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28 pages, 3039 KiB

Open AccessArticle

Assembly of Biologically Functional Structures by Nucleic Acid Templating: Implementation of a Strategy to Overcome Inhibition by Template Excess

by Matthew M. Lawler, James T. Kurnick, Leah Fagundes St. Pierre, Estelle E. Newton, Lenora B. Rose and Ian S. Dunn

Molecules 2022, 27(20), 6831; https://doi.org/10.3390/molecules27206831 - 12 Oct 2022

Viewed by 1287

Abstract

Delivery of therapeutic molecules to pathogenic cells is often hampered by unintended toxicity to normal cells. In principle, this problem can be circumvented if the therapeutic effector molecule is split into two inactive components, and only assembled on or within the target cell [...] Read more.

Delivery of therapeutic molecules to pathogenic cells is often hampered by unintended toxicity to normal cells. In principle, this problem can be circumvented if the therapeutic effector molecule is split into two inactive components, and only assembled on or within the target cell itself. Such an in situ process can be realized by exploiting target-specific molecules as templates to direct proximity-enhanced assembly. Modified nucleic acids carrying inert precursor fragments can be designed to co-hybridize on a target-specific template nucleic acid, such that the enforced proximity accelerates assembly of a functional molecule for antibody recognition. We demonstrate the in vitro feasibility of this adaptation of nucleic acid-templated synthesis (NATS) using oligonucleotides bearing modified peptides (“haplomers”), for templated assembly of a mimotope recognized by the therapeutic antibody trastuzumab. Enforced proximity promotes mimotope assembly via traceless native chemical ligation. Nevertheless, titration of participating haplomers through template excess is a potential limitation of trimolecular NATS. In order to overcome this problem, we devised a strategy where haplomer hybridization can only occur in the presence of target, without being subject to titration effects. This generalizable NATS modification may find future applications in enabling directed targeting of pathological cells. Full article

(This article belongs to the Collection New Frontiers in Nucleic Acid Chemistry)

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18 pages, 2390 KiB

Open AccessArticle

Oxadiazole/Pyridine-Based Ligands: A Structural Tuning for Enhancing G-Quadruplex Binding

by Filippo Doria, Valentina Pirota, Michele Petenzi, Marie-Paule Teulade-Fichou, Daniela Verga and Mauro Freccero

Molecules 2018, 23(9), 2162; https://doi.org/10.3390/molecules23092162 - 28 Aug 2018

Cited by 16 | Viewed by 4241

Abstract

Non-macrocyclic heteroaryls represent a valuable class of ligands for nucleic acid recognition. In this regard, non-macrocyclic pyridyl polyoxazoles and polyoxadiazoles were recently identified as selective G-quadruplex stabilizing compounds with high cytotoxicity and promising anticancer activity. Herein, we describe the synthesis of a new [...] Read more.

Non-macrocyclic heteroaryls represent a valuable class of ligands for nucleic acid recognition. In this regard, non-macrocyclic pyridyl polyoxazoles and polyoxadiazoles were recently identified as selective G-quadruplex stabilizing compounds with high cytotoxicity and promising anticancer activity. Herein, we describe the synthesis of a new family of heteroaryls containing oxadiazole and pyridine moieties targeting DNA G-quadruplexes. To perform a structure–activity analysis identifying determinants of activity and selectivity, we followed a convergent synthetic pathway to modulate the nature and number of the heterocycles (1,3-oxazole vs. 1,2,4-oxadiazole and pyridine vs. benzene). Each ligand was evaluated towards secondary nucleic acid structures, which have been chosen as a prototype to mimic cancer-associated G-quadruplex structures (e.g., the human telomeric sequence, c-myc and c-kit promoters). Interestingly, heptapyridyl-oxadiazole compounds showed preferential binding towards the telomeric sequence (22AG) in competitive conditions vs. duplex DNA. In addition, G4-FID assays suggest a different binding mode from the classical stacking on the external G-quartet. Additionally, CD titrations in the presence of the two most promising compounds for affinity, TOxAzaPy and TOxAzaPhen, display a structural transition of 22AG in K-rich buffer. This investigation suggests that the pyridyl-oxadiazole motif is a promising recognition element for G-quadruplexes, combining seven heteroaryls in a single binding unit. Full article

