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Special Issue "Nucleoside and Nucleotide Analogues"

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

Deadline for manuscript submissions: closed (10 July 2017)

Special Issue Editor

Guest Editor
Dr. Suzanne Peyrottes

Institut des Biomolécules Max Mousseron (IBMM), Nucleosides & Phosphorylated Effectors Team, UMR 5247 CNRS, Université de Montpellier, ENSCM, Campus Triolet, cc 1705, Place Eugène Bataillon, 34095 Montpellier cedex 5, France
Website | E-Mail
Interests: design and synthesis of potential therapeutic agents to treat infections and cancers, mainly nucleoside and nucleotide analogues; new synthetic methodology related to nucleic acid components

Special Issue Information

Dear Colleagues,

Nucleosides and nucleotides are essential building blocks for nucleic acid biosynthesis and they also play important roles in many biological processes. Since the middle of the last century, they have attracted the interest of chemists for the synthesis of analogues and their derivatives, as well as biochemists and biologists to be used both as tools and/or new drugs. As a consequence, many of them are currently used in clinics.

The current Special Issue aims to bring together all researchers working in the field of nucleosides, nucleotides and their analogues, and to give to them the opportunity to report on their work and recent findings in the related area. Contributions on innovative and emerging synthetic methodologies, synthesis or use of original skeletons, as well as on the broad biological applications of these family of compounds (antiviral, anticancer, antibiotic, antiparasitic, etc.) are welcome.

Dr. Suzanne Peyrottes
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Synthesis of nucleos(t)ide and their analogues, prodrugs, poly(phosphorylated)derivatives;
  • Phosphorus chemistry;
  • Drug design;
  • Nucleos(t)ides as probes or tools
  • Medicinal chemistry

Published Papers (8 papers)

