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Special Issue "Bioactive Nucleosides and Nucleotides"

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

Deadline for manuscript submissions: 31 December 2018

Special Issue Editor

Guest Editor
Prof. Dr. Christian Ducho

Department of Pharmacy, Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2 3, 66 123 Saarbrücken, Germany
Website | E-Mail
Interests: medicinal chemistry; antibiotics; natural products; nucleosides; oligonucleotides

Special Issue Information

Dear Colleagues,

It is my pleasure to announce this Special Issue of Molecules on "Bioactive Nucleosides and Nucleotides". Analogues of nucleosides and nucleotides have had a tremendous impact, not only as (bio)chemical tools, but particularly also as drugs for human therapy. Nucleoside and nucleotide derivatives are currently widely used to treat cancer and viral infections, with the introduction of the highly potent anti-HCV drug Sofosbuvir (a nucleotide prodrug) representing the most recent milestone. However, nucleosides also find increasing interest as antibacterial drug candidates, which are urgently needed in the context of emerging resistances against established antibiotics.

For this Special Issue, we welcome contributions from all fields of nucleoside and nucleotide chemistry, may they be related to fundamental science or potential pharmaceutical applications. This also includes work that is mainly or even exclusively focused on organic synthesis. The synthetic preparation of nucleoside and nucleotide analogues is not trivial, and I strongly feel that there is an unfortunate tendency to overlook this highly important part of our daily work as chemists.

Prof. Dr. Christian Ducho
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

  • nucleosides and nucleotides
  • organic synthesis
  • anti-cancer agents
  • antiviral agents
  • antibacterial agents
  • chemical tools and probes

Published Papers (5 papers)

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Research

Open AccessFeature PaperArticle Membrane-Permeable Octanoyloxybenzyl-Masked cNMPs As Novel Tools for Non-Invasive Cell Assays
Molecules 2018, 23(11), 2960; https://doi.org/10.3390/molecules23112960
Received: 12 October 2018 / Revised: 6 November 2018 / Accepted: 7 November 2018 / Published: 13 November 2018
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Abstract
Adenine nucleotide (AN) 2nd messengers, such as 3′,5′-cyclic adenosine monophosphate (cAMP), are central elements of intracellular signaling, but many details of their underlying processes remain elusive. Like all nucleotides, cyclic nucleotide monophosphates (cNMPs) are net-negatively charged at physiologic pH which limits their applicability
[...] Read more.
Adenine nucleotide (AN) 2nd messengers, such as 3′,5′-cyclic adenosine monophosphate (cAMP), are central elements of intracellular signaling, but many details of their underlying processes remain elusive. Like all nucleotides, cyclic nucleotide monophosphates (cNMPs) are net-negatively charged at physiologic pH which limits their applicability in cell-based settings. Thus, many cellular assays rely on sophisticated techniques like microinjection or electroporation. This setup is not feasible for medium- to high-throughput formats, and the mechanic stress that cells are exposed to raises the probability of interfering artefacts or false-positives. Here, we present a short and flexible chemical route yielding membrane-permeable, bio-reversibly masked cNMPs for which we employed the octanoyloxybenzyl (OB) group. We further show hydrolysis studies on chemical stability and enzymatic activation, and present results of real-time assays, where we used cAMP and Ca2+ live cell imaging to demonstrate high permeability and prompt intracellular conversion of some selected masked cNMPs. Based on these results, our novel OB-masked cNMPs constitute valuable precursor-tools for non-invasive studies on intracellular signaling. Full article
(This article belongs to the Special Issue Bioactive Nucleosides and Nucleotides)
Figures

Figure 1

Open AccessArticle Enhanced Stability of DNA Oligonucleotides with Partially Zwitterionic Backbone Structures in Biological Media
Molecules 2018, 23(11), 2941; https://doi.org/10.3390/molecules23112941
Received: 29 October 2018 / Revised: 6 November 2018 / Accepted: 8 November 2018 / Published: 10 November 2018
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Abstract
Deficient stability towards nuclease-mediated degradation is one of the most relevant tasks in the development of oligonucleotide-derived biomedical agents. This hurdle can be overcome through modifications to the native oligonucleotide backbone structure, with the goal of simultaneously retaining the unique hybridization properties of
[...] Read more.
Deficient stability towards nuclease-mediated degradation is one of the most relevant tasks in the development of oligonucleotide-derived biomedical agents. This hurdle can be overcome through modifications to the native oligonucleotide backbone structure, with the goal of simultaneously retaining the unique hybridization properties of nucleic acids. The nucleosyl amino acid (NAA)-modification is a recently introduced artificial cationic backbone linkage. Partially zwitterionic NAA-modified oligonucleotides had previously shown hybridization with DNA strands with retained base-pairing fidelity. In this study, we report the significantly enhanced stability of NAA-modified oligonucleotides towards 3′- and 5′-exonuclease-mediated degradation as well as in complex biological media such as human plasma and whole cell lysate. This demonstrates the potential versatility of the NAA-motif as a backbone modification for the development of biomedically active oligonucleotide analogues. Full article
(This article belongs to the Special Issue Bioactive Nucleosides and Nucleotides)
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Graphical abstract

