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Metal Ions in Life Sciences 2012Metal-mediated base pairs are transition metal complexes formed from complementary nucleosides within nucleic acid double helices. Instead of relying on hydrogen bonds,... (Review)
Review
Metal-mediated base pairs are transition metal complexes formed from complementary nucleosides within nucleic acid double helices. Instead of relying on hydrogen bonds, they are stabilized by coordinative bonds. The nucleosides acting as ligands do not necessarily have to be artificial. In fact, several examples are known of naturally occurring nucleobases (e.g., thymine, cytosine) capable of forming stable metal-mediated base pairs that are highly selective towards certain metal ions. This chapter provides a comprehensive overview of metal-mediated base pairs formed from natural nucleosides or from closely related artificial nucleosides that are pyrimidine or purine derivatives. It addresses the different strategies that lead to the development of these base pairs. The article focuses on structural models for metal-mediated base pairs, their experimental characterization within a nucleic acid, and on their possible applications.
Topics: Base Pairing; Base Sequence; DNA; Metals; Molecular Structure; Nucleic Acids; Purines; Pyrimidine Nucleosides
PubMed: 22210344
DOI: 10.1007/978-94-007-2172-2_11 -
PloS One 2023Tetrahymena are ciliated protists that have been used to study the effects of toxic chemicals, including anticancer drugs. In this study, we tested the inhibitory...
Tetrahymena are ciliated protists that have been used to study the effects of toxic chemicals, including anticancer drugs. In this study, we tested the inhibitory effects of six pyrimidine analogs (5-fluorouracil, floxuridine, 5'-deoxy-5-fluorouridine, 5-fluorouridine, gemcitabine, and cytarabine) on wild-type CU428 and conditional mutant NP1 Tetrahymena thermophila at room temperature and the restrictive temperature (37°C) where NP1 does not form the oral apparatus. We found that phagocytosis was not required for pyrimidine analog entry and that all tested pyrimidine analogs inhibited growth except for cytarabine. IC50 values did not significantly differ between CU428 and NP1 for the same analog at either room temperature or 37°C. To investigate the mechanism of inhibition, we used two pyrimidine bases (uracil and thymine) and three nucleosides (uridine, thymidine, and 5-methyluridine) to determine whether the inhibitory effects from the pyrimidine analogs were reversible. We found that the inhibitory effects from 5-fluorouracil could be reversed by uracil and thymine, from floxuridine could be reversed by thymidine, and from 5'-deoxy-5-fluorouridine could be reversed by uracil. None of the tested nucleobases or nucleosides could reverse the inhibitory effects of gemcitabine or 5-fluorouridine. Our results suggest that the five pyrimidine analogs act on different sites to inhibit T. thermophila growth and that nucleobases and nucleosides are metabolized differently in Tetrahymena.
Topics: Tetrahymena thermophila; Floxuridine; Nucleosides; Thymine; Antimetabolites; Gemcitabine; Pyrimidines; Uracil; Fluorouracil; Cytarabine
PubMed: 37708236
DOI: 10.1371/journal.pone.0284309 -
Blood Advances Apr 2021Since the US Food and Drug Administration (FDA) approvals of parenteral decitabine and azacitidine, DNA methyltransferase inhibitors, otherwise referred to as DNA... (Review)
Review
Since the US Food and Drug Administration (FDA) approvals of parenteral decitabine and azacitidine, DNA methyltransferase inhibitors, otherwise referred to as DNA hypomethylating agents (HMAs), have been a mainstay in the treatment of higher-risk myelodysplastic syndromes. The development of oral HMAs has been an area of active interest; however, oral bioavailability has been quite poor due to rapid metabolism by cytidine deaminase (CDA). This led to the development of the novel CDA inhibitor cedazuridine, which was combined with an oral formulation of decitabine. Preclinical work demonstrated a pharmacokinetic and pharmacodynamic profile approximate to parenteral decitabine, leading to early-phase clinical trials of oral cedazuridine-decitabine (C-DEC) in myelodysplastic syndromes and chronic myelomonocytic leukemia (CMML). A combination of oral decitabine 35 mg with oral cedazuridine 100 mg was established as the recommended phase 2 dose. Phase 2 data confirmed bioequivalence of C-DEC when compared with parenteral decitabine, and a larger phase 3 trial has demonstrated similar results, leading to the FDA approval of C-DEC for use in intermediate/high-risk myelodysplastic syndrome (MDS) and CMML. This review will focus upon the current role of HMA therapy in MDS/CMML, preclinical and clinical development of C-DEC, and potential roles of oral HMA therapy in myeloid malignancies moving forward.
