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Nucleoside and Nucleotide Analogues: Chemical Synthesis and Applications

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: 31 December 2024 | Viewed by 3194

Special Issue Editors


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Guest Editor
Department of Chemistry, University of Turku, FIN-20014 Turku, Finland
Interests: nucleic acids; phosphodiesters; reaction mechanisms; catalysis

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Guest Editor
Department of Chemistry, University of Turku, FIN-20014 Turku, Finland
Interests: nucleic acids; oligonucleotides and their conjugates; nucleic acid-based nanoparticles; liquid phase oligonucleotide synthesis

E-Mail Website
Guest Editor
Department of Chemistry, University of Turku, FIN-20014 Turku, Finland
Interests: organometallic nucleoside analogues; metal-mediated base pairing; base filling; RNA cleavage
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Nucleoside and nucleotide analogs have been intensively studied over the last decades. They have found various applications in chemical and biochemical research, and medicine. The development of nucleoside-based antivirals and pro-drugs started with the AIDS epidemic, and their importance was further emphasized by the recent COVID-19 pandemic. Currently, the majority of research on nucleoside and nucleotide analogs describe the synthesis of potential antiviral agents, with SARS-CoV being the prevailing target.

The applications of nucleoside and nucleotide analogs are, however, much more diverse. Mechanistic studies with analogues are used to obtain information on basic reaction mechanisms and interactions of nucleic acids. A more recent application is the use of fluorescent analogues in detection technology.

While we do not want to exclude any approach in this Special Issue on nucleoside and nucleotide analogs, we would like to concentrate on chemical applications, such as studies on reaction mechanisms, interactions, recognition, and development of detection methods, as well as novel synthetic methods. 

Dr. Satu Mikkola
Prof. Dr. Pasi Virta
Dr. Tuomas Lönnberg
Guest Editors

Manuscript Submission Information

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Keywords

  • nucleoside analogues
  • nucleic acids
  • interactions
  • detection
  • synthesis
  • reaction mechanism

Published Papers (5 papers)