(This article belongs to the Collection New Frontiers in Nucleic Acid Chemistry)

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18 pages, 2275 KiB

Open AccessArticle

A Fragment-Based Approach for the Development of G-Quadruplex Ligands: Role of the Amidoxime Moiety

by Martina Tassinari, Alberto Lena, Elena Butovskaya, Valentina Pirota, Matteo Nadai, Mauro Freccero, Filippo Doria and Sara N. Richter

Molecules 2018, 23(8), 1874; https://doi.org/10.3390/molecules23081874 - 27 Jul 2018

Cited by 11 | Viewed by 5013

Abstract

G-quadruplex (G4) nucleic acid structures have been reported to be involved in several human pathologies, including cancer, neurodegenerative disorders and infectious diseases; however, G4 targeting compounds still need implementation in terms of drug-like properties and selectivity in order to reach the clinical use. [...] Read more.

G-quadruplex (G4) nucleic acid structures have been reported to be involved in several human pathologies, including cancer, neurodegenerative disorders and infectious diseases; however, G4 targeting compounds still need implementation in terms of drug-like properties and selectivity in order to reach the clinical use. So far, G4 ligands have been mainly identified through high-throughput screening methods or design of molecules with pre-set features. Here, we describe the development of new heterocyclic ligands through a fragment-based drug discovery (FBDD) approach. The ligands were designed against the major G4 present in the long terminal repeat (LTR) promoter region of the human immunodeficiency virus-1 (HIV-1), the stabilization of which has been shown to suppress viral gene expression and replication. Our method is based on the generation of molecular fragment small libraries, screened against the target to further elaborate them into lead compounds. We screened 150 small molecules, composed by structurally and chemically different fragments, selected from commercially available and in-house compounds; synthetic elaboration yielded several G4 ligands and two final G4 binders, both embedding an amidoxime moiety; one of these two compounds showed preferential binding for the HIV-1 LTR G4. This work presents the discovery of a novel potential pharmacophore and highlights the possibility to apply a fragment-based approach to develop G4 ligands with unexpected chemical features. Full article

(This article belongs to the Collection New Frontiers in Nucleic Acid Chemistry)

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12 pages, 2670 KiB

Open AccessArticle

Linking Temperature, Cation Concentration and Water Activity for the B to Z Conformational Transition in DNA

by Jaime M. Ferreira and Richard D. Sheardy

Molecules 2018, 23(7), 1806; https://doi.org/10.3390/molecules23071806 - 21 Jul 2018

Cited by 7 | Viewed by 4288

Abstract

High concentrations of Na⁺ or [Co(NH₃)₆]³⁺ can induce the B to Z conformational transition in alternating (dC-dG) oligo and polynucleotides. The use of short DNA oligomers (dC-dG)₄ and (dm⁵C-dG)₄ as models can allow [...] Read more.

High concentrations of Na⁺ or [Co(NH₃)₆]³⁺ can induce the B to Z conformational transition in alternating (dC-dG) oligo and polynucleotides. The use of short DNA oligomers (dC-dG)₄ and (dm⁵C-dG)₄ as models can allow a thermodynamic characterization of the transition. Both form right handed double helical structures (B-DNA) in standard phosphate buffer with 115 mM Na⁺ at 25 °C. However, at 2.0 M Na⁺ or 200 μM [Co(NH₃)₆]³⁺, (dm⁵C-dG)₄ assumes a left handed double helical structure (Z-DNA) while the unmethylated (dC-dG)₄ analogue remains right handed under those conditions. We have previously demonstrated that the enthalpy of the transition at 25 °C for either inducer can be determined using isothermal titration calorimetry (ITC). Here, ITC is used to investigate the linkages between temperature, water activity and DNA conformation. We found that the determined enthalpy for each titration varied linearly with temperature allowing determination of the heat capacity change (ΔC_p) between the initial and final states. As expected, the ΔC_p values were dependent upon the cation (i.e., Na⁺ vs. [Co(NH₃)₆]³⁺) as well as the sequence of the DNA oligomer (i.e., methylated vs. unmethylated). Osmotic stress experiments were carried out to determine the gain or loss of water by the oligomer induced by the titration. The results are discussed in terms of solvent accessible surface areas, electrostatic interactions and the role of water. Full article