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Research

Open AccessArticle Altering Residue 134 Confers an Increased Substrate Range of Alkylated Nucleosides to the E. coli OGT Protein
Molecules 2017, 22(11), 1948; doi:10.3390/molecules22111948
Received: 16 October 2017 / Revised: 1 November 2017 / Accepted: 8 November 2017 / Published: 11 November 2017
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Abstract
O6-Alkylguanine-DNA alkyltransferases (AGTs) are proteins responsible for the removal of mutagenic alkyl adducts at the O6-atom of guanine and O4-atom of thymine. In the current study we set out to understand the role of the Ser134 residue
[...] Read more.
O6-Alkylguanine-DNA alkyltransferases (AGTs) are proteins responsible for the removal of mutagenic alkyl adducts at the O6-atom of guanine and O4-atom of thymine. In the current study we set out to understand the role of the Ser134 residue in the Escherichia coli AGT variant OGT on substrate discrimination. The S134P mutation in OGT increased the ability of the protein to repair both O6-adducts of guanine and O4-adducts of thymine. However, the S134P variant was unable, like wild-type OGT, to repair an interstrand cross-link (ICL) bridging two O6-atoms of guanine in a DNA duplex. When compared to the human AGT protein (hAGT), the S134P OGT variant displayed reduced activity towards O6-alkylation but a much broader substrate range for O4-alkylation damage reversal. The role of residue 134 in OGT is similar to its function in the human homolog, where Pro140 is crucial in conferring on hAGT the capability to repair large adducts at the O6-position of guanine. Finally, a method to generate a covalent conjugate between hAGT and a model nucleoside using a single-stranded oligonucleotide substrate is demonstrated. Full article
(This article belongs to the Special Issue Nucleoside and Nucleotide Analogues)
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Open AccessArticle Synthesis of Disaccharide Nucleosides Utilizing the Temporary Protection of the 2′,3′-cis-Diol of Ribonucleosides by a Boronic Ester
Molecules 2017, 22(10), 1650; doi:10.3390/molecules22101650
Received: 8 September 2017 / Revised: 24 September 2017 / Accepted: 29 September 2017 / Published: 1 October 2017
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Abstract
Disaccharide nucleosides are an important class of natural compounds that have a variety of biological activities. In this study, we report on the synthesis of disaccharide nucleosides utilizing the temporary protection of the 2′,3′-cis-diol of ribonucleosides, such as adenosine, guanosine, uridine,
[...] Read more.
Disaccharide nucleosides are an important class of natural compounds that have a variety of biological activities. In this study, we report on the synthesis of disaccharide nucleosides utilizing the temporary protection of the 2′,3′-cis-diol of ribonucleosides, such as adenosine, guanosine, uridine, 5-metyluridine, 5-fluorouridine and cytidine, by a boronic ester. The temporary protection of the above ribonucleosides permits the regioselective O-glycosylation of the 5’-hydroxyl group with thioglycosides using a p-toluenesulfenyl chloride (p-TolSCl)/silver triflate (AgOTf) promoter system to afford the corresponding disaccharide nucleosides in fairly good chemical yields. The formation of a boronic ester prepared from uridine and 4-(trifluoromethyl)phenylboronic acid was examined by 1H, 11B and 19F NMR spectroscopy. Full article
(This article belongs to the Special Issue Nucleoside and Nucleotide Analogues)
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Open AccessArticle Stringent Nucleotide Recognition by the Ribosome at the Middle Codon Position
Molecules 2017, 22(9), 1427; doi:10.3390/molecules22091427
Received: 25 July 2017 / Revised: 15 August 2017 / Accepted: 22 August 2017 / Published: 29 August 2017
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Abstract
Accurate translation of the genetic code depends on mRNA:tRNA codon:anticodon base pairing. Here we exploit an emissive, isosteric adenosine surrogate that allows direct measurement of the kinetics of codon:anticodon University of California base formation during protein synthesis. Our results suggest that codon:anticodon base
[...] Read more.
Accurate translation of the genetic code depends on mRNA:tRNA codon:anticodon base pairing. Here we exploit an emissive, isosteric adenosine surrogate that allows direct measurement of the kinetics of codon:anticodon University of California base formation during protein synthesis. Our results suggest that codon:anticodon base pairing is subject to tighter constraints at the middle position than at the 5′- and 3′-positions, and further suggest a sequential mechanism of formation of the three base pairs in the codon:anticodon helix. Full article
(This article belongs to the Special Issue Nucleoside and Nucleotide Analogues)
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Open AccessArticle Identification of Optically Active Pyrimidine Derivatives as Selective 5-HT2C Modulators
Molecules 2017, 22(9), 1416; doi:10.3390/molecules22091416
Received: 31 July 2017 / Revised: 22 August 2017 / Accepted: 23 August 2017 / Published: 26 August 2017
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Abstract
A series of pyrimidine derivatives 4ai were synthesized and evaluated for their binding affinities towards 5-HT2C receptors. With regard to designed molecules 4ai, the influence of the size of alkyl ether and the absolute configuration of a
[...] Read more.
A series of pyrimidine derivatives 4ai were synthesized and evaluated for their binding affinities towards 5-HT2C receptors. With regard to designed molecules 4ai, the influence of the size of alkyl ether and the absolute configuration of a stereogenic center on the 5-HT2C binding affinity and selectivity was studied. The most promising diasteromeric mixtures 4d and 4e were selected in the initial radioligand binding assay and they were further synthesized as optically active forms starting from optically active alcohols 5d and 5e, prepared by an enzymatic kinetic resolution. Pyrimidine analogue (R,R)-4e displayed an excellent 5-HT2C binding affinity with good selectivity values against a broad range of other 5-HT receptor subtypes. Full article
(This article belongs to the Special Issue Nucleoside and Nucleotide Analogues)
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Open AccessArticle Synthesis of Compounds of the Pyrimidine Series Based on the Reactions of 3-Arylmethylidenefuran-2(3H)-ones with N,N-Binucleophilic Reagents
Molecules 2017, 22(8), 1251; doi:10.3390/molecules22081251
Received: 10 July 2017 / Revised: 25 July 2017 / Accepted: 25 July 2017 / Published: 28 July 2017
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Abstract
The arylmethylidene derivatives of furan-2(3H)-ones are important building blocks for the synthesis of various heterocyclic compounds containing pyrimidine and pyridazine structural fragments, analogues of nitrogen-containing bases of pyrimidine series. In order to continue the development of constructing of molecules containing pyridine
[...] Read more.