Topics: Azacitidine; Decitabine; Humans; Leukemia, Myelomonocytic, Chronic; Myelodysplastic Syndromes; Uridine
PubMed: 33904891
DOI: 10.1182/bloodadvances.2020002929 -
Archives of Pharmacal Research May 2017Nucleoside analogues play an important role in antiviral, antibacterial and antineoplastic chemotherapy. Herein we report the synthesis, structural characterization and...
Nucleoside analogues play an important role in antiviral, antibacterial and antineoplastic chemotherapy. Herein we report the synthesis, structural characterization and biological activity of some 4'-C -methyl- and -phenyl dioxolane-based nucleosides. In particular, α and β anomers of all natural nucleosides were obtained and characterized by NMR, HR-MS and X-ray crystallography. The compounds were tested for antimicrobial activity against some representative human pathogenic fungi, bacteria and viruses. Antitumor activity was evaluated in a large variety of human cancer cell-lines. Although most of the compounds showed non-significant activity, 23α weakly inhibited HIV-1 multiplication. Moreover, 22α and 32α demonstrated a residual antineoplastic activity, interestingly linked to the unnatural α configuration. These results may provide structural insights for the design of active antiviral and antitumor agents.
Topics: Anti-HIV Agents; Antineoplastic Agents; Cell Line; Cell Proliferation; Crystallography, X-Ray; Dioxolanes; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HIV-1; Humans; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Purine Nucleosides; Pyrimidine Nucleosides; Structure-Activity Relationship
PubMed: 27615010
DOI: 10.1007/s12272-016-0825-6 -
Biopolymers Jan 2021The notion of using synthetic heterocycles instead of the native bases to interface with DNA and RNA has been explored for nearly 60 years. Unnatural bases compatible... (Review)
Review
The notion of using synthetic heterocycles instead of the native bases to interface with DNA and RNA has been explored for nearly 60 years. Unnatural bases compatible with the DNA/RNA coding interface have the potential to expand the genetic code and co-opt the machinery of biology to access new macromolecular function; accordingly, this body of research is core to synthetic biology. While much of the literature on artificial bases focuses on code expansion, there is a significant and growing effort on docking synthetic heterocycles to noncoding nucleic acid interfaces; this approach seeks to illuminate major processes of nucleic acids, including regulation of transcription, translation, transport, and transcript lifetimes. These major avenues of research at the coding and noncoding interfaces have in common fundamental principles in molecular recognition. Herein, we provide an overview of foundational literature in biophysics of base recognition and unnatural bases in coding to provide context for the developing area of targeting noncoding nucleic acid interfaces with synthetic bases, with a focus on systems developed through iterative design and biophysical study.