(This article belongs to the Collection New Frontiers in Nucleic Acid Chemistry)

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5333 KiB

Open AccessArticle

Binding of Harmine Derivatives to DNA: A Spectroscopic Investigation

by Bruno Pagano, Marco Caterino, Rosanna Filosa and Concetta Giancola

Molecules 2017, 22(11), 1831; https://doi.org/10.3390/molecules22111831 - 27 Oct 2017

Cited by 12 | Viewed by 5144

Abstract

Harmine belongs to a group of β-carboline alkaloids endowed with antitumor properties. Harmine and its derivatives are thought to bind to DNA and interfere with topoisomerase activities. We investigated the base-dependent binding of harmine, and three of its synthetic anticancer-active derivatives to the [...] Read more.

Harmine belongs to a group of β-carboline alkaloids endowed with antitumor properties. Harmine and its derivatives are thought to bind to DNA and interfere with topoisomerase activities. We investigated the base-dependent binding of harmine, and three of its synthetic anticancer-active derivatives to the genomic DNA from calf thymus and two synthetic 20-mer double helices, the poly(dG-dC)·poly(dG-dC) and the poly(dA-dT)·poly(dA-dT), by means of UV-Vis and circular dichroism (CD) spectroscopies. The data show that the DNA binding and stabilising properties of the investigated derivatives are base pair-dependent. These results could be used as a guide to design and develop further bioactive analogues. Full article

(This article belongs to the Collection New Frontiers in Nucleic Acid Chemistry)

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2236 KiB

Open AccessArticle

The Molecular Effect of Diagnostic Absorbed Doses from ¹³¹I on Papillary Thyroid Cancer Cells In Vitro

by Mariusz Stasiołek, Zbigniew Adamczewski, Przemysław W. Śliwka, Bartosz Puła, Bolesław Karwowski, Anna Merecz-Sadowska, Marek Dedecjus and Andrzej Lewiński

Molecules 2017, 22(6), 993; https://doi.org/10.3390/molecules22060993 - 15 Jun 2017

Cited by 5 | Viewed by 4541

Abstract

Diagnostic whole-body scan is a standard procedure in patients with thyroid cancer prior to the application of a therapeutic dose of ¹³¹I. Unfortunately, administration of the radioisotope in a diagnostic dose may decrease further radioiodine uptake—the phenomenon called “thyroid stunning”. We estimated [...] Read more.

Diagnostic whole-body scan is a standard procedure in patients with thyroid cancer prior to the application of a therapeutic dose of ¹³¹I. Unfortunately, administration of the radioisotope in a diagnostic dose may decrease further radioiodine uptake—the phenomenon called “thyroid stunning”. We estimated radiation absorbed dose-dependent changes in genetic material, in particular in the sodium iodide symporter (NIS) gene promoter, and the NIS protein level in a K1 cell line derived from the metastasis of a human papillary thyroid carcinoma exposed to ¹³¹I in culture. The different activities applied were calculated to result in absorbed doses of 5, 10 and 20 Gy. Radioiodine did not affect the expression of the NIS gene at the mRNA level, however, we observed significant changes in the NIS protein level in K1 cells. The decrease of the NIS protein level observed in the cells subjected to the lowest absorbed dose was paralleled by a significant increase in 8-oxo-dG concentrations (p < 0.01) and followed by late activation of the DNA repair pathways. Our findings suggest that the impact of ¹³¹I radiation on thyroid cells, in the range compared to doses absorbed during diagnostic procedures, is not linear and depends on various factors including the cellular components of thyroid pathology. Full article

