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Antimicrobial Agents and Chemotherapy Oct 2003Intracellular Toxoplasma gondii grown in human foreskin fibroblast cells transported nitrobenzylthioinosine [NBMPR;...
Intracellular Toxoplasma gondii grown in human foreskin fibroblast cells transported nitrobenzylthioinosine [NBMPR; 6-[(4-nitrobenzyl)mercapto]-9-beta-D-ribofuranosylpurine], an inhibitor of nucleoside transport in mammalian cells, as well as the nonphysiological beta-L-enantiomers of purine nucleosides, beta-L-adenosine, beta-L-deoxyadenosine, and beta-L-guanosine. The beta-L-pyrimidine nucleosides, beta-L-uridine, beta-L-cytidine, and beta-L-thymidine, were not transported. The uptake of NBMPR and the nonphysiological purine nucleoside beta-L-enantiomers by the intracellular parasites also implies that Toxoplasma-infected cells can transport these nucleosides. In sharp contrast, under the same conditions, uninfected fibroblast cells did not transport NBMPR or any of the unnatural beta-L-nucleosides. beta-D-Adenosine and dipyridamole, another inhibitor of nucleoside transport, inhibited the uptake of NBMPR and beta-L-stereoisomers of the purine nucleosides by intracellular Toxoplasma and Toxoplasma-infected cells. Furthermore, infection with a Toxoplasma mutant deficient in parasite adenosine/purine nucleoside transport reduced or abolished the uptake of beta-D-adenosine, NBMPR, and purine beta-L-nucleosides. Hence, the presence of the Toxoplasma adenosine/purine nucleoside transporters is apparently essential for the uptake of NBMPR and purine beta-L-nucleosides by intracellular Toxoplasma and Toxoplasma-infected cells. These results also demonstrate that, in contrast to the mammalian nucleoside transporters, the Toxoplasma adenosine/purine nucleoside transporter(s) lacks stereospecificity and substrate specificity in the transport of purine nucleosides. In addition, infection with T. gondii confers the properties of the parasite's purine nucleoside transport on the parasitized host cells and enables the infected cells to transport purine nucleosides that were not transported by uninfected cells. These unique characteristics of purine nucleoside transport in T. gondii may aid in the identification of new promising antitoxoplasmic drugs.
Topics: Animals; Biological Transport; Cells, Cultured; Dipyridamole; Fibroblasts; Humans; Hypoxanthine; Mice; Mice, Inbred Strains; Nucleoside Transport Proteins; Purine Nucleosides; Stereoisomerism; Thioinosine; Toxoplasma
PubMed: 14506037
DOI: 10.1128/AAC.47.10.3247-3251.2003 -
Chemical Biology & Drug Design Apr 2019A series of ribo- and deoxyribonucleosides bearing 2-aminopurine as a nucleobase with 7,8-difluoro- 3,4-dihydro-3-methyl-2H-[1,4]benzoxazine (conjugated directly or...
A series of ribo- and deoxyribonucleosides bearing 2-aminopurine as a nucleobase with 7,8-difluoro- 3,4-dihydro-3-methyl-2H-[1,4]benzoxazine (conjugated directly or through an aminohexanoyl spacer) was synthesized using an enzymatic transglycosylation reaction. Nucleosides 3-6 were resistant to deamination under action of adenosine deaminase (ADA) Escherichia coli and ADA from calf intestine. The antiviral activity of the modified nucleosides was evaluated against herpes simplex virus type 1 (HSV-1, strain L2). It has been shown that at sub-toxic concentrations, nucleoside (S)-4-[2-amino-9-(β-D-ribofuranosyl)-purin-6-yl]-7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine exhibit significant antiviral activity (SI > 32) on the model of HSV-1 in vitro, including an acyclovir-resistant virus strain (HSV-1, strain L2/R).
Topics: Adenosine Deaminase; Animals; Antiviral Agents; Benzoxazines; Cell Survival; Chlorocebus aethiops; Drug Resistance, Viral; Escherichia coli; Escherichia coli Proteins; Herpesvirus 1, Human; Humans; Purine Nucleosides; Stereoisomerism; Vero Cells
PubMed: 30561886
DOI: 10.1111/cbdd.13458 -
Journal of the American Society For... Aug 2019The 2'-substituent is the primary distinguishing feature between DNA and RNA nucleosides. Modifications to this critical position, both naturally occurring and...