The arylmethylidene derivatives of furan-2(3H)-ones are important building blocks for the synthesis of various heterocyclic compounds containing pyrimidine and pyridazine structural fragments, analogues of nitrogen-containing bases of pyrimidine series. In order to continue the development of constructing of molecules containing pyridine and pyridazine fragments, this article is devoted to the synthesis of new biologically active compounds with these moieties. The introduction of a heterocyclic chromenone fragment changes the previously observed 5-R-3-arylmethylidenefuran-2(3H)-ones route of reaction with guanidine carbonate and leads to 3-[(2-amino-4-(2-hydroxyphenyl)pyrimidin-5-yl)methylene]-5-phenylfuran-2(3H)-ones (2ad). The structure of the reaction products depends on the nature of the aromatic substituent at the C-3 position of the furanone ring. The interaction of 5-aryl-3-arylmethylidenefuran-2(3H)-ones (1eh) with thiourea in the basic medium leads to the isolation of 5-(2-oxo-2-phenylethyl)-6-aryl-2-thioxotetrahydropyrimidine-4(1H)-ones (3ad), demonstrating pronounced plant-growth regulatory activity. Optimal conditions for all discussed processes were developed. Full article
(This article belongs to the Special Issue Nucleoside and Nucleotide Analogues)
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Open AccessArticle Fluorination of Naturally Occurring N6-Benzyladenosine Remarkably Increased Its Antiviral Activity and Selectivity
Molecules 2017, 22(7), 1219; doi:10.3390/molecules22071219
Received: 27 June 2017 / Revised: 13 July 2017 / Accepted: 17 July 2017 / Published: 20 July 2017
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Abstract
Recently, we demonstrated that the natural cytokinin nucleosides N6-isopentenyladenosine (iPR) and N6-benzyladenosine (BAPR) exert a potent and selective antiviral effect on the replication of human enterovirus 71. In order to further characterize the antiviral profile
[...] Read more.
Recently, we demonstrated that the natural cytokinin nucleosides N6-isopentenyladenosine (iPR) and N6-benzyladenosine (BAPR) exert a potent and selective antiviral effect on the replication of human enterovirus 71. In order to further characterize the antiviral profile of this class of compounds, we generated a series of fluorinated derivatives of BAPR and evaluated their activity on the replication of human enterovirus 71 in a cytopathic effect (CPE) reduction assay. The monofluorination of the BAPR-phenyl group changed the selectivity index (SI) slightly because of the concomitant high cell toxicity. Interestingly, the incorporation of a second fluorine atom resulted in a dramatic improvement of selectivity. Moreover, N6-trifluoromethylbenzyladenosine derivatives (911) exhibited also a very interesting profile, with low cytotoxicity observed. In particular, the analogue N6-(3-trifluoromethylbenzyl)-adenosine (10) with a four-fold gain in potency as compared to BAPR and the best SI in the class represents a promising candidate for further development. Full article
(This article belongs to the Special Issue Nucleoside and Nucleotide Analogues)
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Open AccessCommunication Modified Nucleotides as Substrates of Terminal Deoxynucleotidyl Transferase
Molecules 2017, 22(4), 672; doi:10.3390/molecules22040672
Received: 16 March 2017 / Revised: 10 April 2017 / Accepted: 19 April 2017 / Published: 22 April 2017
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Abstract
The synthesis of novel modified nucleotides and their incorporation into DNA sequences opens many possibilities to change the chemical properties of oligonucleotides (ONs), and, therefore, broaden the field of practical applications of modified DNA. The chemical synthesis of nucleotide derivatives, including ones bearing
[...] Read more.
The synthesis of novel modified nucleotides and their incorporation into DNA sequences opens many possibilities to change the chemical properties of oligonucleotides (ONs), and, therefore, broaden the field of practical applications of modified DNA. The chemical synthesis of nucleotide derivatives, including ones bearing thio-, hydrazino-, cyano- and carboxy groups as well as 2-pyridone nucleobase-containing nucleotides was carried out. The prepared compounds were tested as substrates of terminal deoxynucleotidyl transferase (TdT). The nucleotides containing N4-aminocytosine, 4-thiouracil as well as 2-pyridone, 4-chloro- and 4-bromo-2-pyridone as a nucleobase were accepted by TdT, thus allowing enzymatic synthesis of 3’-terminally modified ONs. The successful UV-induced cross-linking of 4-thiouracil-containing ONs to TdT was carried out. Enzymatic post-synthetic 3’-modification of ONs with various photo- and chemically-reactive groups opens novel possibilities for future applications, especially in analysis of the mechanisms of polymerases and the development of photo-labels, sensors, and self-assembling structures. Full article
(This article belongs to the Special Issue Nucleoside and Nucleotide Analogues)
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Open AccessArticle Exploring the Antitumor Mechanism of High-Dose Cytarabine through the Metabolic Perturbations of Ribonucleotide and Deoxyribonucleotide in Human Promyelocytic Leukemia HL-60 Cells
Molecules 2017, 22(3), 499; doi:10.3390/molecules22030499
Received: 8 March 2017 / Revised: 17 March 2017 / Accepted: 20 March 2017 / Published: 21 March 2017
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Abstract
Despite the apparent clinical benefits of high-dose cytarabine (Ara-C) over lower dose Ara-C in acute myeloid leukemia (AML) therapy, the mechanism behind high-dose Ara-C therapy remains uncertain. In this study, a LC-MS-based method was carried out to investigate the metabolic alteration of ribonucleotide
[...] Read more.
Despite the apparent clinical benefits of high-dose cytarabine (Ara-C) over lower dose Ara-C in acute myeloid leukemia (AML) therapy, the mechanism behind high-dose Ara-C therapy remains uncertain. In this study, a LC-MS-based method was carried out to investigate the metabolic alteration of ribonucleotide and deoxyribonucleotide in human promyelocytic leukemia cells (HL-60) after treatment with Ara-C to reveal its antitumor mechanism. The metabolic results revealed that four nucleotides (ATP, ADP, CDP, and dCTP) could be used as potential biomarkers indicating the benefit of high-dose Ara-C over lower dose Ara-C treatment. Combining metabolic perturbation and cell cycle analysis, we conjectured that, apart from the acknowledged mechanism of Ara-C on tumor inhibition, high-dose Ara-C could present a specific action pathway. It was suggested that the pronounced rise in AMP/ATP ratio induced by high-dose Ara-C can trigger AMP-activated protein kinase (AMPK) and subsequently Forkhead Box, class O (FoxO), to promote cell cycle arrest. Moreover, the significant decrease in CDP pool induced by high-dose Ara-C might further accelerate the reduction of dCTP, which then aggravates DNA synthesis disturbance. As a result, all of these alterations led to heightened tumor inhibition. This study provides new insight in the investigation of potential mechanisms in the clinical benefits of high-dose Ara-C in therapy for AML. Full article
(This article belongs to the Special Issue Nucleoside and Nucleotide Analogues)
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