(This article belongs to the Collection New Frontiers in Nucleic Acid Chemistry)

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2934 KiB

Open AccessArticle

Synthesis and Biological Evaluation of Triazolyl 13α-Estrone–Nucleoside Bioconjugates

by Brigitta Bodnár, Erzsébet Mernyák, János Wölfling, Gyula Schneider, Bianka Edina Herman, Mihály Szécsi, Izabella Sinka, István Zupkó, Zoltán Kupihár and Lajos Kovács

Molecules 2016, 21(9), 1212; https://doi.org/10.3390/molecules21091212 - 10 Sep 2016

Cited by 16 | Viewed by 7092

Abstract

2′-Deoxynucleoside conjugates of 13α-estrone were synthesized by applying the copper-catalyzed alkyne–azide click reaction (CuAAC). For the introduction of the azido group the 5′-position of the nucleosides and a propargyl ether functional group on the 3-hydroxy group of 13α-estrone were chosen. The best yields [...] Read more.

2′-Deoxynucleoside conjugates of 13α-estrone were synthesized by applying the copper-catalyzed alkyne–azide click reaction (CuAAC). For the introduction of the azido group the 5′-position of the nucleosides and a propargyl ether functional group on the 3-hydroxy group of 13α-estrone were chosen. The best yields were realized in our hands when the 3′-hydroxy groups of the nucleosides were protected by acetyl groups and the 5′-hydroxy groups were modified by the tosyl–azide exchange method. The commonly used conditions for click reaction between the protected-5′-azidonucleosides and the steroid alkyne was slightly modified by using 1.5 equivalent of Cu(I) catalyst. All the prepared conjugates were evaluated in vitro by means of MTT assays for antiproliferative activity against a panel of human adherent cell lines (HeLa, MCF-7 and A2780) and the potential inhibitory activity of the new conjugates on human 17β-hydroxysteroid dehydrogenase 1 (17β-HSD1) was investigated via in vitro radiosubstrate incubation. Some protected conjugates displayed moderate antiproliferative properties against a panel of human adherent cancer cell lines (the protected cytidine conjugate proved to be the most potent with IC₅₀ value of 9 μM). The thymidine conjugate displayed considerable 17β-HSD1 inhibitory activity (IC₅₀ = 19 μM). Full article

(This article belongs to the Collection New Frontiers in Nucleic Acid Chemistry)

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1251 KiB

Open AccessArticle

DNA Three Way Junction Core Decorated with Amino Acids-Like Residues-Synthesis and Characterization

by Claudia Addamiano, Béatrice Gerland, Corinne Payrastre and Jean-Marc Escudier

Molecules 2016, 21(9), 1082; https://doi.org/10.3390/molecules21091082 - 23 Aug 2016

Cited by 4 | Viewed by 7471

Abstract

Construction and physico-chemical behavior of DNA three way junction (3WJ) functionalized by protein-like residues (imidazole, alcohol and carboxylic acid) at unpaired positions at the core is described. One 5′-C(S)-propargyl-thymidine nucleotide was specifically incorporated on each strand to react through a post [...] Read more.

Construction and physico-chemical behavior of DNA three way junction (3WJ) functionalized by protein-like residues (imidazole, alcohol and carboxylic acid) at unpaired positions at the core is described. One 5′-C(S)-propargyl-thymidine nucleotide was specifically incorporated on each strand to react through a post synthetic CuACC reaction with either protected imidazolyl-, hydroxyl- or carboxyl-azide. Structural impacts of 5′-C(S)-functionalization were investigated to evaluate how 3WJ flexibility/stability is affected. Full article

(This article belongs to the Collection New Frontiers in Nucleic Acid Chemistry)

