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Special Issue "Synthesis of Nucleosides, Nucleotides and Their Derivatives"

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

Deadline for manuscript submissions: closed (31 August 2013)

Special Issue Editor

Guest Editor
Prof. Dr. Carlo Siciliano

Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, I-87036 Arcavacata di Rende, Italy
Website | E-Mail
Interests: synthesis of biomolecules and their analogues; amino acid and peptide chemistry; modification of natural amino acids; chiral templates; design and synthesis of protease inhibitors; steroid chemistry

Special Issue Information

Dear Colleagues,

Nucleosides, nucleotides and their synthetic analogues have been proposed for the diagnostic control and the therapeutic treatment of different kinds of grave pathologies which are related to viral infections and to many types of cancer. The history of these classes of compounds is certainly characterized by their wide biological and pharmaceutical potentialities, while a critical and key role has been played by the plethora of synthetic methodologies developed, time by time, for the preparation on non-natural analogues. A good number of compounds featuring modified heterocycles as nucleobases and/or sugar moieties, and phosphorylated frames showing high similarities with respect to those found in natural congeners, are now available. The scope of this Special Issue is to collect the most recent acquisitions and state of the art concerning chemical procedures used in the design and structural characterization of nucleosides, nucleotides and their modified analogues, corroborated by the results obtained from biological tests. This Special Issue will focus on all aspects regarding the description of new synthetic approaches and methodologies which can usefully be applied to modification of nucleobases, sugar moieties and phosphodiester linkages. Research papers and reviews dealing with the presented fields are welcome for the preparation of this Special Issue of Molecules.

Prof. Dr. Carlo Siciliano
Guest Editor

Submission

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. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as 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 refereed through a 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).

Keywords

  • nuleosides
  • nucleotides
  • modified analogues
  • nucleobases modification
  • sugar moiety modification
  • phosphorylation methods
  • nucleic acid building blocks
  • biological activity
  • anticancer action
  • antiviral action
  • enzyme Inhibition
  • diagnostic potentialities

Published Papers (12 papers)

