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Advances in Nucleoside/Nucleotides and Nucleic Acid Chemistry: A Theme Issue in Honor of Prof. Dr. Piet Herdewijn

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

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 83707

Special Issue Editor

Prof. Dr. Katherine Seley-Radtke

E-Mail Website
Guest Editor
Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore, MD, USA
Interests: nucleos(t)ides; heterocycles; drug design; enzyme inhibitors; antiviral
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Professor Piet Herdewijn (born, Aalst, Belgium, 1954) holds a PhD from KU Leuven working on the synthesis of carbocyclic beta-lactam antibiotics (1981) and a habilitation working on nucleoside analogues as anti-HIV agents. He worked as a fellow of the A von Humboldt foundation at the University of Konstanz, Germany, with Professor W. Pfleiderer on the synthesis of modified oligonucleotides. He then became an Associate Professor at the University of Ghent (Belgium) and the University of Evry-Val-d’Essone (France). He was later promoted to Full Professor at KU Leuven in 1993 and Emeritus Professor in 2019. Professor Herdewijn served as Director of the Laboratory of Medicinal Chemistry at the Rega Institute and is also a member of the Royal Academy of Medicine, Belgium. Professor Herdewijn has mentored 200 PhD and Postdoctoral students in his laboratory and has published over 730 articles.

Professor Herdewijn has made extensive contributions to bioorganic and medicinal chemistry, in particular in the field of nucleosides, nucleotides, and nucleic acids. In that regard, he was one of the founders of the International Society for Nucleosides, Nucleotides, and Nucleic Acids (IS3NA) and continues to play a major role in the Society even today. He developed numerous synthetic methods and schemes to make synthetically challenging nucleoside analogues more readily available. His main focus in medicinal chemistry has been towards developing inhibitors for infectious diseases (antivirals, antibiotics) as well as immunology. He was a pioneer in the development of anti-HIV nucleosides but also contributed to research on anti-HSV, anti-HBV, and anti-HCV compounds with different modes of actions. In immunology, he worked on the problem of immunotolerance. He has contributed fundamentally to research on backbone modified nucleic acids, design, synthesis, structural research and applications, such as HNA and ZNA. He is also a pioneer in chemical synthetic biology, by in vivo implementation of artificial nucleic acids and genes.

It is with this in mind that we honor him on the occasion of his retirement for his outstanding achievements in the areas of nucleoside/tide and nucleic acid chemistry, medicinal chemistry, and immunology, as well as his critical role in advancing the field. He remains an inspiration to all and we are pleased to invite you to submit a publication for this Special Issue.

Prof. Katherine Seley-Radtke
Guest Editor

Manuscript Submission Information

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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 semimonthly 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 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

  • Nucleosides
  • Nucleotides
  • Nucleic acids
  • Immunology
  • Medicinal chemistry
  • Antiviral
  • Anticancer
  • Antibiotics
  • siRNA
  • Enzyme inhibition
  • Biological activity
  • Synthesis

Published Papers (24 papers)