Topics: Base Pairing; DNA; Hydrogen Bonding; Purine Nucleosides; Pyrimidine Nucleosides; RNA; Synthetic Biology
PubMed: 32969496
DOI: 10.1002/bip.23399 -
Cancer Science Feb 2004Nucleoside analogues which show antimetabolic activity in cells have been successfully used in the treatment of various tumors. Nucleosides such as... (Review)
Review
Nucleoside analogues which show antimetabolic activity in cells have been successfully used in the treatment of various tumors. Nucleosides such as 1-beta-D-arabinofuranosylcytosine (araC), 6-mercaptopurine, fludarabine and cladribine play an important role in the treatment of leukemias, while gemcitabine, 5-fluorouracil and its prodrugs are used extensively in the treatment of many types of solid tumors. All of these compounds are metabolized similarly to endogenous nucleosides and nucleotides. Active metabolites interfere with the de novo synthesis of nucleosides and nucleotides or inhibit the DNA chain elongation after being incorporated into the DNA strand as terminators. Furthermore, nucleoside antimetabolites incorporated into the DNA strand induce strand-breaks and finally cause apoptosis. Nucleoside antimetabolites target one or more specific enzyme(s). The mode of inhibitory action on the target enzyme is not always similar even among nucleoside antimetabolites which have the same nucleoside base, such as araC and gemcitabine. Although both nucleosides are phosphorylated by deoxycytidine kinase and are also good substrates of cytidine deaminase, only gemcitabine shows antitumor activity against solid tumors. This suggests that differences in the pharmacological activity of these nucleoside antimetabolites may reflect different modes of action on target molecules. The design, in vitro cytotoxicity, in vivo antitumor activity, metabolism and mechanism of action of sugar-modified cytosine nucleosides, such as (2'S)-2'-deoxy-2'-C-methylcytidine (SMDC), 1-(2-deoxy-2-methylene-beta-D-erythro-pentofuranosyl)cytosine (DMDC), 1-(2-C-cyano-2-deoxy-1-beta-D-arabino-pentofuranosyl)cytosine (CNDAC) and 1-(3-C-ethynyl-beta-D-ribo-pentofura-nosyl)cytosine (ECyd), developed by our groups, are discussed here.
Topics: Animals; Antimetabolites, Antineoplastic; Carbohydrates; Cytosine; Humans; Neoplasms; Pyrimidine Nucleosides
PubMed: 14965358
DOI: 10.1111/j.1349-7006.2004.tb03189.x -
Journal of Bacteriology Aug 2018The genome of the hyperthermophilic archaeon contains an open reading frame, Pcal_0041, annotated as encoding a PfkB family ribokinase, consisting of...
The genome of the hyperthermophilic archaeon contains an open reading frame, Pcal_0041, annotated as encoding a PfkB family ribokinase, consisting of phosphofructokinase and pyrimidine kinase domains. Among the biochemically characterized enzymes, the Pcal_0041 protein was 37% identical to the phosphofructokinase (Ape_0012) from , which displayed kinase activity toward a broad spectrum of substrates, including sugars, sugar phosphates, and nucleosides, and 36% identical to a phosphofructokinase from To examine the biochemical function of the Pcal_0041 protein, we cloned and expressed the gene and purified the recombinant protein. Although the Pcal_0041 protein contained a putative phosphofructokinase domain, it exhibited only low levels of phosphofructokinase activity. The recombinant enzyme catalyzed the phosphorylation of nucleosides and, to a lower extent, sugars and sugar phosphates. Surprisingly, among the substrates tested, the highest activity was detected with ribose 1-phosphate (R1P), followed by cytidine and uridine. The catalytic efficiency (/ ) toward R1P was 11.5 mM · s ATP was the most preferred phosphate donor, followed by GTP. Activity measurements with cell extracts of indicated the presence of nucleoside phosphorylase activity, which would provide the means to generate R1P from nucleosides. The study suggests that, in addition to the recently identified ADP-dependent ribose 1-phosphate kinase (R1P kinase) in that functions in the pentose bisphosphate pathway, R1P kinase is also present in members of the Crenarchaeota. The discovery of the pentose bisphosphate pathway in has clarified how this archaeon can degrade nucleosides. Homologs of the enzymes of this pathway are present in many members of the Thermococcales, suggesting that this metabolism occurs in these organisms. However, this is not the case in other archaea, and degradation mechanisms for nucleosides or ribose 1-phosphate are still unknown. This study reveals an important first step in understanding nucleoside metabolism in Crenarchaeota and identifies an ATP-dependent ribose 1-phosphate kinase in The enzyme is structurally distinct from previously characterized archaeal members of the ribokinase family and represents a group of proteins found in many crenarchaea.
Topics: Enzyme Stability; Phosphofructokinases; Phosphorylation; Pyrimidine Nucleosides; Pyrobaculum; Recombinant Proteins; Ribosemonophosphates; Substrate Specificity
PubMed: 29866806
DOI: 10.1128/JB.00284-18 -
Angewandte Chemie (International Ed. in... Apr 2021Nucleosidic and oligonucleotidic diarylethenes (DAEs) are an emerging class of photochromes with high application potential. However, their further development is...