Open AccessArticle Analogues of Muraymycin Nucleoside Antibiotics with Epimeric Uridine-Derived Core Structures
Molecules 2018, 23(11), 2868; https://doi.org/10.3390/molecules23112868
Received: 21 September 2018 / Revised: 28 October 2018 / Accepted: 30 October 2018 / Published: 3 November 2018
PDF Full-text (2897 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Nucleoside analogues have found widespread application as antiviral and antitumor agents, but not yet as antibacterials. Naturally occurring uridine-derived ‘nucleoside antibiotics’ target the bacterial membrane protein MraY, an enzyme involved in peptidoglycan biosynthesis and a promising target for the development of novel antibacterial
[...] Read more.
Nucleoside analogues have found widespread application as antiviral and antitumor agents, but not yet as antibacterials. Naturally occurring uridine-derived ‘nucleoside antibiotics’ target the bacterial membrane protein MraY, an enzyme involved in peptidoglycan biosynthesis and a promising target for the development of novel antibacterial agents. Muraymycins represent a nucleoside-peptide subgroup of such MraY-inhibiting natural products. As part of detailed structure-activity relationship (SAR) studies on muraymycins and their analogues, we now report novel insights into the effects of stereochemical variations in the nucleoside core structure. Using a simplified version of the muraymycin scaffold, it was shown that some formal inversions of stereochemistry led to about one order of magnitude loss in inhibitory potency towards the target enzyme MraY. In contrast, epimers of the core motif with retained inhibitory activity were also identified. These 5′,6′-anti-configured analogues might serve as novel chemically tractable variations of the muraymycin scaffold for the future development of uridine-derived drug candidates. Full article
(This article belongs to the Special Issue Bioactive Nucleosides and Nucleotides)
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Graphical abstract

Open AccessArticle Anti-Hepatitis C Virus Activity of Uridine Derivatives of 2-Deoxy Sugars
Molecules 2018, 23(7), 1547; https://doi.org/10.3390/molecules23071547
Received: 24 May 2018 / Revised: 22 June 2018 / Accepted: 26 June 2018 / Published: 27 June 2018
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Abstract
Hepatitis C virus (HCV), the etiological agent of the most common and dangerous diseases of the liver, is a major health problem worldwide. Despite many attempts, there is still no vaccine available. Although many drugs have been approved for use mostly in combination
[...] Read more.
Hepatitis C virus (HCV), the etiological agent of the most common and dangerous diseases of the liver, is a major health problem worldwide. Despite many attempts, there is still no vaccine available. Although many drugs have been approved for use mostly in combination regimen, their high costs make them out of reach in less developed regions. Previously, we have synthesized a series of compounds belonging to uridine derivatives of 2-deoxy sugars and have proved that some of them possess antiviral activity against influenza A virus associated with N-glycosylation inhibition. Here, we analyze the antiviral properties of these compounds against HCV. Using cell culture-derived HCV (HCVcc), HCV pseudoparticles (HCVpp), and replicon cell lines, we have shown high anti-HCV activity of two compounds. Our results indicated that compounds 2 and 4 significantly reduced HCVcc propagation with IC50 values in low μM range. Further experiments using the HCVpp system confirmed that both compounds significantly impaired the infectivity of produced HCVpp due to the inhibition of the correct maturation of viral glycoproteins. Overall, our results suggest that inhibiting the glycosylation process might be a good target for new therapeutics not only against HCV, but other important viral pathogens which contain envelopes with highly glycosylated proteins. Full article
(This article belongs to the Special Issue Bioactive Nucleosides and Nucleotides)
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Graphical abstract

Open AccessArticle Phosphorus Pentachloride Promoted gem-Dichlorination of 2′- and 3′-Deoxynucleosides
Molecules 2018, 23(6), 1457; https://doi.org/10.3390/molecules23061457
Received: 29 May 2018 / Revised: 11 June 2018 / Accepted: 11 June 2018 / Published: 15 June 2018
PDF Full-text (1561 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Halogen substitution at various positions of canonical nucleosides has generated a number of bioactive structural variants. Herein, the synthesis of two unique series of sugar modified nucleosides bearing a gem-dichloro group is presented. The synthetic plan entails the controlled addition of phosphorus
[...] Read more.
Halogen substitution at various positions of canonical nucleosides has generated a number of bioactive structural variants. Herein, the synthesis of two unique series of sugar modified nucleosides bearing a gem-dichloro group is presented. The synthetic plan entails the controlled addition of phosphorus pentachloride to suitably protected 2′- or 3′-ketodeoxynucleoside intermediates as the key step, facilitating the rapid construction of such functionalized molecules. Under the same reaction conditions, the highest chemoselectivity was observed for the formation of 2′,2′-dichloro-2′,3′-dideoxynucleosides, while a competing 2′,3′-elimination process occurred in the case of the 3′,3′-dichloro counterparts. Full article
(This article belongs to the Special Issue Bioactive Nucleosides and Nucleotides)
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Graphical abstract

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