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19 pages, 2887 KiB  
Article
Synthesis and Antiviral Activity of a Series of 2′-C-Methyl-4′-thionucleoside Monophosphate Prodrugs
by Zackery W. Dentmon, Thomas M. Kaiser and Dennis C. Liotta
Molecules 2020, 25(21), 5165; https://doi.org/10.3390/molecules25215165 - 06 Nov 2020
Cited by 8 | Viewed by 3037
Abstract
The NS5B RNA-dependent RNA polymerase of the hepatitis C virus (HCV) is a validated target for nucleoside antiviral drug therapy. We endeavored to synthesize and test a series of 4′-thionucleosides with a monophosphate prodrug moiety for their antiviral activity against HCV and other [...] Read more.
The NS5B RNA-dependent RNA polymerase of the hepatitis C virus (HCV) is a validated target for nucleoside antiviral drug therapy. We endeavored to synthesize and test a series of 4′-thionucleosides with a monophosphate prodrug moiety for their antiviral activity against HCV and other related viruses in the Flaviviridae family. Nucleoside analogs were prepared via the stereoselective Vorbrüggen glycosylation of various nucleobases with per-acetylated 2-C-methyl-4-thio-d-ribose built in a 10-step synthetic sequence from the corresponding ribonolactone. Conjugation of the thionucleoside to a ProTide phosphoramidate allowed for evaluation of the prodrugs in the cellular HCV replicon assay with anti-HCV activities ranging from single-digit micromolar (μM) to >200 μM. The diminished anti-HCV potency of our best compound compared to its 4′-oxo congener is the subject of ongoing research in our lab and is proposed to stem from changes in sugar geometry imparted by the larger sulfur atom. Full article
(This article belongs to the Special Issue Advances in Nucleoside/Nucleotides and Nucleic Acid Chemistry: A Theme Issue in Honor of Prof. Dr. Piet Herdewijn)
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12 pages, 2048 KiB  
Article
Effects of Modifying Thioflavin T at the N3-Position on Its G4 Binding and Fluorescence Emission
by Yuka Kataoka, Hiroto Fujita, Tamaki Endoh, Naoki Sugimoto and Masayasu Kuwahara
Molecules 2020, 25(21), 4936; https://doi.org/10.3390/molecules25214936 - 26 Oct 2020
Cited by 5 | Viewed by 2219
Abstract
We previously synthesized thioflavin T (ThT) with a hydroxyethyl group introduced at the N3-position (ThT-HE), which binds predominantly to the parallel G-quadruplex (G4) structure found in c-Myc and emits strong fluorescence. In this study, to investigate the effects of introduced substituents [...] Read more.
We previously synthesized thioflavin T (ThT) with a hydroxyethyl group introduced at the N3-position (ThT-HE), which binds predominantly to the parallel G-quadruplex (G4) structure found in c-Myc and emits strong fluorescence. In this study, to investigate the effects of introduced substituents on G4 binding and fluorescence emission, a ThT derivative in which the hydroxyl group of ThT-HE was replaced with an amino group (ThT-AE) was synthesized for the first time. Furthermore, three other N3-modified ThT derivatives (ThT-OE2, ThT-SP, and ThT-OE11) having different substituent structures were synthesized by the N-acylation of the terminal amino group of ThT-AE, and their G4-binding and emission properties were investigated. The results showed that, although ThT-AE shows binding selectivity depending on the type of G4, its emission intensity is significantly decreased as compared to that of ThT-HE. However, ThT-OE11, which features an 11-unit oxyethylene chain attached to the terminal amino group of ThT-AE, regained about one-half of the emission intensity of ThT-HE while retaining selectivity for G4s. Accordingly, ThT-OE11 may be used as a key intermediate for synthesizing the conjugates of G4 binders and probes. Full article
(This article belongs to the Special Issue Advances in Nucleoside/Nucleotides and Nucleic Acid Chemistry: A Theme Issue in Honor of Prof. Dr. Piet Herdewijn)
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15 pages, 3514 KiB  
Article
New Chemical Probe Targeting Bacterial NAD Kinase
by David A. Clément, Clarisse Leseigneur, Muriel Gelin, Dylan Coelho, Valérie Huteau, Corinne Lionne, Gilles Labesse, Olivier Dussurget and Sylvie Pochet
Molecules 2020, 25(21), 4893; https://doi.org/10.3390/molecules25214893 - 22 Oct 2020
Cited by 2 | Viewed by 2575
Abstract
Nicotinamide adenine dinucleotide (NAD) kinases are essential and ubiquitous enzymes involved in the tight regulation of NAD/nicotinamide adenine dinucleotide phosphate (NADP) levels in many metabolic pathways. Consequently, they represent promising therapeutic targets in cancer and antibacterial treatments. We previously reported diadenosine derivatives as [...] Read more.
Nicotinamide adenine dinucleotide (NAD) kinases are essential and ubiquitous enzymes involved in the tight regulation of NAD/nicotinamide adenine dinucleotide phosphate (NADP) levels in many metabolic pathways. Consequently, they represent promising therapeutic targets in cancer and antibacterial treatments. We previously reported diadenosine derivatives as NAD kinase inhibitors with bactericidal activities on Staphylococcus aureus. Among them, one compound (namely NKI1) was found effective in vivo in a mouse infection model. With the aim to gain detailed knowledge about the selectivity and mechanism of action of this lead compound, we planned to develop a chemical probe that could be used in affinity-based chemoproteomic approaches. Here, we describe the first functionalized chemical probe targeting a bacterial NAD kinase. Aminoalkyl functional groups were introduced on NKI1 for further covalent coupling to an activated SepharoseTM matrix. Inhibitory properties of functionalized NKI1 derivatives together with X-ray characterization of their complexes with the NAD kinase led to identify candidate compounds that are amenable to covalent coupling to a matrix. Full article
(This article belongs to the Special Issue Advances in Nucleoside/Nucleotides and Nucleic Acid Chemistry: A Theme Issue in Honor of Prof. Dr. Piet Herdewijn)
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16 pages, 2605 KiB  
Article
Structure of a DNA G-Quadruplex Related to Osteoporosis with a G-A Bulge Forming a Pseudo-loop
by Martina Lenarčič Živković, Jan Rozman and Janez Plavec
Molecules 2020, 25(20), 4867; https://doi.org/10.3390/molecules25204867 - 21 Oct 2020
Cited by 4 | Viewed by 3080
Abstract
Bone remodeling is a fine-tuned process principally regulated by a cascade triggered by interaction of receptor activator of NF-κB (RANK) and RANK ligand (RANKL). Excessive activity of the RANKL gene leads to increased bone resorption and can influence the incidence of osteoporosis. Although [...] Read more.