The 2'-substituent is the primary distinguishing feature between DNA and RNA nucleosides. Modifications to this critical position, both naturally occurring and synthetic, can produce biologically valuable nucleoside analogues. The unique properties of fluorine make it particularly interesting and medically useful as a synthetic nucleoside modification. In this work, the effects of 2'-fluoro modification on the protonated gas-phase purine nucleosides are examined using complementary tandem mass spectrometry and computational methods. Direct comparisons are made with previous studies on related nucleosides. Infrared multiple photon dissociation action spectroscopy performed in both the fingerprint and hydrogen-stretching regions allows for the determination of the experimentally populated conformations. The populated conformers of protonated 2'-fluoro-2'-deoxyadenosine, [Adofl+H], and 2'-fluoro-2'-deoxyguanosine, [Guofl+H], are highly parallel to their respective canonical DNA and RNA counterparts. Both N3 and N1 protonation sites are accessed by [Adofl+H], stabilizing syn and anti nucleobase orientations, respectively. N7 protonation and anti nucleobase orientation dominates in [Guofl+H]. Spectroscopically observable intramolecular hydrogen-bonding interactions with fluorine allow more definitive sugar puckering determinations than possible for the canonical systems. [Adofl+H] adopts C2'-endo sugar puckering, whereas [Guofl+H] adopts both C2'-endo and C3'-endo sugar puckering. Energy-resolved collision-induced dissociation experiments with survival yield analyses provide relative glycosidic bond stabilities. The N-glycosidic bond stabilities of the protonated 2'-fluoro-substituted purine nucleosides are found to exceed those of their canonical analogues. Further, the N-glycosidic bond stability is found to increase with increasing electronegativity of the 2'-substituent, i.e., H < OH < F. The N-glycosidic bond stability is also greater for the adenine nucleoside analogues than the guanine nucleoside analogues.
Topics: Deoxyadenosines; Dideoxynucleosides; Halogenation; Hydrogen Bonding; Models, Molecular; Molecular Conformation; Protons; Purine Nucleosides; Spectrophotometry, Infrared
PubMed: 31111413
DOI: 10.1007/s13361-019-02222-6 -
Nucleosides, Nucleotides & Nucleic Acids 2006The first reported synthesis of 2'-amino-LNA purine nucleosides via a transnucleosidation is accomplished enabling the preparation of oligonucleotides incorporating...
The first reported synthesis of 2'-amino-LNA purine nucleosides via a transnucleosidation is accomplished enabling the preparation of oligonucleotides incorporating 2'-amino-LNA with all four natural bases.
Topics: Adenosine; Bridged-Ring Compounds; Guanosine; Purine Nucleosides
PubMed: 16901815
DOI: 10.1080/15257770600793729 -
Molecules (Basel, Switzerland) Sep 2020An efficient route to acylated acyclic nucleosides containing a branched hemiaminal ether moiety is reported via three-component alkylation of -heterocycle (purine...
An efficient route to acylated acyclic nucleosides containing a branched hemiaminal ether moiety is reported via three-component alkylation of -heterocycle (purine nucleobase) with acetal (cyclic or acyclic, variously branched) and anhydride (preferentially acetic anhydride). The procedure employs cheap and easily available acetals, acetic anhydride, and trimethylsilyl trifluoromethanesulfonate (TMSOTf). The multi-component reaction is carried out in acetonitrile at room temperature for 15 min and provides moderate to high yields (up to 88%) of diverse acyclonucleosides branched at the aliphatic side chain. The procedure exhibits a broad substrate scope of -heterocycles and acetals, and, in the case of purine derivatives, also excellent regioselectivity, giving almost exclusively -9 isomers.
Topics: Acetals; Acetic Anhydrides; Alkylation; Lewis Acids; Mesylates; Purine Nucleosides; Solvents; Stereoisomerism
PubMed: 32961820
DOI: 10.3390/molecules25184307 -
The Journal of Organic Chemistry Mar 2019The Cu(I)- or Ag(I)-catalyzed cycloaddition between 8-ethynyladenine or guanine nucleosides and TMSN gave 8-(1- H-1,2,3-triazol-4-yl) nucleosides in good yields. On the...
The Cu(I)- or Ag(I)-catalyzed cycloaddition between 8-ethynyladenine or guanine nucleosides and TMSN gave 8-(1- H-1,2,3-triazol-4-yl) nucleosides in good yields. On the other hand, reactions of 5-ethynyluracil or cytosine nucleosides with TMSN led to the chemoselective formation of triazoles via Cu(I)-catalyzed cycloaddition or vinyl azides via Ag(I)-catalyzed hydroazidation. These nucleosides with a minimalistic triazolyl modification showed excellent fluorescent properties with 8-(1- H-1,2,3-triazol-4-yl)-2'-deoxyadenosine (8-TrzdA), exhibiting a quantum yield of 44%. The 8-TrzdA 5'-triphosphate was incorporated into duplex DNA containing a one-nucleotide gap by DNA polymerase β.
Topics: Catalysis; Copper; Fluorescence; Molecular Structure; Purine Nucleosides; Pyrimidine Nucleosides; Silver; Triazoles
PubMed: 30806513
DOI: 10.1021/acs.joc.8b03135 -
Current Protocols in Nucleic Acid... Jun 20206-Methylpurine (MeP) is a cytotoxic adenine analog that does not exhibit selectivity when administered systemically and could be very useful in a gene therapy approach...