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2286 KiB

Open AccessArticle

Chemical Incorporation of Chain-Terminating Nucleoside Analogs as 3′-Blocking DNA Damage and Their Removal by Human ERCC1-XPF Endonuclease

by Junpei Yamamoto, Chiaki Takahata, Isao Kuraoka, Kouji Hirota and Shigenori Iwai

Molecules 2016, 21(6), 766; https://doi.org/10.3390/molecules21060766 - 11 Jun 2016

Cited by 3 | Viewed by 7097

Abstract

Nucleoside/nucleotide analogs that lack the 3′-hydroxy group are widely utilized for HIV therapy. These chain-terminating nucleoside analogs (CTNAs) block DNA synthesis after their incorporation into growing DNA, leading to the antiviral effects. However, they are also considered to be DNA damaging agents, and [...] Read more.

Nucleoside/nucleotide analogs that lack the 3′-hydroxy group are widely utilized for HIV therapy. These chain-terminating nucleoside analogs (CTNAs) block DNA synthesis after their incorporation into growing DNA, leading to the antiviral effects. However, they are also considered to be DNA damaging agents, and tyrosyl-DNA phosphodiesterase 1, a DNA repair enzyme, is reportedly able to remove such CTNA-modifications of DNA. Here, we have synthesized phosphoramidite building blocks of representative CTNAs, such as acyclovir, abacavir, carbovir, and lamivudine, and oligonucleotides with the 3′-CTNAs were successfully synthesized on solid supports. Using the chemically synthesized oligonucleotides, we investigated the excision of the 3′-CTNAs in DNA by the human excision repair cross complementing protein 1-xeroderma pigmentosum group F (ERCC1-XPF) endonuclease, which is one of the main components of the nucleotide excision repair pathway. A biochemical analysis demonstrated that the ERCC1-XPF endonuclease cleaved 2–7 nt upstream from the 3′-blocking CTNAs, and that DNA synthesis by the Klenow fragment was resumed after the removal of the CTNAs, suggesting that ERCC1-XPF participates in the repair of the CTNA-induced DNA damage. Full article

(This article belongs to the Collection New Frontiers in Nucleic Acid Chemistry)

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382 KiB

Open AccessArticle

Supramolecular Ring Structures of 7-Methylguanine: A Computational Study of Its Self-assembly and Anion Binding

by Gábor Paragi, Zoltán Kupihár, Célia Fonseca Guerra, F. Matthias Bickelhaupt and Lajos Kovács

Molecules 2013, 18(1), 225-235; https://doi.org/10.3390/molecules18010225 - 27 Dec 2012

Cited by 3 | Viewed by 6010

Abstract

The density functional theory calculations of 7-methylguanine clusters revealed that stable ring assemblies can be formed with or without anions in the center position and hexameric clusters are the most stable and most planar ones. The coordination of anions (Cl⁻, Br [...] Read more.

The density functional theory calculations of 7-methylguanine clusters revealed that stable ring assemblies can be formed with or without anions in the center position and hexameric clusters are the most stable and most planar ones. The coordination of anions (Cl⁻, Br⁻, NO₃⁻) stabilizes and thus favors the formation of planar aggregates. We believe that the predicted planar structures stabilized by anions are good models for self-assembly structures formed at solid-liquid or solid-gas interfaces. Comparing the bonding and average H-bond energy to reference ribbon calculations we pointed out the presence of the previously introduced cooperativity effect in circular supramolecular structures of 7-methylguanine. Full article

(This article belongs to the Special Issue Nucleic Acid Analogs)

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285 KiB

Open AccessArticle

Oligonucleotide-Peptide Conjugates: Solid-Phase Synthesis under Acidic Conditions and Use in ELISA Assays

by Anna Aviñó, Maria José Gómara, Morteza Malakoutikhah, Isabel Haro and Ramon Eritja

Molecules 2012, 17(12), 13825-13843; https://doi.org/10.3390/molecules171213825 - 22 Nov 2012

Cited by 10 | Viewed by 8575

Abstract

Here we used solid-phase methods to prepare oligonucleotides carrying fibrin/ filaggrin citrullinated peptides. Post-synthetic conjugation protocols were successfully applied for the synthesis of oligonucleotides carrying small peptides. A stepwise protocol using acid treatment for the final deprotection allowed the preparation of polypyrimidine oligonucleotides [...] Read more.

