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Nucleoside Modifications

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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 March 2015) | Viewed by 99342

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Prof. Dr. Mahesh K. Lakshman

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Guest Editor

Department of Chemistry, The City College and The City University of New York, New York, NY 10031, USA
Interests: nucleoside modification via metal-catalyzed and uncatalyzed processes; synthesis of novel nucleoside structures; chemical carcinogenesis; site-specific DNA modification; synthesis of polycyclic aromatic hydrocarbons and their metabolites; aryne chemistry; generally applicable synthetic methodology

Prof. Dr. Fumi Nagatsugi

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Guest Editor

Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai-shi, Japan
Interests: oligonucleotides; artificial molecules for binding to DNA and RNA; selective chemical reactions to DNA and RNA

Special Issue Information

Dear Colleagues,

Nucleosides are the fundamental components of genetic material, and are present in all living organisms, and in viruses. By virtue of their ubiquity, they are highly important biomolecules. Nucleosides consist of a heterocyclic aglycone and a sugar unit. For several decades, the natural nucleoside structures have inspired the development of chemical and biochemical modifications, leading to new nucleoside-like entities via aglycone, as well as saccharide, modifications. As a result, modified nucleosides and nucleoside analogues have wide spread utilities in biochemistry, biology, as pharmaceutical agents, and as biological probes. There is a constant need for access to novel nucleoside analogues for a plethora of applications, prompting the development of new methodologies. This Special Issue aims to provide a forum for the dissemination of the latest information on new chemical methods for access to modified nucleosides, nucleoside analogues, and applications of these new molecules.

Professor Mahesh K. Lakshman
Professor Fumi Nagatsugi
Guest Editors

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Published Papers (14 papers)

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Research

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870 KiB

Open AccessArticle

Site-Selective Ribosylation of Fluorescent Nucleobase Analogs Using Purine-Nucleoside Phosphorylase as a Catalyst: Effects of Point Mutations

by Alicja Stachelska-Wierzchowska, Jacek Wierzchowski, Agnieszka Bzowska and Beata Wielgus-Kutrowska

Molecules 2016, 21(1), 44; https://doi.org/10.3390/molecules21010044 - 28 Dec 2015

Cited by 10 | Viewed by 4805

Abstract

Enzymatic ribosylation of fluorescent 8-azapurine derivatives, like 8-azaguanine and 2,6-diamino-8-azapurine, with purine-nucleoside phosphorylase (PNP) as a catalyst, leads to N9, N8, and N7-ribosides. The final proportion of the products may be modulated by point mutations in the enzyme active site. As an example, ribosylation of the latter substrate by wild-type calf PNP gives N7- and N8-ribosides, while the N243D mutant directs the ribosyl substitution at N9- and N7-positions. The same mutant allows synthesis of the fluorescent N7-β-d-ribosyl-8-azaguanine. The mutated form of the E. coli PNP, D204N, can be utilized to obtain non-typical ribosides of 8-azaadenine and 2,6-diamino-8-azapurine as well. The N7- and N8-ribosides of the 8-azapurines can be analytically useful, as illustrated by N7-β-d-ribosyl-2,6-diamino-8-azapurine, which is a good fluorogenic substrate for mammalian forms of PNP, including human blood PNP, while the N8-riboside is selective to the E. coli enzyme. Full article

(This article belongs to the Special Issue Nucleoside Modifications)

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Open AccessArticle

Cladribine Analogues via O⁶-(Benzotriazolyl) Derivatives of Guanine Nucleosides

by Sakilam Satishkumar, Prasanna K. Vuram, Siva Subrahmanyam Relangi, Venkateshwarlu Gurram, Hong Zhou, Robert J. Kreitman, Michelle M. Martínez Montemayor, Lijia Yang, Muralidharan Kaliyaperumal, Somesh Sharma, Narender Pottabathini and Mahesh K. Lakshman

Molecules 2015, 20(10), 18437-18463; https://doi.org/10.3390/molecules201018437 - 09 Oct 2015