6-Methylpurine (MeP) is a cytotoxic adenine analog that does not exhibit selectivity when administered systemically and could be very useful in a gene therapy approach to cancer treatment involving Escherichia coli purine nucleoside phosphorylase (PNP). 9-(6-Deoxy-β-D-allofuranosyl)-6-methylpurine [methyl(allo)-MePR, 18] and 9-(6-deoxy-α-L-talofuranosyl)-6-methylpurine [methyl(talo)-MePR, 21] were synthesized as potential prodrugs for MeP in the E. coli PNP/prodrug cancer gene therapy approach. The detailed syntheses of [methyl(allo)-MePR] and [methyl(talo)-MePR] are described. The glycosyl donors, 1,2-di-O-acetyl-3,5-di-O-benzyl-α-D-allofuranose (12) and 1-O-acetyl-3-O-benzyl-2,5-di-O-benzoyl-α-L-talofuranose (16) were prepared from 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (4) in nine and eleven steps, respectively. Vorbrüggen coupling of the latter glycosyl donors with 6-methylpurine (3), followed by deprotection of the sugar hydroxyl groups, gave the title compounds in good overall yields. © 2020 by John Wiley & Sons, Inc. Basic Protocol 1: Preparation of 6-methylpurine Basic Protocol 2: Preparation of the D-allofuranose derivative (12) Basic Protocol 3: Preparation of 6-deoxy-α-L-talofuranoside Basic Protocol 4: Preparation of methyl(allo)-MePR (18) Basic Protocol 5: Preparation of methyl(talo)-MePR (21).
Topics: Chromatography, Thin Layer; Mass Spectrometry; Proton Magnetic Resonance Spectroscopy; Purine Nucleosides; Structure-Activity Relationship
PubMed: 32255553
DOI: 10.1002/cpnc.105 -
Nucleosides & Nucleotides 1999L-nucleosides selectively enter malaria infected erythrocytes and have the unique ability to be metabolised by the malarial adenosine deaminase. This has allowed us to...
L-nucleosides selectively enter malaria infected erythrocytes and have the unique ability to be metabolised by the malarial adenosine deaminase. This has allowed us to design novel L-nucleosides as potential anti-malarials.
Topics: Adenosine Deaminase; Animals; Antimalarials; Chromatography, High Pressure Liquid; Erythrocytes; Plasmodium falciparum; Purine Nucleosides
PubMed: 10432703
DOI: 10.1080/15257779908041593 -
Journal of Neurochemistry Apr 2009Axonal degeneration is a key component of many neurodegenerative diseases. Injured axons undergo a program of self-destruction termed Wallerian degeneration that is an... (Comparative Study)
Comparative Study
Axonal degeneration is a key component of many neurodegenerative diseases. Injured axons undergo a program of self-destruction termed Wallerian degeneration that is an active, well-regulated process. The pathways leading to axon fragmentation are uncharacterized, but experiments with wld(s) mutant mice led to the discovery that over-expression of NMN adenylyltransferase 1 or treatment with NAD(+) can inhibit axonal degeneration. In this study, we show that the purine nucleosides adenosine and guanosine, but not inosine, inhibit injury-induced axonal degeneration in cultured dorsal root ganglia neurons. Axons can be preserved by adding adenosine within 6 h of the axonal injury. The presence of adenosine was required continuously after the injury to maintain axonal protection. Together these results suggest that adenosine does not alter the neuronal response to injury, but instead inhibits a local axonal pathway necessary for the commitment and/or execution of the axon destructive program.
Topics: Adenosine; Animals; Axons; Cells, Cultured; Ganglia, Spinal; Guanosine; Mice; Nerve Degeneration; Purine Nucleosides; Wallerian Degeneration
PubMed: 19245660
DOI: 10.1111/j.1471-4159.2009.06002.x -
Natural Product Reports Jun 2024Covering: 2019 to 2023Nucleoside analogues represent one of the most important classes of small molecule pharmaceuticals and their therapeutic development is... (Review)
Review
Covering: 2019 to 2023Nucleoside analogues represent one of the most important classes of small molecule pharmaceuticals and their therapeutic development is successfully established within oncology and for the treatment of viral infections. However, there are currently no nucleoside analogues in clinical use for the management of bacterial infections. Despite this, a significant number of clinically recognised nucleoside analogues are known to possess some antibiotic activity, thereby establishing a potential source for new therapeutic discovery in this area. Furthermore, given the rise in antibiotic resistance, the discovery of new clinical candidates remains an urgent global priority and natural product-derived nucleoside analogues may also present a rich source of discovery space for new modalities. This Highlight, covering work published from 2019 to 2023, presents a current perspective surrounding the synthesis of natural purine nucleoside antibiotics. By amalgamating recent efforts from synthetic chemistry with advances in biosynthetic understanding and the use of recombinant enzymes, prospects towards different structural classes of purines are detailed.
Topics: Anti-Bacterial Agents; Purine Nucleosides; Biological Products; Molecular Structure; Humans
PubMed: 38197414
DOI: 10.1039/d3np00051f