Here we used solid-phase methods to prepare oligonucleotides carrying fibrin/ filaggrin citrullinated peptides. Post-synthetic conjugation protocols were successfully applied for the synthesis of oligonucleotides carrying small peptides. A stepwise protocol using acid treatment for the final deprotection allowed the preparation of polypyrimidine oligonucleotides carrying longer and arginine-rich peptides. An ELISA-based test using the oligonucleotide-citrullinated peptide conjugates was developed for the detection of anti-citrullinated protein/peptide antibodies in human serum from rheumatoid arthritis patients. Full article

(This article belongs to the Special Issue Nucleic Acid Analogs)

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901 KiB

Open AccessArticle

5'-Chloro-5'-deoxy-(±)-ENBA, a Potent and Selective Adenosine A₁ Receptor Agonist, Alleviates Neuropathic Pain in Mice Through Functional Glial and Microglial Changes without Affecting Motor or Cardiovascular Functions

by Livio Luongo, Riccardo Petrelli, Luisa Gatta, Catia Giordano, Francesca Guida, Patrizia Vita, Palmarisa Franchetti, Mario Grifantini, Vito De Novellis, Loredana Cappellacci and Sabatino Maione

Molecules 2012, 17(12), 13712-13726; https://doi.org/10.3390/molecules171213712 - 22 Nov 2012

Cited by 49 | Viewed by 8532

Abstract

This study was undertaken in order to investigate the effect of chronic treatment with 5′-chloro-5′-deoxy-(±)-ENBA, a potent and highly selective agonist of human adenosine A₁ receptor, on thermal hyperalgesia and mechanical allodynia in a mouse model of neuropathic pain, the Spared Nerve [...] Read more.

This study was undertaken in order to investigate the effect of chronic treatment with 5′-chloro-5′-deoxy-(±)-ENBA, a potent and highly selective agonist of human adenosine A₁ receptor, on thermal hyperalgesia and mechanical allodynia in a mouse model of neuropathic pain, the Spared Nerve Injury (SNI) of the sciatic nerve. Chronic systemic administration of 5′-chloro-5′-deoxy-(±)-ENBA (0.5 mg/kg, i.p.) reduced both mechanical allodynia and thermal hyperalgesia 3 and 7 days post-SNI, in a way prevented by DPCPX (3 mg/kg, i.p.), a selective A₁ adenosine receptor antagonist, without exerting any significant change on the motor coordination or arterial blood pressure. In addition, a single intraperitoneal injection of 5′-chloro-5′-deoxy-(±)-ENBA (0.5 mg/kg, i.p.) 7 days post-SNI also reduced both symptoms for at least two hours. SNI was associated with spinal changes in microglial activation ipsilaterally to the nerve injury. Activated, hypertrophic microglia were significantly reduced by 5′-chloro-5′-deoxy-(±)-ENBA chronic treatment. Our results demonstrated an involvement of adenosine A₁ receptor in the amplified nociceptive thresholds and in spinal glial and microglial changes occurred in neuropathic pain, without affecting motor coordination or blood pressure. Our data suggest a possible use of adenosine A₁ receptor agonist in neuropathic pain symptoms. Full article

(This article belongs to the Special Issue Nucleic Acid Analogs)

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520 KiB

Open AccessArticle

Endo-S-c-di-GMP Analogues-Polymorphism and Binding Studies with Class I Riboswitch

by Jie Zhou, David A. Sayre, Jingxin Wang, Nirmal Pahadi and Herman O. Sintim

Molecules 2012, 17(11), 13376-13389; https://doi.org/10.3390/molecules171113376 - 09 Nov 2012

Cited by 18 | Viewed by 7105

Abstract

C-di-GMP, a cyclic guanine dinucleotide, has been shown to regulate biofilm formation as well as virulence gene expression in a variety of bacteria. Analogues of c-di-GMP have the potential to be used as chemical probes to study c-di-GMP signaling and could even become [...] Read more.