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Research

Jump to: Review

Open AccessArticle A Tractable and Efficient One-Pot Synthesis of 5'-Azido-5'-deoxyribonucleosides
Molecules 2014, 19(2), 2434-2444; doi:10.3390/molecules19022434
Received: 11 September 2013 / Revised: 11 February 2014 / Accepted: 12 February 2014 / Published: 21 February 2014
Cited by 2 | PDF Full-text (251 KB) | HTML Full-text | XML Full-text
Abstract
Synthetic routes to 5'-azidoribonucleosides are reported for adenosine, cytidine, guanosine, and uridine, resulting in a widely applicable one-pot methodology for the synthesis of these and related compounds. The target compounds are appropriate as precursors in a variety of purposive syntheses, as the synthetic
[...] Read more.
Synthetic routes to 5'-azidoribonucleosides are reported for adenosine, cytidine, guanosine, and uridine, resulting in a widely applicable one-pot methodology for the synthesis of these and related compounds. The target compounds are appropriate as precursors in a variety of purposive syntheses, as the synthetic and therapeutic relevance of azido- and amino-modified nucleosides is expansive. Furthermore, in the conversion of alcohols to azides, these methods offer a tractable alternative to the Mitsunobu and other more difficult reactions. Full article
(This article belongs to the Special Issue Synthesis of Nucleosides, Nucleotides and Their Derivatives)
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Open AccessArticle Novel Method of Synthesis of 5''-Phosphate 2'-O-ribosyl-ribonucleosides and Their 3'-Phosphoramidites
Molecules 2013, 18(12), 14780-14796; doi:10.3390/molecules181214780
Received: 27 September 2013 / Revised: 23 November 2013 / Accepted: 25 November 2013 / Published: 29 November 2013
PDF Full-text (345 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Synthesis of 5''-phosphate 2'-O-ribosylribonucleosides [Nr(p)] of four common ribonucleosides, and 3'-phosphoramidites of 5''-phosphate 2'-O-ribosyladenosine and 2'-O-ribosylguanosine using the H-phosphonate chemistry is described. An additional ring protected by benzoyl groups was incorporated into the main
[...] Read more.
Synthesis of 5''-phosphate 2'-O-ribosylribonucleosides [Nr(p)] of four common ribonucleosides, and 3'-phosphoramidites of 5''-phosphate 2'-O-ribosyladenosine and 2'-O-ribosylguanosine using the H-phosphonate chemistry is described. An additional ring protected by benzoyl groups was incorporated into the main ribosyl ring in the reaction with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-d-ribofuranose in the presence of SnCl4. The obtained 2'-O-ribosylribonucleosides (Nr) were applied in the subsequent transformations with selective deprotection. Ethanolamine was applied as a very convenient reagent for selective removal of benzoyl groups. Additionally, the tetraisopropyldisiloxane-1,3-diyl (TIPDSi) group was found to be stable under these deprotection conditions. Thus, the selectively deprotected 5''-hydroxyl group of Nr was transformed into an H-phosphonate monoester which was found to be stable under the following conditions: the removal of the TIPDSi group with triethylammonium fluoride and the dimethoxytritylation of the 5''-hydroxyl function. The 5''-H-phosphonate of Nr precursors was easily transformed to the corresponding dicyanoethyl 5''-O-phosphotriesters before phosphitylation, which gave 3'-phosphoramidite units of Nr(p) in high yield. The derived phosphoramidite units were used in an automated oligonucleotide synthesizer to produce dimer Ar(p)T via the phosphoramidite approach. The obtained products were fully deprotected under standard deprotection conditions giving dimers with a 5''-phosphate monoester function. Application of an alkaline phosphatase to prove the presence of an additional phosphate group was described. Full article
(This article belongs to the Special Issue Synthesis of Nucleosides, Nucleotides and Their Derivatives)
Open AccessArticle Pd0-Catalyzed Methyl Transfer on Nucleosides and Oligonucleotides, Envisaged as a PET Tracer
Molecules 2013, 18(11), 13654-13665; doi:10.3390/molecules181113654
Received: 26 August 2013 / Revised: 14 October 2013 / Accepted: 23 October 2013 / Published: 5 November 2013
Cited by 2 | PDF Full-text (289 KB) | HTML Full-text | XML Full-text
Abstract
The methyl transfer reaction from activated monomethyltin, via a modified Stille coupling reaction, was studied under “ligandless” conditions on fully deprotected 5'-modified nucleosides and one dinucleotide. The reaction was optimized to proceed in a few minutes and quantitative yield, even under dilute conditions,
[...] Read more.
The methyl transfer reaction from activated monomethyltin, via a modified Stille coupling reaction, was studied under “ligandless” conditions on fully deprotected 5'-modified nucleosides and one dinucleotide. The reaction was optimized to proceed in a few minutes and quantitative yield, even under dilute conditions, thus affording a rapid and efficient new method for oligonucleotide labelling with carbon-11. Full article
(This article belongs to the Special Issue Synthesis of Nucleosides, Nucleotides and Their Derivatives)
Open AccessCommunication Oligonucleotide Labelling Using a Fluorogenic “Click” Reaction with a Hemicarboxonium Salt
Molecules 2013, 18(10), 12966-12976; doi:10.3390/molecules181012966
Received: 28 August 2013 / Revised: 30 September 2013 / Accepted: 9 October 2013 / Published: 17 October 2013
PDF Full-text (558 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract Two fluorescent streptocyanine labelled oligonucleotides have been synthesized by a simple “click” reaction between a non-fluorescent hemicarboxonium salt and aminoalkyl functionalized thymidines within the oligonucleotide and their spectrophotometric properties have been studied. Full article
(This article belongs to the Special Issue Synthesis of Nucleosides, Nucleotides and Their Derivatives)
Figures