Bone remodeling is a fine-tuned process principally regulated by a cascade triggered by interaction of receptor activator of NF-κB (RANK) and RANK ligand (RANKL). Excessive activity of the RANKL gene leads to increased bone resorption and can influence the incidence of osteoporosis. Although much has been learned about the intracellular signals activated by RANKL/RANK complex, significantly less is known about the molecular mechanisms of regulation of RANKL expression. Here, we report on the structure of an unprecedented DNA G-quadruplex, well-known secondary structure-mediated gene expression regulator, formed by a G-rich sequence found in the regulatory region of a RANKL gene. Solution-state NMR structural study reveals the formation of a three-layered parallel-type G-quadruplex characterized by an unique features, including a G-A bulge. Although a guanine within a G-tract occupies syn glycosidic conformation, bulge-forming residues arrange in a pseudo-loop conformation to facilitate partial 5/6-ring stacking, typical of G-quadruplex structures with parallel G-tracts orientation. Such distinctive structural features protruding from the core of the structure can represent a novel platform for design of highly specific ligands with anti-osteoporotic function. Additionally, our study suggests that the expression of RANKL gene may be regulated by putative folding of its G-rich region into non-B-DNA structure(s). Full article
(This article belongs to the Special Issue Advances in Nucleoside/Nucleotides and Nucleic Acid Chemistry: A Theme Issue in Honor of Prof. Dr. Piet Herdewijn)
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19 pages, 1570 KiB  
Article
Novel Nucleoside Analogues as Effective Antiviral Agents for Zika Virus Infections
by Marcella Bassetto, Cecilia M. Cima, Mattia Basso, Martina Salerno, Frank Schwarze, Daniela Friese, Joachim J. Bugert and Andrea Brancale
Molecules 2020, 25(20), 4813; https://doi.org/10.3390/molecules25204813 - 20 Oct 2020
Cited by 8 | Viewed by 3173
Abstract
Previously considered a neglected flavivirus, Zika virus has recently emerged as a public health concern due to its ability to spread rapidly and cause severe neurological disorders, such as microcephaly in newborn babies from infected mothers, and Guillain-Barré syndrome in adults. Despite [...] Read more.
Previously considered a neglected flavivirus, Zika virus has recently emerged as a public health concern due to its ability to spread rapidly and cause severe neurological disorders, such as microcephaly in newborn babies from infected mothers, and Guillain-Barré syndrome in adults. Despite extensive efforts towards the identification of effective therapies, specific antivirals are still not available. As part of ongoing medicinal chemistry studies to identify new antiviral agents, we screened against Zika virus replication in vitro in a targeted internal library of small-molecule agents, comprising both nucleoside and non-nucleoside agents. Among the compounds evaluated, novel aryloxyphosphoramidate prodrugs of the nucleosides 2′-C-methyl-adenosine, 2-CMA, and 7-deaza-2′C-methyl-adenosine, 7-DMA, were found to significantly inhibit the virus-induced cytopathic effect in multiple relevant cell lines. In addition, one of these prodrugs exhibits a synergistic antiviral effect against Zika virus when applied in combination with an indirect antiviral agent, a l-dideoxy bicyclic pyrimidine nucleoside analogue, which potently inhibits vaccinia and measles viruses in vitro by targeting a host pathway. Our findings provide a solid basis for further development of an antiviral therapy for Zika virus infections, possibly exploiting a dual approach combining two different agents, one targeting the viral polymerase (direct-acting antiviral), the second targeting a host-directed autophagy mechanism. Full article
(This article belongs to the Special Issue Advances in Nucleoside/Nucleotides and Nucleic Acid Chemistry: A Theme Issue in Honor of Prof. Dr. Piet Herdewijn)
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24 pages, 4950 KiB  
Article
Synthesis and Biological Evaluation of 1,3-Dideazapurine-Like 7-Amino-5-Hydroxymethyl-Benzimidazole Ribonucleoside Analogues as Aminoacyl-tRNA Synthetase Inhibitors
by Baole Zhang, Luping Pang, Manesh Nautiyal, Steff De Graef, Bharat Gadakh, Eveline Lescrinier, Jef Rozenski, Sergei V. Strelkov, Stephen D. Weeks and Arthur Van Aerschot
Molecules 2020, 25(20), 4751; https://doi.org/10.3390/molecules25204751 - 16 Oct 2020
Cited by 2 | Viewed by 2648
Abstract
Aminoacyl-tRNA synthetases (aaRSs) have become viable targets for the development of antimicrobial agents due to their crucial role in protein translation. A series of six amino acids were coupled to the purine-like 7-amino-5-hydroxymethylbenzimidazole nucleoside analogue following an optimized synthetic pathway. These compounds were [...] Read more.
Aminoacyl-tRNA synthetases (aaRSs) have become viable targets for the development of antimicrobial agents due to their crucial role in protein translation. A series of six amino acids were coupled to the purine-like 7-amino-5-hydroxymethylbenzimidazole nucleoside analogue following an optimized synthetic pathway. These compounds were designed as aaRS inhibitors and can be considered as 1,3-dideazaadenine analogues carrying a 2-hydroxymethyl substituent. Despite our intentions to obtain N1-glycosylated 4-aminobenzimidazole congeners, resembling the natural purine nucleosides glycosylated at the N9-position, we obtained the N3-glycosylated benzimidazole derivatives as the major products, resembling the respective purine N7-glycosylated nucleosides. A series of X-ray crystal structures of class I and II aaRSs in complex with newly synthesized compounds revealed interesting interactions of these “base-flipped” analogues with their targets. While the exocyclic amine of the flipped base mimics the reciprocal interaction of the N3-purine atom of aminoacyl-sulfamoyl adenosine (aaSA) congeners, the hydroxymethyl substituent of the flipped base apparently loses part of the standard interactions of the adenine N1 and the N6-amine as seen with aaSA analogues. Upon the evaluation of the inhibitory potency of the newly obtained analogues, nanomolar inhibitory activities were noted for the leucine and isoleucine analogues targeting class I aaRS enzymes, while rather weak inhibitory activity against the corresponding class II aaRSs was observed. This class bias could be further explained by detailed structural analysis. Full article
(This article belongs to the Special Issue Advances in Nucleoside/Nucleotides and Nucleic Acid Chemistry: A Theme Issue in Honor of Prof. Dr. Piet Herdewijn)
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13 pages, 1408 KiB  
Article
Synthesis of New Imidazopyridine Nucleoside Derivatives Designed as Maribavir Analogues
by Georgios Papadakis, Maria Gerasi, Robert Snoeck, Panagiotis Marakos, Graciela Andrei, Nikolaos Lougiakis and Nicole Pouli
Molecules 2020, 25(19), 4531; https://doi.org/10.3390/molecules25194531 - 03 Oct 2020