Cited by 13 | Viewed by 7679

Abstract

Cladribine, 2-chloro-2′-deoxyadenosine, is a highly efficacious, clinically used nucleoside for the treatment of hairy cell leukemia. It is also being evaluated against other lymphoid malignancies and has been a molecule of interest for well over half a century. In continuation of our interest in the amide bond-activation in purine nucleosides via the use of (benzotriazol-1yl-oxy)tris(dimethylamino)phosphonium hexafluorophosphate, we have evaluated the use of O⁶-(benzotriazol-1-yl)-2′-deoxyguanosine as a potential precursor to cladribine and its analogues. These compounds, after appropriate deprotection, were assessed for their biological activities, and the data are presented herein. Against hairy cell leukemia (HCL), T-cell lymphoma (TCL) and chronic lymphocytic leukemia (CLL), cladribine was the most active against all. The bromo analogue of cladribine showed comparable activity to the ribose analogue of cladribine against HCL, but was more active against TCL and CLL. The bromo ribose analogue of cladribine showed activity, but was the least active among the C6-NH₂-containing compounds. Substitution with alkyl groups at the exocyclic amino group appears detrimental to activity, and only the C6 piperidinyl cladribine analogue demonstrated any activity. Against adenocarcinoma MDA-MB-231 cells, cladribine and its ribose analogue were most active. Full article

(This article belongs to the Special Issue Nucleoside Modifications)

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Open AccessArticle

Non-Nucleosidic Analogues of Polyaminonucleosides and Their Influence on Thermodynamic Properties of Derived Oligonucleotides

by Jolanta Brzezinska and Wojciech T. Markiewicz

Molecules 2015, 20(7), 12652-12669; https://doi.org/10.3390/molecules200712652 - 13 Jul 2015

Viewed by 4872

Abstract

The rationale for the synthesis of cationic modified nucleosides is higher expected nuclease resistance and potentially better cellular uptake due to an overall reduced negative charge based on internal charge compensation. Due to the ideal distance between cationic groups, polyamines are perfect counterions for oligodeoxyribonucleotides. We have synthesized non-nucleosidic analogues built from units that carry different diol structures instead of sugar residues and functionalized with polyamines. The non-nucleosidic analogues were attached as internal or 5′-terminal modifications in oligodeoxyribonucleotide strands. The thermodynamic studies of these polyaminooligonucleotide analogues revealed stabilizing or destabilizing effects that depend on the linker or polyamine used. Full article

(This article belongs to the Special Issue Nucleoside Modifications)

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Open AccessArticle

Carboxylated Acyclonucleosides: Synthesis and RNase A Inhibition

by Kaustav Chakraborty, Swagata Dasgupta and Tanmaya Pathak

Molecules 2015, 20(4), 5924-5941; https://doi.org/10.3390/molecules20045924 - 03 Apr 2015

Cited by 1 | Viewed by 6842

Abstract

Strategically designed carboxylated acyclonucleosides have been probed as a new class of RNase A inhibitors. Several experimental and theoretical studies have been performed to compile relevant qualitative and quantitative information regarding the nature and extent of inhibition. The inhibition constant (K_i) values were determined using a UV-based kinetics experiment. The changes in the secondary structure of the enzyme upon binding with the inhibitors were obtained from circular dichroism studies. The binding constants for enzyme-inhibitor interactions were determined with the help of fluorescence spectroscopy. Docking studies were performed to reveal the possible binding sites of the inhibitors within the enzyme. The cytosine analogues were found to possess better inhibitory properties in comparison to the corresponding uracil derivatives. An increment in the number of carboxylic acid groups (-COOH) in the inhibitor backbone was found to result in better inhibition. Full article

(This article belongs to the Special Issue Nucleoside Modifications)

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702 KiB

Open AccessArticle

Synthesis and Biological Properties of 5-(1H-1,2,3-Triazol-4-yl)isoxazolidines: A New Class of C-Nucleosides

by Salvatore V. Giofrè, Roberto Romeo, Caterina Carnovale, Raffaella Mancuso, Santa Cirmi, Michele Navarra, Adriana Garozzo and Maria A. Chiacchio

Molecules 2015, 20(4), 5260-5275; https://doi.org/10.3390/molecules20045260 - 24 Mar 2015

Cited by 26 | Viewed by 6331

Abstract

A novel series of C-nucleosides, featuring the presence of a 1,2,3-triazole ring linked to an isoxazolidine system, has been designed as mimetics of the pyrimidine nucleobases. An antiproliferative effect was observed for compounds 17a and 17b: the growth inhibitory effect reaches [...] Read more.