Open AccessArticle An Efficient and Facile Methodology for Bromination of Pyrimidine and Purine Nucleosides with Sodium Monobromoisocyanurate (SMBI)
Molecules 2013, 18(10), 12740-12750; doi:10.3390/molecules181012740
Received: 2 September 2013 / Revised: 2 October 2013 / Accepted: 9 October 2013 / Published: 15 October 2013
Cited by 1 | PDF Full-text (199 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
An efficient and facile strategy has been developed for bromination of nucleosides using sodium monobromoisocyanurate (SMBI). Our methodology demonstrates bromination at the C-5 position of pyrimidine nucleosides and the C-8 position of purine nucleosides. Unprotected and also several protected nucleosides were brominated in
[...] Read more.
An efficient and facile strategy has been developed for bromination of nucleosides using sodium monobromoisocyanurate (SMBI). Our methodology demonstrates bromination at the C-5 position of pyrimidine nucleosides and the C-8 position of purine nucleosides. Unprotected and also several protected nucleosides were brominated in moderate to high yields following this procedure. Full article
(This article belongs to the Special Issue Synthesis of Nucleosides, Nucleotides and Their Derivatives)
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Open AccessArticle Enzymatic Synthesis of Highly Fluorescent 8-Azapurine Ribosides Using a Purine Nucleoside Phosphorylase Reverse Reaction: Variable Ribosylation Sites
Molecules 2013, 18(10), 12587-12598; doi:10.3390/molecules181012587
Received: 30 August 2013 / Revised: 25 September 2013 / Accepted: 30 September 2013 / Published: 11 October 2013
Cited by 4 | PDF Full-text (414 KB) | HTML Full-text | XML Full-text
Abstract
Various forms of purine-nucleoside phosphorylase (PNP) were used as catalysts of enzymatic ribosylation of selected fluorescent 8-azapurines. It was found that the recombinant calf PNP catalyzes ribosylation of 2,6-diamino-8-azapurine in a phosphate-free medium, with ribose-1-phosphate as ribose donor, but the ribosylation site is
[...] Read more.
Various forms of purine-nucleoside phosphorylase (PNP) were used as catalysts of enzymatic ribosylation of selected fluorescent 8-azapurines. It was found that the recombinant calf PNP catalyzes ribosylation of 2,6-diamino-8-azapurine in a phosphate-free medium, with ribose-1-phosphate as ribose donor, but the ribosylation site is predominantly N7 and N8, with the proportion of N8/N7 ribosylated products markedly dependent on the reaction conditions. Both products are fluorescent. Application of the E. coli PNP gave a mixture of N8 and N9-substituted ribosides. Fluorescence of the ribosylated 2,6-diamino-8-azapurine has been briefly characterized. The highest quantum yield, ~0.9, was obtained for N9-β-d-riboside (λmax 365 nm), while for N8-β-d-riboside, emitting at ~430 nm, the fluorescence quantum yield was found to be close to 0.4. Ribosylation of 8-azaguanine with calf PNP as a catalyst goes exclusively to N9. By contrast, the E. coli PNP ribosylates 8-azaGua predominantly at N9, with minor, but highly fluorescent products ribosylated at N8/N7. Full article
(This article belongs to the Special Issue Synthesis of Nucleosides, Nucleotides and Their Derivatives)
Open AccessArticle Glycosyl-Nucleolipids as New Bioinspired Amphiphiles
Molecules 2013, 18(10), 12241-12263; doi:10.3390/molecules181012241
Received: 28 August 2013 / Revised: 25 September 2013 / Accepted: 25 September 2013 / Published: 30 September 2013
Cited by 4 | PDF Full-text (417 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Four new Glycosyl-NucleoLipid (GNL) analogs featuring either a single fluorocarbon or double hydrocarbon chains were synthesized in good yields from azido thymidine as starting material. Physicochemical studies (surface tension measurements, differential scanning calorimetry) indicate that hydroxybutanamide-based GNLs feature endothermic phase transition temperatures like
[...] Read more.
Four new Glycosyl-NucleoLipid (GNL) analogs featuring either a single fluorocarbon or double hydrocarbon chains were synthesized in good yields from azido thymidine as starting material. Physicochemical studies (surface tension measurements, differential scanning calorimetry) indicate that hydroxybutanamide-based GNLs feature endothermic phase transition temperatures like the previously reported double chain glycerol-based GNLs. The second generation of GNFs featuring a free nucleobase reported here presents a better surface activity (lower glim) compared to the first generation of GNFs. Full article
(This article belongs to the Special Issue Synthesis of Nucleosides, Nucleotides and Their Derivatives)
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Open AccessArticle Synthesis of a Novel Carbocyclic Analog of Bredinin
Molecules 2013, 18(9), 11576-11585; doi:10.3390/molecules180911576
Received: 23 August 2013 / Revised: 5 September 2013 / Accepted: 10 September 2013 / Published: 17 September 2013