Cited by 6 | Viewed by 3844
Abstract
The strong inhibition of Human Cytomegalovirus (HCMV) replication by benzimidazole nucleosides, like Triciribine and Maribavir, has prompted us to expand the structure–activity relationships of the benzimidazole series, using as a central core the imidazo[4,5-b]pyridine scaffold. We have thus synthesized a number of novel [...] Read more.
The strong inhibition of Human Cytomegalovirus (HCMV) replication by benzimidazole nucleosides, like Triciribine and Maribavir, has prompted us to expand the structure–activity relationships of the benzimidazole series, using as a central core the imidazo[4,5-b]pyridine scaffold. We have thus synthesized a number of novel amino substituted imidazopyridine nucleoside derivatives, which can be considered as 4-(or 7)-aza-d-isosters of Maribavir and have evaluated their potential antiviral activity. The target compounds were synthesized upon glycosylation of suitably substituted 2-aminoimidazopyridines, which were prepared in six steps starting from 2-amino-6-chloropyridine. Even if the new compounds possessed only a slight structural modification when compared to the original drug, they were not endowed with interesting antiviral activity. Even so, three derivatives showed promising cytotoxic potential. Full article
(This article belongs to the Special Issue Advances in Nucleoside/Nucleotides and Nucleic Acid Chemistry: A Theme Issue in Honor of Prof. Dr. Piet Herdewijn)
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23 pages, 1871 KiB  
Article
Efficient Synthesis of α-Branched Purine-Based Acyclic Nucleosides: Scopes and Limitations of the Method
by Jan Frydrych, Lenka Poštová Slavětínská, Martin Dračínský and Zlatko Janeba
Molecules 2020, 25(18), 4307; https://doi.org/10.3390/molecules25184307 - 19 Sep 2020
Cited by 4 | Viewed by 3567
Abstract
An efficient route to acylated acyclic nucleosides containing a branched hemiaminal ether moiety is reported via three-component alkylation of N-heterocycle (purine nucleobase) with acetal (cyclic or acyclic, variously branched) and anhydride (preferentially acetic anhydride). The procedure employs cheap and easily available acetals, [...] Read more.
An efficient route to acylated acyclic nucleosides containing a branched hemiaminal ether moiety is reported via three-component alkylation of N-heterocycle (purine nucleobase) with acetal (cyclic or acyclic, variously branched) and anhydride (preferentially acetic anhydride). The procedure employs cheap and easily available acetals, acetic anhydride, and trimethylsilyl trifluoromethanesulfonate (TMSOTf). The multi-component reaction is carried out in acetonitrile at room temperature for 15 min and provides moderate to high yields (up to 88%) of diverse acyclonucleosides branched at the aliphatic side chain. The procedure exhibits a broad substrate scope of N-heterocycles and acetals, and, in the case of purine derivatives, also excellent regioselectivity, giving almost exclusively N-9 isomers. Full article
(This article belongs to the Special Issue Advances in Nucleoside/Nucleotides and Nucleic Acid Chemistry: A Theme Issue in Honor of Prof. Dr. Piet Herdewijn)
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11 pages, 2938 KiB  
Article
In Vitro Selection of an ATP-Binding TNA Aptamer
by Li Zhang and John C. Chaput
Molecules 2020, 25(18), 4194; https://doi.org/10.3390/molecules25184194 - 13 Sep 2020
Cited by 18 | Viewed by 3814
Abstract
Recent advances in polymerase engineering have made it possible to isolate aptamers from libraries of synthetic genetic polymers (XNAs) with backbone structures that are distinct from those found in nature. However, nearly all of the XNA aptamers produced thus far have been generated [...] Read more.
Recent advances in polymerase engineering have made it possible to isolate aptamers from libraries of synthetic genetic polymers (XNAs) with backbone structures that are distinct from those found in nature. However, nearly all of the XNA aptamers produced thus far have been generated against protein targets, raising significant questions about the ability of XNA aptamers to recognize small molecule targets. Here, we report the evolution of an ATP-binding aptamer composed entirely of α-L-threose nucleic acid (TNA). A chemically synthesized version of the best aptamer sequence shows high affinity to ATP and strong specificity against other naturally occurring ribonucleotide triphosphates. Unlike its DNA and RNA counterparts that are susceptible to nuclease digestion, the ATP-binding TNA aptamer exhibits high biological stability against hydrolytic enzymes that rapidly degrade DNA and RNA. Based on these findings, we suggest that TNA aptamers could find widespread use as molecular recognition elements in diagnostic and therapeutic applications that require high biological stability. Full article
(This article belongs to the Special Issue Advances in Nucleoside/Nucleotides and Nucleic Acid Chemistry: A Theme Issue in Honor of Prof. Dr. Piet Herdewijn)
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11 pages, 2000 KiB  
Article
Effect of Molecular Crowding on DNA Polymerase Reactions along Unnatural DNA Templates
by Shuntaro Takahashi, Piet Herdwijn and Naoki Sugimoto
Molecules 2020, 25(18), 4120; https://doi.org/10.3390/molecules25184120 - 10 Sep 2020
Cited by 3 | Viewed by 2573
Abstract
Unnatural nucleic acids are promising materials to expand genetic information beyond the natural bases. During replication, substrate nucleotide incorporation should be strictly controlled for optimal base pairing with template strand bases. Base-pairing interactions occur via hydrogen bonding and base stacking, which could be [...] Read more.
Unnatural nucleic acids are promising materials to expand genetic information beyond the natural bases. During replication, substrate nucleotide incorporation should be strictly controlled for optimal base pairing with template strand bases. Base-pairing interactions occur via hydrogen bonding and base stacking, which could be perturbed by the chemical environment. Although unnatural nucleobases and sugar moieties have undergone extensive structural improvement for intended polymerization, the chemical environmental effect on the reaction is less understood. In this study, we investigated how molecular crowding could affect native DNA polymerization along various templates comprising unnatural nucleobases and sugars. Under non-crowding conditions, the preferred incorporation efficiency of pyrimidine deoxynucleotide triphosphates (dNTPs) by the Klenow fragment (KF) was generally high with low fidelity, whereas that of purine dNTPs was the opposite. However, under crowding conditions, the efficiency remained almost unchanged with varying preferences in each case. These results suggest that hydrogen bonding and base-stacking interactions could be perturbed by crowding conditions in the bulk solution and polymerase active center during transient base pairing before polymerization. This study highlights that unintended dNTP incorporation against unnatural nucleosides could be differentiated in cases of intracellular reactions. Full article
