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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) | Viewed by 55923

Special Issue Editor


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Guest Editor
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
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

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 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 (9 papers)

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Research

18 pages, 6183 KiB  
Article
Functional Characterization of the Saccharomyces cerevisiae Equilibrative Nucleoside Transporter 1 (ScENT1)
by Rebba C. Boswell-Casteel, Jennifer M. Johnson and Franklin A. Hays
Molecules 2018, 23(4), 732; https://doi.org/10.3390/molecules23040732 - 22 Mar 2018
Cited by 3 | Viewed by 4084
Abstract
Equilibrative nucleoside transporters (ENTs) are polytopic membrane transporters responsible for the translocation of nucleosides, nucleobases—to a lesser extent—and nucleoside analog therapeutics across cellular membranes. ENTs function in a diffusion controlled bidirectional manner and are thought to utilize an alternating access transport mechanism. However, [...] Read more.
Equilibrative nucleoside transporters (ENTs) are polytopic membrane transporters responsible for the translocation of nucleosides, nucleobases—to a lesser extent—and nucleoside analog therapeutics across cellular membranes. ENTs function in a diffusion controlled bidirectional manner and are thought to utilize an alternating access transport mechanism. However, a detailed understanding of ENT function at the molecular level has remained elusive. ScENT1 (formerly known as Function Unknown Now 26 or FUN26) is the only known ENT ortholog endogenously expressed in S. cerevisiae, and a proteoliposome assay system was used to study homogenously overexpressed and purified ScENT1 (wildtype relative to L390A and F249I mutants). L390 and F249 are highly conserved residues and were found to alter transporter function. L390A produced a reduction of mean transport activity while F249I increased mean substrate translocation relative to wildtype protein. However, both mutations resulted in transport of UTP—a novel gain of function for any ENT. These residues were then mapped onto an ab initio model of FUN26 which suggests they function in substrate translocation (L390) or cytoplasmic gating (F249). Furthermore, wildtype, L390A, and F249I were found to be sensitive to the presence of alcohols. Ethanol attenuated ScENT1-mediated transport of uridine by ~50%. These findings further demonstrate functional similarities between ScENT1 and human ENT isoforms and support identification of FUN26 as ScENT1, the first ENT isoform in S. cerevisiae. Full article
(This article belongs to the Special Issue Nucleoside and Nucleotide Analogues)
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2745 KiB  
Article
Altering Residue 134 Confers an Increased Substrate Range of Alkylated Nucleosides to the E. coli OGT Protein
by Nadia M. Schoonhoven, Derek K. O’Flaherty, Francis P. McManus, Lauralicia Sacre, Anne M. Noronha, M. Judith Kornblatt and Christopher J. Wilds
Molecules 2017, 22(11), 1948; https://doi.org/10.3390/molecules22111948 - 11 Nov 2017
Cited by 3 | Viewed by 3556
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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2227 KiB  
Article
Synthesis of Disaccharide Nucleosides Utilizing the Temporary Protection of the 2′,3′-cis-Diol of Ribonucleosides by a Boronic Ester
by Hidehisa Someya, Taiki Itoh and Shin Aoki
Molecules 2017, 22(10), 1650; https://doi.org/10.3390/molecules22101650 - 1 Oct 2017
Cited by 9 | Viewed by 7462
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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1664 KiB  
Article
Stringent Nucleotide Recognition by the Ribosome at the Middle Codon Position
by Wei Liu, Dongwon Shin, Martin Ng, Karissa Y. Sanbonmatsu, Yitzhak Tor and Barry S. Cooperman
Molecules 2017, 22(9), 1427; https://doi.org/10.3390/molecules22091427 - 29 Aug 2017
Cited by 4 | Viewed by 3962
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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993 KiB  
Article
Identification of Optically Active Pyrimidine Derivatives as Selective 5-HT2C Modulators
by Juhyeon Kim, Hanbyeol Jo, Hyunseung Lee, Hyunah Choo, Hak Joong Kim, Ae Nim Pae, Yong Seo Cho and Sun-Joon Min
Molecules 2017, 22(9), 1416; https://doi.org/10.3390/molecules22091416 - 26 Aug 2017
Cited by 2 | Viewed by 4987
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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779 KiB  
Article
Synthesis of Compounds of the Pyrimidine Series Based on the Reactions of 3-Arylmethylidenefuran-2(3H)-ones with N,N-Binucleophilic Reagents
by Tatyana Aniskova, Vyacheslav Grinev and Alevtina Yegorova
Molecules 2017, 22(8), 1251; https://doi.org/10.3390/molecules22081251 - 28 Jul 2017
Cited by 3 | Viewed by 5441
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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2852 KiB  
Article
Fluorination of Naturally Occurring N6-Benzyladenosine Remarkably Increased Its Antiviral Activity and Selectivity
by Vladimir E. Oslovsky, Mikhail S. Drenichev, Liang Sun, Nikolay N. Kurochkin, Vladislav E. Kunetsky, Carmen Mirabelli, Johan Neyts, Pieter Leyssen and Sergey N. Mikhailov
Molecules 2017, 22(7), 1219; https://doi.org/10.3390/molecules22071219 - 20 Jul 2017
Cited by 17 | Viewed by 4897
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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1773 KiB  
Communication
Modified Nucleotides as Substrates of Terminal Deoxynucleotidyl Transferase
by Daiva Tauraitė, Jevgenija Jakubovska, Julija Dabužinskaitė, Maksim Bratchikov and Rolandas Meškys
Molecules 2017, 22(4), 672; https://doi.org/10.3390/molecules22040672 - 22 Apr 2017
Cited by 17 | Viewed by 9461
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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2311 KiB  
Article
Exploring the Antitumor Mechanism of High-Dose Cytarabine through the Metabolic Perturbations of Ribonucleotide and Deoxyribonucleotide in Human Promyelocytic Leukemia HL-60 Cells
by Zheng Li, Jian-Ru Guo, Qian-Qian Chen, Cai-Yun Wang, Wei-Jia Zhang, Mei-Cun Yao and Wei Zhang
Molecules 2017, 22(3), 499; https://doi.org/10.3390/molecules22030499 - 21 Mar 2017
Cited by 29 | Viewed by 11039
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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