Cited by 1 | PDF Full-text (248 KB) | HTML Full-text | XML Full-text
Abstract
The natural nucleoside antibiotic, bredinin, exhibits antiviral and other biological activities. While various nucleosides related to bredinin have been synthesized, its carbocyclic analog has remained unknown. Synthesis of this heretofore unknown analog of bredinin is described. The key precursor, (3aS,4R
[...] Read more.
The natural nucleoside antibiotic, bredinin, exhibits antiviral and other biological activities. While various nucleosides related to bredinin have been synthesized, its carbocyclic analog has remained unknown. Synthesis of this heretofore unknown analog of bredinin is described. The key precursor, (3aS,4R,6R,6aR)-6-((methoxy-methoxy)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-amine (5), was prepared from the commercially available compound, (1R,4S)-2-azabicyclo[2.2.1] hept-5-en-3-one (4). Our initial approach used intermediate 6, derived in three transformations from 5, for the key photolytic step to produce the desired ring-opened precursor to the target compound. This photochemical transformation was unsuccessful. However, an appropriately protected and related precursor was synthesized from 5 through the following side-chain functional group transformations: elaboration of the amino group through malonyl ester formation, oximation at the central carbon, conversion of ester to amide and catalytic reduction of the oxime group. This precursor, on treatment with triethylorthoformate and catalytic acetic acid in ethanol, underwent cyclization to produce the desired 4-carbamoyl-imidazolium-5-olate ring. Deprotection of the latter product proceeded smoothly to give the carbocyclic analog of bredinin. This target molecule exhibits antiviral activity, albeit low, against a number of RNA viruses. Further biological evaluations are in progress. Full article
(This article belongs to the Special Issue Synthesis of Nucleosides, Nucleotides and Their Derivatives)
Open AccessArticle Synthesis and Biological Evaluation of a New Acyclic Pyrimidine Derivative as a Probe for Imaging Herpes Simplex Virus Type 1 Thymidine Kinase Gene Expression
Molecules 2013, 18(7), 8535-8549; doi:10.3390/molecules18078535
Received: 27 May 2013 / Revised: 12 July 2013 / Accepted: 16 July 2013 / Published: 19 July 2013
Cited by 1 | PDF Full-text (494 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
With the idea of finding a more selective radiotracer for imaging herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene expression by means of positron emission tomography (PET), a novel [18F]fluorine radiolabeled pyrimidine with 4-hydroxy-3-(hydroxymethyl)butyl side chain at N-1 (HHB-5-[
[...] Read more.
With the idea of finding a more selective radiotracer for imaging herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene expression by means of positron emission tomography (PET), a novel [18F]fluorine radiolabeled pyrimidine with 4-hydroxy-3-(hydroxymethyl)butyl side chain at N-1 (HHB-5-[18F]FEP) was prepared and evaluated as a potential PET probe. Unlabeled reference compound, HHB-5-FEP, was synthesized via a five-step reaction sequence starting from 5-(2-acetoxyethyl)-4-methoxypyrimidin-2-one. The radiosynthesis of HHB-[18F]-FEP was accomplished by nucleophilic radiofluorination of a tosylate precursor using [18F]fluoride-cryptate complex in 45% ± 4 (n = 4) radiochemical yields and high purity (>99%). The biological evaluation indicated the feasibility of using HHB-5-[18F]FEP as a PET radiotracer for monitoring HSV1-tk expression in vivo. Full article
(This article belongs to the Special Issue Synthesis of Nucleosides, Nucleotides and Their Derivatives)
Open AccessArticle A Straightforward Diphenylmethyl Protection Method and Deprotection of Some Pyrimidine Nucleosides
Molecules 2013, 18(7), 8524-8534; doi:10.3390/molecules18078524
Received: 31 May 2013 / Revised: 10 July 2013 / Accepted: 16 July 2013 / Published: 18 July 2013
Cited by 5 | PDF Full-text (237 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Benzhydryl protection of primary and secondary alcohols has been reported previously via reaction with metal alcoholates. Our aim was to find generally useful and very mild conditions for the alcoholic protection and deprotection of nucleosides with the diphenylmethyl group. This was accomplished for
[...] Read more.
Benzhydryl protection of primary and secondary alcohols has been reported previously via reaction with metal alcoholates. Our aim was to find generally useful and very mild conditions for the alcoholic protection and deprotection of nucleosides with the diphenylmethyl group. This was accomplished for some pyrimidine nucleosides using PdCl2 as the transition metal catalyst, and with optimization yields of 70–90% have been achieved. A lack of solubility of other nucleosides hampers its more general use. Full article
(This article belongs to the Special Issue Synthesis of Nucleosides, Nucleotides and Their Derivatives)