(This article belongs to the Special Issue Advances in Nucleoside/Nucleotides and Nucleic Acid Chemistry: A Theme Issue in Honor of Prof. Dr. Piet Herdewijn)
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5 pages, 1690 KiB  
Communication
5′-Nor-3-Deaza-1′,6′-Isoneplanocin, the Synthesis and Antiviral Study
by Qi Chen, Stewart W. Schneller, Chong Liu, Kathryn L. Jones and Tyler Singer
Molecules 2020, 25(17), 3865; https://doi.org/10.3390/molecules25173865 - 25 Aug 2020
Cited by 1 | Viewed by 2270
Abstract
The arbocyclic nucleosides aristeromycin and neplanocin have been studied as a source for new antiviral agents. A convenient synthesis of C-5′-truncated 3-deaza-1′,6′-isoneplanocin, which combines the features of antiviral candidates 5′-noraristeromycin and 3-deaza-1′,6′-isoneplanocin is reported from (−)-cyclopentenone to give the two C-4′ epimers of [...] Read more.
The arbocyclic nucleosides aristeromycin and neplanocin have been studied as a source for new antiviral agents. A convenient synthesis of C-5′-truncated 3-deaza-1′,6′-isoneplanocin, which combines the features of antiviral candidates 5′-noraristeromycin and 3-deaza-1′,6′-isoneplanocin is reported from (−)-cyclopentenone to give the two C-4′ epimers of 5′-nor-3-deaza isoneplanocin. Antiviral assays showed activity against the JC virus (EC50 = 1.12 µM for (4′R)-8; EC50 = 59.14 µM for (4′S)-7) and inactivity of both compounds against several DNA and RNA viruses. Both compounds lacked cytotoxicity. Full article
(This article belongs to the Special Issue Advances in Nucleoside/Nucleotides and Nucleic Acid Chemistry: A Theme Issue in Honor of Prof. Dr. Piet Herdewijn)
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9 pages, 1070 KiB  
Article
Synthesis and Antiviral Evaluation of 3′-Fluoro-5′-norcarbocyclic Nucleoside Phosphonates Bearing Uracil and Cytosine as Potential Antiviral Agents
by Pierre-Yves Geant, Jean-Pierre Uttaro, Christian Périgaud and Christophe Mathé
Molecules 2020, 25(16), 3708; https://doi.org/10.3390/molecules25163708 - 14 Aug 2020
Cited by 3 | Viewed by 2061
Abstract
Carbocyclic nucleoside analogues are an essential class of antiviral agents and are commonly used in the treatment of viral diseases (hepatitis B, AIDS). Recently, we reported the racemic synthesis and the anti-human immunodeficiency virus activities (HIV) of 3′-fluoro-5′-norcarbocyclic nucleoside phosphonates bearing purines as [...] Read more.
Carbocyclic nucleoside analogues are an essential class of antiviral agents and are commonly used in the treatment of viral diseases (hepatitis B, AIDS). Recently, we reported the racemic synthesis and the anti-human immunodeficiency virus activities (HIV) of 3′-fluoro-5′-norcarbocyclic nucleoside phosphonates bearing purines as heterocyclic base. Based on these results, the corresponding racemic norcarbocyclic nucleoside phosphonates bearing pyrimidine bases were synthesized. The prepared compounds were evaluated against HIV, but none of them showed marked antiviral activity compared to their purine counterparts. Full article
(This article belongs to the Special Issue Advances in Nucleoside/Nucleotides and Nucleic Acid Chemistry: A Theme Issue in Honor of Prof. Dr. Piet Herdewijn)
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13 pages, 8467 KiB  
Article
Inhibition of Tyrosyl-DNA Phosphodiesterase 1 by Lipophilic Pyrimidine Nucleosides
by Alexandra L. Zakharenko, Mikhail S. Drenichev, Nadezhda S. Dyrkheeva, Georgy A. Ivanov, Vladimir E. Oslovsky, Ekaterina S. Ilina, Irina A. Chernyshova, Olga I. Lavrik and Sergey N. Mikhailov
Molecules 2020, 25(16), 3694; https://doi.org/10.3390/molecules25163694 - 13 Aug 2020
Cited by 7 | Viewed by 2065
Abstract
Inhibition of DNA repair enzymes tyrosyl-DNA phosphodiesterase 1 and poly(ADP-ribose)polymerases 1 and 2 in the presence of pyrimidine nucleoside derivatives was studied here. New effective Tdp1 inhibitors were found in a series of nucleoside derivatives possessing 2′,3′,5′-tri-O-benzoyl-d-ribofuranose and 5-substituted [...] Read more.
Inhibition of DNA repair enzymes tyrosyl-DNA phosphodiesterase 1 and poly(ADP-ribose)polymerases 1 and 2 in the presence of pyrimidine nucleoside derivatives was studied here. New effective Tdp1 inhibitors were found in a series of nucleoside derivatives possessing 2′,3′,5′-tri-O-benzoyl-d-ribofuranose and 5-substituted uracil moieties and have half-maximal inhibitory concentrations (IC50) in the lower micromolar and submicromolar range. 2′,3′,5′-Tri-O-benzoyl-5-iodouridine manifested the strongest inhibitory effect on Tdp1 (IC50 = 0.6 μM). A decrease in the number of benzoic acid residues led to a marked decline in the inhibitory activity, and pyrimidine nucleosides lacking lipophilic groups (uridine, 5-fluorouridine, 5-chlorouridine, 5-bromouridine, 5-iodouridine, and ribothymidine) did not cause noticeable inhibition of Tdp1 (IC50 > 50 μM). No PARP1/2 inhibitors were found among the studied compounds (residual activity in the presence of 1 mM substances was 50–100%). Several O-benzoylated uridine and cytidine derivatives strengthened the action of topotecan on HeLa cervical cancer cells. Full article
(This article belongs to the Special Issue Advances in Nucleoside/Nucleotides and Nucleic Acid Chemistry: A Theme Issue in Honor of Prof. Dr. Piet Herdewijn)
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17 pages, 1243 KiB  
Article
Uracil-Containing Heterodimers of a New Type: Synthesis and Study of Their Anti-Viral Properties
by Anna A. Maslova, Elena S. Matyugina, Robert Snoeck, Graciela Andrei, Sergey N. Kochetkov, Anastasia L. Khandazhinskaya and Mikhail S. Novikov
Molecules 2020, 25(15), 3350; https://doi.org/10.3390/molecules25153350 - 23 Jul 2020
Cited by 6 | Viewed by 2115
Abstract
Widespread latent herpes viral infections within a population can lead to the development of co-infections in HIV-infected patients. These infections are not particularly dangerous for healthy individuals and often occur with minimal symptoms, but for those who are immunocompromised, these infections can accelerate [...] Read more.
Widespread latent herpes viral infections within a population can lead to the development of co-infections in HIV-infected patients. These infections are not particularly dangerous for healthy individuals and often occur with minimal symptoms, but for those who are immunocompromised, these infections can accelerate the acute phase of HIV infection and AIDS. Thus, the idea of designing compounds that could combine activity against HIV and co-infections would seem promising. In that regard, eleven compounds were synthesized that represent conjugates of non-nucleoside HIV reverse transcriptase inhibitors and nucleoside inhibitors of the herpes family viruses with the hope that these novel heterodimers will result in dual activity against HIV and concomitant herpes virus infections. Full article