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Research

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11 pages, 1730 KiB  
Article
Recognition of 8-Oxo-2′-deoxyguanosine in DNA Using the Triphosphate of 2′-Deoxycytidine Connecting the 1,3-Diazaphenoxazine Unit, dCdapTP
by Takato Sakurada, Yuta Chikada, Ryo Miyahara and Yosuke Taniguchi
Molecules 2024, 29(10), 2270; https://doi.org/10.3390/molecules29102270 - 11 May 2024
Viewed by 339
Abstract
DNA is constantly damaged by various external and internal factors. In particular, oxidative damage occurs in a steady state, and 8-oxo-2′-deoxyguanosine (oxodG) is known as the main oxidative damage. OxodG is a strong genotoxic nucleoside and is thought to be involved in the [...] Read more.
DNA is constantly damaged by various external and internal factors. In particular, oxidative damage occurs in a steady state, and 8-oxo-2′-deoxyguanosine (oxodG) is known as the main oxidative damage. OxodG is a strong genotoxic nucleoside and is thought to be involved in the pathogenesis of cancer and neurological diseases. However, a breakthrough method to detect the position of oxodG in DNA has not yet been developed. Therefore, we attempted to develop a novel method to detect oxodG in DNA using artificial nucleosides. Recently, we have succeeded in the recognition of oxodG in DNA by a single nucleotide elongation reaction using nucleoside derivatives based on a purine skeleton with a 1,3-diazaphenoxazine unit. In this study, we developed a new nucleoside derivative with a pyrimidine skeleton in order to further improve the recognition ability and enzymatic reaction efficiency. We, therefore, designed and synthesized 2′-deoxycytidine-1,3-diazaphenoxazine (Cdap) and its triphosphate derivatives. The results showed that it was incorporated into the primer strand relative to the dG template because of its cytidine skeleton, but it was more effective at the complementary position of the oxodG template. These results indicate that the new nucleoside derivative can be considered as one of the new candidates for the detection of oxodG in DNA. Full article
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13 pages, 2279 KiB  
Article
Zinc N,N-bis(2-picolyl)amine Chelates Show Substitution-Dependent Cleavage of Phosphodiesters in Models as Well as of PNAzyme-RNA Bulges
by Søren W. Svenningsen, Olivia Luige, Zeyed Abdulkarim, Roger Strömberg and Nicholas H. Williams
Molecules 2024, 29(9), 2123; https://doi.org/10.3390/molecules29092123 - 3 May 2024
Viewed by 459
Abstract
PNAzymes are a group of artificial enzymes which show promising results in selective and efficient cleavage of RNA targets. In the present study, we introduce a series of metal chelating groups based on N,N-bis(2-picolyl) groups (parent, 6-methyl and 6-amino substituted) [...] Read more.
PNAzymes are a group of artificial enzymes which show promising results in selective and efficient cleavage of RNA targets. In the present study, we introduce a series of metal chelating groups based on N,N-bis(2-picolyl) groups (parent, 6-methyl and 6-amino substituted) as the active sites of novel PNAzymes. An improved synthetic route for the 6-amino analogues is described. The catalytic activity of the chelating groups for cleaving phosphodiesters were assessed with the model substrate 2-hydroxypropyl p-nitrophenyl phosphate (HPNPP), confirming that the zinc complexes have the reactivity order of parent < 2-methyl < 2-amino. The three ligands were conjugated to a PNA oligomer to form three PNAzymes which showed the same order of reactivity and some sensitivity to the size of the RNA bulge designed into the catalyst–substrate complex. This work demonstrates that the kinetic activity observed for the model substrate HPNPP could be translated onto the PNAzymes, but that more reactive Zn complexes are required for such PNAzymes to be viable therapeutic agents. Full article
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26 pages, 7873 KiB  
Article
Synthesis of 4′-Thionucleoside Analogues Bearing a C2′ Stereogenic All-Carbon Quaternary Center
by Carla Eymard, Amarender Manchoju, Abir Almazloum, Starr Dostie, Michel Prévost, Mona Nemer and Yvan Guindon
Molecules 2024, 29(7), 1647; https://doi.org/10.3390/molecules29071647 - 6 Apr 2024
Viewed by 603
Abstract
The design of novel 4′-thionucleoside analogues bearing a C2′ stereogenic all-carbon quaternary center is described. The synthesis involves a highly diastereoselective Mukaiyama aldol reaction, and a diastereoselective radical-based vinyl group transfer to generate the all-carbon stereogenic C2′ center, along with different approaches to [...] Read more.
The design of novel 4′-thionucleoside analogues bearing a C2′ stereogenic all-carbon quaternary center is described. The synthesis involves a highly diastereoselective Mukaiyama aldol reaction, and a diastereoselective radical-based vinyl group transfer to generate the all-carbon stereogenic C2′ center, along with different approaches to control the selectivity of the N-glycosidic bond. Intramolecular SN2-like cyclization of a mixture of acyclic thioaminals provided analogues with a pyrimidine nucleobase. A kinetic bias favoring cyclization of the 1′,2′-anti thioaminal furnished the desired β-D-4′-thionucleoside analogue in a 7:1 ratio. DFT calculations suggest that this kinetic resolution originates from additional steric clash in the SN2-like transition state for 1′,4′-trans isomers, causing a significant decrease in their reaction rate relative to 1′,4′-cis counterparts. N-glycosylation of cyclic glycosyl donors with a purine nucleobase enabled the formation of novel 2-chloroadenine 4′-thionucleoside analogues. These proprietary molecules and other derivatives are currently being evaluated both in vitro and in vivo to establish their biological profiles. Full article
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19 pages, 2630 KiB  
Article
1H-1,2,3-triazolyl-1,6-naphthyridin-7(6H)-ones as Potential Fluorescent Nucleoside Analogues: Synthesis and Optical Properties
by Anissa Beghennou, Océane Rondot, Vincent Corcé and Candice Botuha
Molecules 2024, 29(3), 687; https://doi.org/10.3390/molecules29030687 - 1 Feb 2024
Viewed by 690
Abstract
In this article, we present the synthesis and the optical properties of three original molecules as potential fluorescent ribonucleoside analogues incorporating a 1,6-naphthyridin-7(6H)-one scaffold as a fluorescent nucleobase and a 1,2,3-triazole as a linkage. The nucleosides were prepared via a Cu [...] Read more.
In this article, we present the synthesis and the optical properties of three original molecules as potential fluorescent ribonucleoside analogues incorporating a 1,6-naphthyridin-7(6H)-one scaffold as a fluorescent nucleobase and a 1,2,3-triazole as a linkage. The nucleosides were prepared via a Cu alkyne-azide cycloaddition (CuAAC) reaction between a ribofuranosyl azide and a 4-ethynylpyridine partner. Construction of substituted 1,6-naphthyridin-7(6H)-ones was achieved through two additional steps. Optical property studies were investigated on nucleoside analogues. Powerful fluorescence properties have been evidenced with a remarkable change of emissivity depending on the polarity of the solvent, making these molecules suitable as a new class of artificial fluorescent nucleosides for investigating enzyme binding sites as well as probing nucleic acids. In addition, we are convinced that such analogues could be of great interest in the search for new antiviral or antitumoral drugs based on nucleosides. Full article
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Review

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44 pages, 15060 KiB  
Review
Synthesis of Fluorinated Nucleosides/Nucleotides and Their Antiviral Properties
by Yugandhar Kothapalli, Ransom A. Jones, Chung K. Chu and Uma S. Singh
Molecules 2024, 29(10), 2390; https://doi.org/10.3390/molecules29102390 - 19 May 2024
Viewed by 697
Abstract
The FDA has approved several drugs based on the fluorinated nucleoside pharmacophore, and numerous drugs are currently in clinical trials. Fluorine-containing nucleos(t)ides offer significant antiviral and anticancer activity. The insertion of a fluorine atom, either in the base or sugar of nucleos(t)ides, alters [...] Read more.
The FDA has approved several drugs based on the fluorinated nucleoside pharmacophore, and numerous drugs are currently in clinical trials. Fluorine-containing nucleos(t)ides offer significant antiviral and anticancer activity. The insertion of a fluorine atom, either in the base or sugar of nucleos(t)ides, alters its electronic and steric parameters and transforms the lipophilicity, pharmacodynamic, and pharmacokinetic properties of these moieties. The fluorine atom restricts the oxidative metabolism of drugs and provides enzymatic metabolic stability towards the glycosidic bond of the nucleos(t)ide. The incorporation of fluorine also demonstrates additional hydrogen bonding interactions in receptors with enhanced biological profiles. The present article discusses the synthetic methodology and antiviral activities of FDA-approved drugs and ongoing fluoro-containing nucleos(t)ide drug candidates in clinical trials. Full article
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