(This article belongs to the Special Issue Nucleoside Modifications)

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1197 KiB

Open AccessArticle

Synthesis of Peptide Nucleic Acids Containing a Crosslinking Agent and Evaluation of Their Reactivities

by Takuya Akisawa, Yuki Ishizawa and Fumi Nagatsugi

Molecules 2015, 20(3), 4708-4719; https://doi.org/10.3390/molecules20034708 - 13 Mar 2015

Cited by 9 | Viewed by 8083

Abstract

Peptide nucleic acids (PNAs) are structural mimics of nucleic acids that form stable hybrids with DNA and RNA. In addition, PNAs can invade double-stranded DNA. Due to these characteristics, PNAs are widely used as biochemical tools, for example, in antisense/antigene therapy. Interstrand crosslink formation in nucleic acids is one of the strategies for preparing a stable duplex by covalent bond formation. In this study, we have synthesized PNAs incorporating 4-amino-6-oxo-2-vinylpyrimidine (AOVP) as a crosslinking agent and evaluated their reactivities for targeting DNA and RNA. Full article

(This article belongs to the Special Issue Nucleoside Modifications)

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655 KiB

Open AccessArticle

Construction of an Isonucleoside on a 2,6-Dioxobicyclo[3.2.0]-heptane Skeleton

by Yuichi Yoshimura, Satoshi Kobayashi, Hitomi Kaneko, Takeshi Suzuki and Tomozumi Imamichi

Molecules 2015, 20(3), 4623-4634; https://doi.org/10.3390/molecules20034623 - 12 Mar 2015

Cited by 3 | Viewed by 6056

Abstract

We have built a new isonucleoside derivative on a 2,6-dioxobicyclo[3.2.0]heptane skeleton as a potential anti-HIV agent. To synthesize the target compound, an acetal-protected dihydroxyacetone was first converted to a 2,3-epoxy-tetrahydrofuran derivative. Introduction of an azide group, followed by the formation of an oxetane ring, gave a pseudosugar derivative with a 2,6-dioxobicyclo[3.2.0]heptane skeleton. The desired isonucleoside was obtained by constructing a purine base moiety on the scaffold, followed by amination. Full article

(This article belongs to the Special Issue Nucleoside Modifications)

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Tethering in RNA: An RNA-Binding Fragment Discovery Tool

by Kiet Tran, Michelle R. Arkin and Peter A. Beal

Molecules 2015, 20(3), 4148-4161; https://doi.org/10.3390/molecules20034148 - 04 Mar 2015

Cited by 1 | Viewed by 7066

Abstract

Tethering has been extensively used to study small molecule interactions with proteins through reversible disulfide bond forming reactions to cysteine residues. We describe the adaptation of Tethering to the study of small molecule binding to RNA using a thiol-containing adenosine analog (A_SH). Among 30 disulfide-containing small molecules screened for efficient Tethering to A_SH-bearing RNAs derived from pre-miR21, a benzotriazole-containing compound showed prominent adduct formation and selectivity for one of the RNAs tested. The results of this screen demonstrate the viability of using thiol-modified nucleic acids to discover molecules with binding affinity and specificity for the purpose of therapeutic compound lead discovery. Full article

(This article belongs to the Special Issue Nucleoside Modifications)

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1221 KiB

Open AccessArticle

Hybridisation Potential of 1',3'-Di-O-methylaltropyranoside Nucleic Acids

by Akkaladevi Venkatesham, Dhuldeo Kachare, Guy Schepers, Jef Rozenski, Mathy Froeyen and Arthur Van Aerschot