(This article belongs to the Special Issue Advances in Nucleoside/Nucleotides and Nucleic Acid Chemistry: A Theme Issue in Honor of Prof. Dr. Piet Herdewijn)
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19 pages, 2991 KiB  
Article
Synthesis of Triazole-Linked SAM-Adenosine Conjugates: Functionalization of Adenosine at N-1 or N-6 Position without Protecting Groups
by Colette Atdjian, Dylan Coelho, Laura Iannazzo, Mélanie Ethève-Quelquejeu and Emmanuelle Braud
Molecules 2020, 25(14), 3241; https://doi.org/10.3390/molecules25143241 - 16 Jul 2020
Cited by 9 | Viewed by 3498
Abstract
More than 150 RNA chemical modifications have been identified to date. Among them, methylation of adenosine at the N-6 position (m6A) is crucial for RNA metabolism, stability and other important biological events. In particular, this is the most abundant mark found [...] Read more.
More than 150 RNA chemical modifications have been identified to date. Among them, methylation of adenosine at the N-6 position (m6A) is crucial for RNA metabolism, stability and other important biological events. In particular, this is the most abundant mark found in mRNA in mammalian cells. The presence of a methyl group at the N-1 position of adenosine (m1A) is mostly found in ncRNA and mRNA and is mainly responsible for stability and translation fidelity. These modifications are installed by m6A and m1A RNA methyltransferases (RNA MTases), respectively. In human, deregulation of m6A RNA MTases activity is associated with many diseases including cancer. To date, the molecular mechanism involved in the methyl transfer, in particular substrate recognition, remains unclear. We report the synthesis of new SAM-adenosine conjugates containing a triazole linker branched at the N-1 or N-6 position of adenosine. Our methodology does not require protecting groups for the functionalization of adenosine at these two positions. The molecules described here were designed as potential bisubstrate analogues for m6A and m1A RNA MTases that could be further employed for structural studies. This is the first report of compounds mimicking the transition state of the methylation reaction catalyzed by m1A RNA MTases. Full article
(This article belongs to the Special Issue Advances in Nucleoside/Nucleotides and Nucleic Acid Chemistry: A Theme Issue in Honor of Prof. Dr. Piet Herdewijn)
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15 pages, 2599 KiB  
Article
Conjugation of Doxorubicin to siRNA Through Disulfide-based Self-immolative Linkers
by Florian Gauthier, Jean-Rémi Bertrand, Jean-Jacques Vasseur, Christelle Dupouy and Françoise Debart
Molecules 2020, 25(11), 2714; https://doi.org/10.3390/molecules25112714 - 11 Jun 2020
Cited by 16 | Viewed by 4663
Abstract
Co-delivery systems of siRNA and chemotherapeutic drugs have been developed as an attractive strategy to optimize the efficacy of chemotherapy towards cancer cells with multidrug resistance. In these typical systems, siRNAs are usually associated to drugs within a carrier but without covalent interactions [...] Read more.
Co-delivery systems of siRNA and chemotherapeutic drugs have been developed as an attractive strategy to optimize the efficacy of chemotherapy towards cancer cells with multidrug resistance. In these typical systems, siRNAs are usually associated to drugs within a carrier but without covalent interactions with the risk of a premature release and degradation of the drugs inside the cells. To address this issue, we propose a covalent approach to co-deliver a siRNA-drug conjugate with a redox-responsive self-immolative linker prone to intracellular glutathione-mediated disulfide cleavage. Herein, we report the use of two disulfide bonds connected by a pentane spacer or a p-xylene spacer as self-immolative linker between the primary amine of the anticancer drug doxorubicin (Dox) and the 2′-position of one or two ribonucleotides in RNA. Five Dox-RNA conjugates were successfully synthesized using two successive thiol-disulfide exchange reactions. The Dox-RNA conjugates were annealed with their complementary strands and the duplexes were shown to form an A-helix sufficiently stable under physiological conditions. The enzymatic stability of Dox-siRNAs in human serum was enhanced compared to the unmodified siRNA, especially when two Dox are attached to siRNA. The release of native Dox and RNA from the bioconjugate was demonstrated under reducing conditions suggesting efficient linker disintegration. These results demonstrate the feasibility of making siRNA-drug conjugates via disulfide-based self-immolative linkers for potential therapeutic applications. Full article
(This article belongs to the Special Issue Advances in Nucleoside/Nucleotides and Nucleic Acid Chemistry: A Theme Issue in Honor of Prof. Dr. Piet Herdewijn)
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23 pages, 2344 KiB  
Article
Model Substrate/Inactivation Reactions for MoaA and Ribonucleotide Reductases: Loss of Bromo, Chloro, or Tosylate Groups from C2 of 1,5-Dideoxyhomoribofuranoses upon Generation of an α-Oxy Radical at C3
by Stanislaw F. Wnuk, Mukesh M. Mudgal, Ireneusz Nowak and Morris J. Robins
Molecules 2020, 25(11), 2539; https://doi.org/10.3390/molecules25112539 - 29 May 2020
Cited by 1 | Viewed by 2530
Abstract
We report studies on radical-initiated fragmentations of model 1,5-dideoxyhomoribofuranose derivatives with bromo, chloro, and tosyloxy substituents on C2. The effects of stereochemical inversion at C2 were probed with the corresponding arabino epimers. In all cases, the elimination of bromide, chloride, and tosylate anions [...] Read more.
We report studies on radical-initiated fragmentations of model 1,5-dideoxyhomoribofuranose derivatives with bromo, chloro, and tosyloxy substituents on C2. The effects of stereochemical inversion at C2 were probed with the corresponding arabino epimers. In all cases, the elimination of bromide, chloride, and tosylate anions occurred when the 3-hydroxyl group was unprotected. The isolation of deuterium-labeled furanone products established heterolytic cleavage followed by the transfer of deuterium from labeled tributylstannane. In contrast, 3-O-methyl derivatives underwent the elimination of bromine or chlorine radicals to give the 2,3-alkene with no incorporation of label in the methyl vinyl ether. More drastic fragmentation occurred with both of the 3-O-methyl-2-tosyloxy epimers to give an aromatized furan derivative with no deuterium label. Contrasting results observed with the present anhydroalditol models relative to our prior studies with analogously substituted nucleoside models have demonstrated that insights from biomimetic chemical reactions can provide illumination of mechanistic pathways employed by ribonucleotide reductases (RNRs) and the MoaA enzyme involved in the biosynthesis of molybdopterin. Full article