Nucleosidic and oligonucleotidic diarylethenes (DAEs) are an emerging class of photochromes with high application potential. However, their further development is hampered by the poor understanding of how the chemical structure modulates the photochromic properties. Here we synthesized 26 systematically varied deoxyuridine- and deoxycytidine-derived DAEs and analyzed reaction quantum yields, composition of the photostationary states, thermal and photochemical stability, and reversibility. This analysis identified two high-performance photoswitches with near-quantitative, fully reversible back-and-forth switching and no detectable thermal or photochemical deterioration. When incorporated into an oligonucleotide with the sequence of a promotor, the nucleotides maintained their photochromism and allowed the modulation of the transcription activity of T7 RNA polymerase with an up to 2.4-fold turn-off factor, demonstrating the potential for optochemical control of biological processes.
Topics: Bacteriophage T7; DNA-Directed RNA Polymerases; Drug Development; Enzyme Inhibitors; Ethylenes; Oligonucleotides; Photochemical Processes; Pyrimidine Nucleosides; Viral Proteins
PubMed: 33476096
DOI: 10.1002/anie.202014878 -
Organic Letters Dec 2022An efficient two-step procedure for the syntheses of pyrimidine nucleosides is presented. A series of glycosyl 5-(aminomethylene)-1,3-dioxane-4,6-dione derivatives were...
An efficient two-step procedure for the syntheses of pyrimidine nucleosides is presented. A series of glycosyl 5-(aminomethylene)-1,3-dioxane-4,6-dione derivatives were prepared from β-anomeric isonitriles by reaction with Meldrum's acid or by allowing aminomethylene Meldrum's acid to react with an 1-aldofuranosyl halide or acetate. The resultant 5-(aminomethylene)-1,3-dioxane-4,6-dione derivatives underwent reaction with benzyl- or 2,4-dimethoxybenzyl isocyanate via transacylation to provide uridine-5-carboxylic acid derivatives and related nucleosides. These nucleoside carboxylic acids were converted into other C-5 derivatives by bromo-decarboxylation with -bromosuccinimide.
Topics: Dioxanes; Pyrimidine Nucleosides; Uridine; Nucleosides
PubMed: 36331529
DOI: 10.1021/acs.orglett.2c03152 -
Molecules (Basel, Switzerland) Aug 2020Inhibition of DNA repair enzymes tyrosyl-DNA phosphodiesterase 1 and poly(ADP-ribose)polymerases 1 and 2 in the presence of pyrimidine nucleoside derivatives was studied...
Inhibition of DNA repair enzymes tyrosyl-DNA phosphodiesterase 1 and poly(ADP-ribose)polymerases 1 and 2 in the presence of pyrimidine nucleoside derivatives was studied here. New effective Tdp1 inhibitors were found in a series of nucleoside derivatives possessing 2',3',5'-tri--benzoyl-d-ribofuranose and 5-substituted uracil moieties and have half-maximal inhibitory concentrations (IC) in the lower micromolar and submicromolar range. 2',3',5'-Tri--benzoyl-5-iodouridine manifested the strongest inhibitory effect on Tdp1 (IC = 0.6 μM). A decrease in the number of benzoic acid residues led to a marked decline in the inhibitory activity, and pyrimidine nucleosides lacking lipophilic groups (uridine, 5-fluorouridine, 5-chlorouridine, 5-bromouridine, 5-iodouridine, and ribothymidine) did not cause noticeable inhibition of Tdp1 (IC > 50 μM). No PARP1/2 inhibitors were found among the studied compounds (residual activity in the presence of 1 mM substances was 50-100%). Several -benzoylated uridine and cytidine derivatives strengthened the action of topotecan on HeLa cervical cancer cells.
Topics: Dose-Response Relationship, Drug; Enzyme Inhibitors; HeLa Cells; Humans; Hydrophobic and Hydrophilic Interactions; Phosphoric Diester Hydrolases; Pyrimidine Nucleosides
PubMed: 32823658
DOI: 10.3390/molecules25163694