composed of L-deoxyribose, the mirror image molecule of natural D-deoxyribose. In this paper, we report the synthesis of four L-deoxynucleosides and the L-oligonucleotide-ethidium bromide interactions. The L-deoxyribose synthon 9 was synthesized from L-arabinose with an over all yield of 28.5% via the Barton-McCombie reaction. The L-deoxynucleosides were obtained by a glycosylation of appropriate nucleobase derivatives with the 1-chloro sugar 9. After derivatization to nucleoside phosphoramidites, L-deoxycytidine and L-deoxyguanosine were incorporated into a hexadeoxynucleotide, L-d(CGCGCG) by a solid-phase beta-cyanoethylphosphoramidite method. This L-hexanucleotide was resistant to digestion with nuclease P1. The conformations of L-d(CGCGCG) were an exact mirror image of that of the corresponding natural one as described previously, and the conformations of the L-d(CGCGCG)-ethidium bromide complex were also the mirror images of those of the D-d(CGCGCG)-ethidium bromide complex under both low and high salt conditions. These results suggest that ethidium bromide prefers not a right-handed helical sense, but the base-base stacking geometry of the B-form rather than that of the Z-form. Thus, L-DNA would be a useful tool for studying DNA-drug interactions.
Topics: Chromatography, High Pressure Liquid; Deoxyribonucleosides; Nucleic Acid Conformation; Oligodeoxyribonucleotides
PubMed: 1630904
DOI: 10.1093/nar/20.13.3325 -
Antimicrobial Agents and Chemotherapy May 1995In summary, many isomeric analogs of ddNs of both D-related and L-related absolute stereochemistries have been synthesized and evaluated in vitro for their antiviral... (Review)
Review
In summary, many isomeric analogs of ddNs of both D-related and L-related absolute stereochemistries have been synthesized and evaluated in vitro for their antiviral activities. A few of these compounds exhibit potent antiviral activity and, interestingly, belong to both the D and L families. The synthetic methodologies developed will allow accessibility to many more novel modified nucleosides. While some structure-activity relationships are emerging from this work, it is clear that these chiral isomeric nucleosides have opened a new chapter in the field of antiviral nucleosides.
Topics: Animals; Antiviral Agents; Dideoxynucleosides; Humans; Stereoisomerism
PubMed: 7625783
DOI: 10.1128/AAC.39.5.1017 -
Applied and Environmental Microbiology Sep 2004Bacillus mojavensis strains JF-2 (ATCC 39307), ROB2, and ABO21191(T) and Bacillus subtilis strains 168 (ATCC 23857) and ATCC 12332 required four deoxyribonucleosides or...
Bacillus mojavensis strains JF-2 (ATCC 39307), ROB2, and ABO21191(T) and Bacillus subtilis strains 168 (ATCC 23857) and ATCC 12332 required four deoxyribonucleosides or DNA for growth under strict anaerobic conditions. Bacillus licheniformis strains L89-11 and L87-11, Bacillus sonorensis strain TG8-8, and Bacillus cereus (ATCC 14579) did not require DNA for anaerobic growth. The requirement for the deoxyribonucleosides or DNA did not occur under aerobic growth conditions. The addition of a mixture of five nucleic acid bases, four ribonucleotides, or four ribonucleosides to the basal medium did not replace the requirement of B. mojavensis JF-2 for the four deoxyribonucleosides. However, the addition of salmon sperm DNA, herring sperm DNA, Escherichia coli DNA, or synthetic DNA (single or double stranded) to the basal medium supported anaerobic growth. The addition of four deoxyribonucleosides to the basal medium allowed aerobic growth of B. mojavensis JF-2 in the presence of hydroxyurea. B. mojavensis did not grow in DNA-supplemented basal medium that lacked sucrose as the energy source. These data provide strong evidence that externally supplied deoxyribonucleosides can be used to maintain a balanced deoxyribonucleotide pool for DNA synthesis and suggest that ribonucleotide reductases may not be essential to the bacterial cell cycle nor are they necessarily part of a minimal bacterial genome.
Topics: Amino Acids; Anaerobiosis; Bacillus; Bacillus subtilis; Culture Media; DNA, Bacterial; Deoxyribonucleosides; Kinetics
PubMed: 15345407
DOI: 10.1128/AEM.70.9.5252-5257.2004 -
Nucleic Acids Research Oct 2010Humans are exposed to both endogenous and exogenous N-nitroso compounds (NOCs), and many NOCs can be metabolically activated to generate a highly reactive species,...
Synthesis and characterization of oligodeoxyribonucleotides containing a site-specifically incorporated N6-carboxymethyl-2'-deoxyadenosine or N4-carboxymethyl-2'-deoxycytidine.
Humans are exposed to both endogenous and exogenous N-nitroso compounds (NOCs), and many NOCs can be metabolically activated to generate a highly reactive species, diazoacetate, which is capable of inducing carboxymethylation of nucleobases in DNA. Here we report, for the first time, the chemical syntheses of authentic N(6)-carboxymethyl-2'-deoxyadenosine (N(6)-CMdA) and N(4)-carboxymethyl-2'-deoxycytidine (N(4)-CMdC), liquid chromatography-ESI tandem MS confirmation of their formation in calf thymus DNA upon diazoacetate exposure, and the preparation of oligodeoxyribonucleotides containing a site-specifically incorporated N(6)-CMdA or N(4)-CMdC. Additionally, thermodynamic studies showed that the substitutions of a dA with N(6)-CMdA and dC with N(4)-CMdC in a 12-mer duplex increased Gibbs free energy for duplex formation at 25°C by 5.3 and 6.8 kcal/mol, respectively. Moreover, primer extension assay revealed that N(4)-CMdC was a stronger blockade to Klenow fragment-mediated primer extension than N(6)-CMdA. The polymerase displayed substantial frequency of misincorporation of dAMP opposite N(6)-CMdA and, to a lesser extent, misinsertion of dAMP and dTMP opposite N(4)-CMdC. The formation and the mutagenic potential of N(6)-CMdA and N(4)-CMdC suggest that these lesions may bear important implications in the etiology of NOC-induced tumor development.
Topics: Azo Compounds; DNA; DNA Replication; Deoxyadenosines; Deoxycytidine; Glycine; Oligodeoxyribonucleotides; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Thermodynamics
PubMed: 20507914
DOI: 10.1093/nar/gkq458