Molecules 2015, 20(3), 4020-4041; https://doi.org/10.3390/molecules20034020 - 03 Mar 2015

Cited by 2 | Viewed by 5397

Abstract

In further study of our series of six-membered ring-containing nucleic acids, different 1',3'-di-O-methyl altropyranoside nucleoside analogs (DMANA) were synthesized comprising all four base moieties, adenine, cytosine, uracil and guanine. Following assembly into oligonucleotides (ONs), their affinity for natural oligonucleotides was evaluated by thermal denaturation of the respective duplexes. Data were compared with results obtained previously for both anhydrohexitol (HNAs) and 3'-O-methylated altrohexitol modified ONs (MANAs). We hereby demonstrate that ONs modified with DMANA monomers, unlike some of our previously described analogues with constrained 6-membered hexitol rings, did not improve thermodynamic stability of dsRNA complexes, most probably in view of an energetic penalty when forced in the required 1C4 pairing conformation. Overall, a single incorporation was more or less tolerated or even positive for the adenine congener, but incorporation of a second modification afforded a slight destabilization (except for A), while a fully modified sequence displayed a thermal stability of −0.3 °C per modification. The selectivity of pairing remained very high, and the new modification upon incorporation into a DNA strand, strongly destabilized the corresponding DNA duplexes. Unfortunately, this new modification does not bring any advantage to be further evaluated for antisense or siRNA applications. Full article

(This article belongs to the Special Issue Nucleoside Modifications)

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887 KiB

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Development of New 1,3-Diazaphenoxazine Derivatives (ThioG-Grasp) to Covalently Capture 8-Thioguanosine

by Yasufumi Fuchi, Hideto Obayashi and Shigeki Sasaki

Molecules 2015, 20(1), 1078-1087; https://doi.org/10.3390/molecules20011078 - 09 Jan 2015

Cited by 7 | Viewed by 6245

Abstract

The derivatives of 8-thioguanosine are thought to be included in the signal transduction system related to 8-nitroguanosine. In this study, we attempted to develop new 1,3-diazaphenoxazine (G-clamp) derivatives to covalently capture 8-thioguanosine (thioG-grasp). It was expected that the chlorine atom at the end of the linker would be displaced by the nucleophilic attack by the sulfur atom of 8-thioguanosine via multiple hydrogen-bonded complexes. The thioG-grasp derivative with a propyl linker reacted efficiently with 8-thioguanosine to form the corresponding adduct. Full article

(This article belongs to the Special Issue Nucleoside Modifications)

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794 KiB

Open AccessCommunication

Design and Synthesis of a Series of Truncated Neplanocin Fleximers

by Sarah C. Zimmermann, Elizaveta O'Neill, Godwin U. Ebiloma, Lynsey J. M. Wallace, Harry P. De Koning and Katherine L. Seley-Radtke

Molecules 2014, 19(12), 21200-21214; https://doi.org/10.3390/molecules191221200 - 16 Dec 2014

Cited by 11 | Viewed by 6949

Abstract

In an effort to study the effects of flexibility on enzyme recognition and activity, we have developed several different series of flexible nucleoside analogues in which the purine base is split into its respective imidazole and pyrimidine components. The focus of this particular study was to synthesize the truncated neplanocin A fleximers to investigate their potential anti-protozoan activities by inhibition of S-adenosylhomocysteine hydrolase (SAHase). The three fleximers tested displayed poor anti-trypanocidal activities, with EC₅₀ values around 200 μM. Further studies of the corresponding ribose fleximers, most closely related to the natural nucleoside substrates, revealed low affinity for the known T. brucei nucleoside transporters P1 and P2, which may be the reason for the lack of trypanocidal activity observed. Full article

(This article belongs to the Special Issue Nucleoside Modifications)

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449 KiB

Open AccessArticle

Formation of Mixed-Ligand Complexes of Pd²⁺ with Nucleoside 5'-Monophosphates and Some Metal-Ion-Binding Nucleoside Surrogates

by Oleg Golubev, Tuomas Lönnberg and Harri Lönnberg

Molecules 2014, 19(10), 16976-16986; https://doi.org/10.3390/molecules191016976 - 22 Oct 2014