Review

Jump to: Research

Open AccessReview Fluorescent Probes for Nucleic Acid Visualization in Fixed and Live Cells
Molecules 2013, 18(12), 15357-15397; doi:10.3390/molecules181215357
Received: 23 September 2013 / Revised: 20 November 2013 / Accepted: 5 December 2013 / Published: 11 December 2013
Cited by 30 | PDF Full-text (1305 KB) | HTML Full-text | XML Full-text
Abstract
This review analyses the literature concerning non-fluorescent and fluorescent probes for nucleic acid imaging in fixed and living cells from the point of view of their suitability for imaging intracellular native RNA and DNA. Attention is mainly paid to fluorescent probes for fluorescence
[...] Read more.
This review analyses the literature concerning non-fluorescent and fluorescent probes for nucleic acid imaging in fixed and living cells from the point of view of their suitability for imaging intracellular native RNA and DNA. Attention is mainly paid to fluorescent probes for fluorescence microscopy imaging. Requirements for the target-binding part and the fluorophore making up the probe are formulated. In the case of native double-stranded DNA, structure-specific and sequence-specific probes are discussed. Among the latest, three classes of dsDNA-targeting molecules are described: (i) sequence-specific peptides and proteins; (ii) triplex-forming oligonucleotides and (iii) polyamide oligo(N-methylpyrrole/N-methylimidazole) minor groove binders. Polyamides seem to be the most promising targeting agents for fluorescent probe design, however, some technical problems remain to be solved, such as the relatively low sequence specificity and the high background fluorescence inside the cells. Several examples of fluorescent probe applications for DNA imaging in fixed and living cells are cited. In the case of intracellular RNA, only modified oligonucleotides can provide such sequence-specific imaging. Several approaches for designing fluorescent probes are considered: linear fluorescent probes based on modified oligonucleotide analogs, molecular beacons, binary fluorescent probes and template-directed reactions with fluorescence probe formation, FRET donor-acceptor pairs, pyrene excimers, aptamers and others. The suitability of all these methods for living cell applications is discussed. Full article
(This article belongs to the Special Issue Synthesis of Nucleosides, Nucleotides and Their Derivatives)
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Open AccessReview General Approach for Introduction of Various Chemical Labels in Specific RNA Locations Based on Insertion of Amino Linkers
Molecules 2013, 18(12), 14455-14469; doi:10.3390/molecules181214455
Received: 8 October 2013 / Revised: 12 November 2013 / Accepted: 18 November 2013 / Published: 25 November 2013
Cited by 5 | PDF Full-text (1331 KB) | HTML Full-text | XML Full-text
Abstract
Introduction of reporter groups at designed RNA sites is a widely accepted approach to gain information about the molecular environment of RNAs in their complexes with other biopolymers formed during various cellular processes. A general approach to obtain RNAs bearing diverse reporter groups
[...] Read more.
Introduction of reporter groups at designed RNA sites is a widely accepted approach to gain information about the molecular environment of RNAs in their complexes with other biopolymers formed during various cellular processes. A general approach to obtain RNAs bearing diverse reporter groups at designed locations is based on site-specific insertion of groups containing primary aliphatic amine functions (amino linkers) with their subsequent selective derivatization by appropriate chemicals. This article is a brief review on methods for site-specific introduction of amino linkers in different RNAs. These methods comprise: (i) incorporation of a nucleoside carrying an amino-linker or a function that can be substituted with it into oligoribonucleotides in the course of their chemical synthesis; (ii) assembly of amino linker-containing RNAs from short synthetic fragments via their ligation; (iii) synthesis of amino linker-modified RNAs using T7 RNA polymerase; (iv) insertion of amino linkers into unmodified RNAs at functional groups of a certain type such as the 5'-phosphates and N7 of guanosine residues and (v) introduction of an amino linker into long highly structured RNAs exploiting an approach based on sequence-specific modification of nucleic acids. Particular reporter groups used for derivatization of amino linker-containing RNAs together with types of RNA derivatives obtained and fields of their application are presented. Full article
(This article belongs to the Special Issue Synthesis of Nucleosides, Nucleotides and Their Derivatives)

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