(This article belongs to the Special Issue Advances in Nucleoside/Nucleotides and Nucleic Acid Chemistry: A Theme Issue in Honor of Prof. Dr. Piet Herdewijn)
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21 pages, 5874 KiB  
Article
Fluorescent Biaryl Uracils with C5-Dihydro- and Quinazolinone Heterocyclic Appendages in PNA
by Ali Heidari, Arash Ghorbani-Choghamarani, Maryam Hajjami and Robert H. E. Hudson
Molecules 2020, 25(8), 1995; https://doi.org/10.3390/molecules25081995 - 24 Apr 2020
Cited by 6 | Viewed by 3036
Abstract
There has been much effort to exploit fluorescence techniques in the detection of nucleic acids. Canonical nucleic acids are essentially nonfluorescent; however, the modification of the nucleobase has proved to be a fruitful way to engender fluorescence. Much of the chemistry used to [...] Read more.
There has been much effort to exploit fluorescence techniques in the detection of nucleic acids. Canonical nucleic acids are essentially nonfluorescent; however, the modification of the nucleobase has proved to be a fruitful way to engender fluorescence. Much of the chemistry used to prepare modified nucleobases relies on expensive transition metal catalysts. In this work, we describe the synthesis of biaryl quinazolinone-uracil nucleobase analogs prepared by the condensation of anthranilamide derivatives and 5-formyluracil using inexpensive copper salts. A selection of modified nucleobases were prepared, and the effect of methoxy- or nitro- group substitution on the photophysical properties was examined. Both the dihydroquinazolinone and quinazolinone modified uracils have much larger molar absorptivity (~4–8×) than natural uracil and produce modest blue fluorescence. The quinazolinone-modified uracils display higher quantum yields than the corresponding dihydroquinazolinones and also show temperature and viscosity dependent emission consistent with molecular rotor behavior. Peptide nucleic acid (PNA) monomers possessing quinazolinone modified uracils were prepared and incorporated into oligomers. In the sequence context examined, the nitro-substituted, methoxy-substituted and unmodified quinazolinone inserts resulted in a stabilization (∆Tm = +4.0/insert; +2.0/insert; +1.0/insert, respectively) relative to control PNA sequence upon hybridization to complementary DNA. All three derivatives responded to hybridization by the “turn-on” of fluorescence intensity by ca. 3-to-4 fold and may find use as probes for complementary DNA sequences. Full article
(This article belongs to the Special Issue Advances in Nucleoside/Nucleotides and Nucleic Acid Chemistry: A Theme Issue in Honor of Prof. Dr. Piet Herdewijn)
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13 pages, 1928 KiB  
Article
Synthesis of 4′-Substituted-2′-Deoxy-2′-α-Fluoro Nucleoside Analogs as Potential Antiviral Agents
by Mahesh Kasthuri, Chengwei Li, Kiran Verma, Olivia Ollinger Russell, Lyndsey Dickson, Louise McCormick, Leda Bassit, Franck Amblard and Raymond F. Schinazi
Molecules 2020, 25(6), 1258; https://doi.org/10.3390/molecules25061258 - 11 Mar 2020
Cited by 6 | Viewed by 3611
Abstract
Nucleoside analogs are widely used for the treatment of viral diseases (Hepatitis B/C, herpes and human immunodeficiency virus, HIV) and various malignancies. ALS-8176, a prodrug of the 4′-chloromethyl-2′-deoxy-2′-fluoro nucleoside ALS-8112, was evaluated in hospitalized infants for the treatment of respiratory syncytial virus (RSV), [...] Read more.
Nucleoside analogs are widely used for the treatment of viral diseases (Hepatitis B/C, herpes and human immunodeficiency virus, HIV) and various malignancies. ALS-8176, a prodrug of the 4′-chloromethyl-2′-deoxy-2′-fluoro nucleoside ALS-8112, was evaluated in hospitalized infants for the treatment of respiratory syncytial virus (RSV), but was abandoned for unclear reasons. Based on the structure of ALS-8112, a series of novel 4′-modified-2′-deoxy-2′-fluoro nucleosides were synthesized. Newly prepared compounds were evaluated against RSV, but also against a panel of RNA viruses, including Dengue, West Nile, Chikungunya, and Zika viruses. Unfortunately, none of the compounds showed marked antiviral activity against these viruses. Full article
(This article belongs to the Special Issue Advances in Nucleoside/Nucleotides and Nucleic Acid Chemistry: A Theme Issue in Honor of Prof. Dr. Piet Herdewijn)
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12 pages, 2421 KiB  
Article
Enhanced Hybridization Selectivity Using Structured GammaPNA Probes
by Taylor D. Canady, April S. Berlyoung, Joe A. Martinez, Cole Emanuelson, Cheryl A. Telmer, Marcel P. Bruchez and Bruce A. Armitage
Molecules 2020, 25(4), 970; https://doi.org/10.3390/molecules25040970 - 21 Feb 2020
Cited by 9 | Viewed by 2894
Abstract
High affinity nucleic acid analogues such as gammaPNA (γPNA) are capable of invading stable secondary and tertiary structures in DNA and RNA targets but are susceptible to off-target binding to mismatch-containing sequences. We introduced a hairpin secondary structure into a γPNA oligomer to [...] Read more.
High affinity nucleic acid analogues such as gammaPNA (γPNA) are capable of invading stable secondary and tertiary structures in DNA and RNA targets but are susceptible to off-target binding to mismatch-containing sequences. We introduced a hairpin secondary structure into a γPNA oligomer to enhance hybridization selectivity compared with a hairpin-free analogue. The hairpin structure features a five base PNA mask that covers the proximal five bases of the γPNA probe, leaving an additional five γPNA bases available as a toehold for target hybridization. Surface plasmon resonance experiments demonstrated that the hairpin probe exhibited slower on-rates and faster off-rates (i.e., lower affinity) compared with the linear probe but improved single mismatch discrimination by up to a factor of five, due primarily to slower on-rates for mismatch vs. perfect match targets. The ability to discriminate against single mismatches was also determined in a cell-free mRNA translation assay using a luciferase reporter gene, where the hairpin probe was two-fold more selective than the linear probe. These results validate the hairpin design and present a generalizable approach to improving hybridization selectivity. Full article
(This article belongs to the Special Issue Advances in Nucleoside/Nucleotides and Nucleic Acid Chemistry: A Theme Issue in Honor of Prof. Dr. Piet Herdewijn)
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Review