Cited by 9 | Viewed by 5722

Abstract

Formation of mixed-ligand Pd²⁺ complexes between canonical nucleoside 5'-monophosphates and five metal-ion-binding nucleoside analogs has been studied by ¹H-NMR spectroscopy to test the ability of these nucleoside surrogates to discriminate between unmodified nucleobases by Pd²⁺-mediated base pairing. The nucleoside analogs studied included 2,6-bis(3,5-dimethylpyrazol-1-yl)-, 2,6-bis(1-methylhydrazinyl)- and 6-(3,5-dimethylpyrazol-1-yl)-substituted 9-(β-d-ribofuranosyl)purines 1–3, and 2,4-bis(3,5-dimethylpyrazol-1-yl)- and 2,4-bis(1-methylhydrazinyl)-substituted 5-(β-d-ribofuranosyl)-pyrimidines 4–5. Among these, the purine derivatives 1-3 bound Pd²⁺ much more tightly than the pyrimidine derivatives 4, 5 despite apparently similar structures of the potential coordination sites. Compounds 1 and 2 formed markedly stable mixed-ligand Pd²⁺ complexes with UMP and GMP, UMP binding favored by 1 and GMP by 2. With 3, formation of mixed-ligand complexes was retarded by binding of two molecules of 3 to Pd²⁺. Full article

(This article belongs to the Special Issue Nucleoside Modifications)

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Review

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1539 KiB

Open AccessReview

Palladium-Catalyzed Modification of Unprotected Nucleosides, Nucleotides, and Oligonucleotides

by Kevin H. Shaughnessy

Molecules 2015, 20(5), 9419-9454; https://doi.org/10.3390/molecules20059419 - 22 May 2015

Cited by 75 | Viewed by 10734

Abstract

Synthetic modification of nucleoside structures provides access to molecules of interest as pharmaceuticals, biochemical probes, and models to study diseases. Covalent modification of the purine and pyrimidine bases is an important strategy for the synthesis of these adducts. Palladium-catalyzed cross-coupling is a powerful method to attach groups to the base heterocycles through the formation of new carbon-carbon and carbon-heteroatom bonds. In this review, approaches to palladium-catalyzed modification of unprotected nucleosides, nucleotides, and oligonucleotides are reviewed. Polar reaction media, such as water or polar aprotic solvents, allow reactions to be performed directly on the hydrophilic nucleosides and nucleotides without the need to use protecting groups. Homogeneous aqueous-phase coupling reactions catalyzed by palladium complexes of water-soluble ligands provide a general approach to the synthesis of modified nucleosides, nucleotides, and oligonucleotides. Full article

(This article belongs to the Special Issue Nucleoside Modifications)

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1785 KiB

Open AccessReview

Modification of Purine and Pyrimidine Nucleosides by Direct C-H Bond Activation

by Yong Liang and Stanislaw F. Wnuk

Molecules 2015, 20(3), 4874-4901; https://doi.org/10.3390/molecules20034874 - 17 Mar 2015

Cited by 42 | Viewed by 11501

Abstract

Transition metal-catalyzed modifications of the activated heterocyclic bases of nucleosides as well as DNA or RNA fragments employing traditional cross-coupling methods have been well-established in nucleic acid chemistry. This review covers advances in the area of cross-coupling reactions in which nucleosides are functionalized via direct activation of the C8-H bond in purine and the C5-H or C6-H bond in uracil bases. The review focuses on Pd/Cu-catalyzed couplings between unactivated nucleoside bases with aryl halides. It also discusses cross-dehydrogenative arylations and alkenylations as well as other reactions used for modification of nucleoside bases that avoid the use of organometallic precursors and involve direct C-H bond activation in at least one substrate. The scope and efficiency of these coupling reactions along with some mechanistic considerations are discussed. Full article

(This article belongs to the Special Issue Nucleoside Modifications)

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