Jump to: Research

47 pages, 2493 KiB  
Review
Cellular Targeting of Oligonucleotides by Conjugation with Small Molecules
by Manuel Hawner and Christian Ducho
Molecules 2020, 25(24), 5963; https://doi.org/10.3390/molecules25245963 - 16 Dec 2020
Cited by 15 | Viewed by 6044
Abstract
Drug candidates derived from oligonucleotides (ON) are receiving increased attention that is supported by the clinical approval of several ON drugs. Such therapeutic ON are designed to alter the expression levels of specific disease-related proteins, e.g., by displaying antigene, antisense, and RNA interference [...] Read more.
Drug candidates derived from oligonucleotides (ON) are receiving increased attention that is supported by the clinical approval of several ON drugs. Such therapeutic ON are designed to alter the expression levels of specific disease-related proteins, e.g., by displaying antigene, antisense, and RNA interference mechanisms. However, the high polarity of the polyanionic ON and their relatively rapid nuclease-mediated cleavage represent two major pharmacokinetic hurdles for their application in vivo. This has led to a range of non-natural modifications of ON structures that are routinely applied in the design of therapeutic ON. The polyanionic architecture of ON often hampers their penetration of target cells or tissues, and ON usually show no inherent specificity for certain cell types. These limitations can be overcome by conjugation of ON with molecular entities mediating cellular ‘targeting’, i.e., enhanced accumulation at and/or penetration of a specific cell type. In this context, the use of small molecules as targeting units appears particularly attractive and promising. This review provides an overview of advances in the emerging field of cellular targeting of ON via their conjugation with small-molecule targeting structures. Full article
(This article belongs to the Special Issue Advances in Nucleoside/Nucleotides and Nucleic Acid Chemistry: A Theme Issue in Honor of Prof. Dr. Piet Herdewijn)
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18 pages, 2734 KiB  
Review
Synthetic Life with Alternative Nucleic Acids as Genetic Materials
by Peng Nie, Yanfen Bai and Hui Mei
Molecules 2020, 25(15), 3483; https://doi.org/10.3390/molecules25153483 - 31 Jul 2020
Cited by 21 | Viewed by 5281
Abstract
DNA, the fundamental genetic polymer of all living organisms on Earth, can be chemically modified to embrace novel functions that do not exist in nature. The key chemical and structural parameters for genetic information storage, heredity, and evolution have been elucidated, and many [...] Read more.
DNA, the fundamental genetic polymer of all living organisms on Earth, can be chemically modified to embrace novel functions that do not exist in nature. The key chemical and structural parameters for genetic information storage, heredity, and evolution have been elucidated, and many xenobiotic nucleic acids (XNAs) with non-canonical structures are developed as alternative genetic materials in vitro. However, it is still particularly challenging to replace DNAs with XNAs in living cells. This review outlines some recent studies in which the storage and propagation of genetic information are achieved in vivo by expanding genetic systems with XNAs. Full article
(This article belongs to the Special Issue Advances in Nucleoside/Nucleotides and Nucleic Acid Chemistry: A Theme Issue in Honor of Prof. Dr. Piet Herdewijn)
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37 pages, 12455 KiB  
Review
Synthesis of Nucleobase-Modified RNA Oligonucleotides by Post-Synthetic Approach
by Karolina Bartosik, Katarzyna Debiec, Anna Czarnecka, Elzbieta Sochacka and Grazyna Leszczynska
Molecules 2020, 25(15), 3344; https://doi.org/10.3390/molecules25153344 - 23 Jul 2020
Cited by 22 | Viewed by 6224
Abstract
The chemical synthesis of modified oligoribonucleotides represents a powerful approach to study the structure, stability, and biological activity of RNAs. Selected RNA modifications have been proven to enhance the drug-like properties of RNA oligomers providing the oligonucleotide-based therapeutic agents in the antisense and [...] Read more.
The chemical synthesis of modified oligoribonucleotides represents a powerful approach to study the structure, stability, and biological activity of RNAs. Selected RNA modifications have been proven to enhance the drug-like properties of RNA oligomers providing the oligonucleotide-based therapeutic agents in the antisense and siRNA technologies. The important sites of RNA modification/functionalization are the nucleobase residues. Standard phosphoramidite RNA chemistry allows the site-specific incorporation of a large number of functional groups to the nucleobase structure if the building blocks are synthetically obtainable and stable under the conditions of oligonucleotide chemistry and work-up. Otherwise, the chemically modified RNAs are produced by post-synthetic oligoribonucleotide functionalization. This review highlights the post-synthetic RNA modification approach as a convenient and valuable method to introduce a wide variety of nucleobase modifications, including recently discovered native hypermodified functional groups, fluorescent dyes, photoreactive groups, disulfide crosslinks, and nitroxide spin labels. Full article
(This article belongs to the Special Issue Advances in Nucleoside/Nucleotides and Nucleic Acid Chemistry: A Theme Issue in Honor of Prof. Dr. Piet Herdewijn)
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13 pages, 1045 KiB  
Review
8-Oxo-7,8-Dihydro-2′-Deoxyguanosine (8-oxodG) and 8-Hydroxy-2′-Deoxyguanosine (8-OHdG) as a Potential Biomarker for Gestational Diabetes Mellitus (GDM) Development
by Sandra K. Urbaniak, Karolina Boguszewska, Michał Szewczuk, Julia Kaźmierczak-Barańska and Bolesław T. Karwowski
Molecules 2020, 25(1), 202; https://doi.org/10.3390/molecules25010202 - 03 Jan 2020
Cited by 47 | Viewed by 5365
Abstract
The growing clinical and epidemiological significance of gestational diabetes mellitus results from its constantly increasing worldwide prevalence, obesity, and overall unhealthy lifestyle among women of childbearing age. Oxidative stress seems to be the most important predictor of gestational diabetes mellitus development. Disturbances in [...] Read more.
The growing clinical and epidemiological significance of gestational diabetes mellitus results from its constantly increasing worldwide prevalence, obesity, and overall unhealthy lifestyle among women of childbearing age. Oxidative stress seems to be the most important predictor of gestational diabetes mellitus development. Disturbances in the cell caused by oxidative stress lead to different changes in biomolecules, including DNA. The nucleobase which is most susceptible to oxidative stress is guanine. Its damage results in two main modifications: 8-hydroxy-2′-deoxyguanosineor 8-oxo-7,8-dihydro-2′-deoxyguanosine. Their significant level can indicate pathological processes during pregnancy, like gestational diabetes mellitus and probably, type 2 diabetes mellitus after pregnancy. This review provides an overview of current knowledge on the use of 8-hydroxy-2′-deoxyguanosineand/or 8-oxo-7,8-dihydro-2′-deoxyguanosine as a biomarker in gestational diabetes mellitus and allows us to understand the mechanism of 8-hydroxy-2′-deoxyguanosineand/or 8-oxo-7,8-dihydro-2′-deoxyguanosine generation during this disease. Full article
(This article belongs to the Special Issue Advances in Nucleoside/Nucleotides and Nucleic Acid Chemistry: A Theme Issue in Honor of Prof. Dr. Piet Herdewijn)
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