C-di-GMP, a cyclic guanine dinucleotide, has been shown to regulate biofilm formation as well as virulence gene expression in a variety of bacteria. Analogues of c-di-GMP have the potential to be used as chemical probes to study c-di-GMP signaling and could even become drug leads for the development of anti-biofilm compounds. Herein we report the synthesis and biophysical studies of a series of c-di-GMP analogues, which have both phosphate and sugar moieties simultaneously modified (called endo-S-c-di-GMP analogues). We used computational methods to predict the relative orientation of the guanine nucleobases in c-di-GMP and analogues. DOSY NMR of the endo-S-c-di-GMP series showed that the polymorphism of c-di-GMP can be tuned with conservative modifications to the phosphate and sugar moieties (conformational steering). Binding studies with Vc2 RNA (a class I c-di-GMP riboswitch) revealed that conservative modifications to the phosphate and 2'-positions of c-di-GMP dramatically affected binding to class I riboswitch. Full article

(This article belongs to the Special Issue Nucleic Acid Analogs)

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505 KiB

Open AccessArticle

Amplification and Re-Generation of LNA-Modified Libraries

by Holger Doessing, Lykke H. Hansen, Rakesh N. Veedu, Jesper Wengel and Birte Vester

Molecules 2012, 17(11), 13087-13097; https://doi.org/10.3390/molecules171113087 - 05 Nov 2012

Cited by 10 | Viewed by 7772

Abstract

Locked nucleic acids (LNA) confer high thermal stability and nuclease resistance to oligonucleotides. The discovery of polymerases that accept LNA triphosphates has led us to propose a scheme for the amplification and re-generation of LNA-containing oligonucleotide libraries. Such libraries could be used for [...] Read more.

Locked nucleic acids (LNA) confer high thermal stability and nuclease resistance to oligonucleotides. The discovery of polymerases that accept LNA triphosphates has led us to propose a scheme for the amplification and re-generation of LNA-containing oligonucleotide libraries. Such libraries could be used for in vitro selection of e.g., native LNA aptamers. We maintained an oligonucleotide library encoding 40 randomized positions with LNA ATP, GTP, CTP, and TTP for 7 rounds of ‘mock’ in vitro selection in the absence of a target and analyzed the sequence composition after rounds 1, 4 and 7. We observed a decrease in LNA-A content from 20.5% in round 1 to 6.6% in round 7. This decrease was accompanied by a substantial bias against successive LNA-As (poly-LNA adenosine tracts) and a relative over-representation of single LNA-As. Maintaining a library with LNA TTP yielded similar results. Together, these results suggest that dispersed LNA monomers are tolerated in our in vitro selection protocol, and that LNA-modified libraries can be sustained for up to at least seven selection rounds, albeit at reduced levels. This enables the discovery of native LNA aptamers and similar oligonucleotide structures. Full article

(This article belongs to the Special Issue Nucleic Acid Analogs)

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316 KiB

Open AccessArticle

Synthesis of a Cholesteryl-HEG Phosphoramidite Derivative and Its Application to Lipid-conjugates of the Anti-HIV ^5'TGGGAG^3' Hotoda’s Sequence

by Domenica Musumeci and Daniela Montesarchio

Molecules 2012, 17(10), 12378-12392; https://doi.org/10.3390/molecules171012378 - 22 Oct 2012

Cited by 12 | Viewed by 8853

Abstract

A novel phosphoramidite derivative of cholesterol, with an ether-linked hexaethylene glycol (HEG) spacer arm, has been obtained through simple and reproducible solid phase modified oligonucleotide synthesis manipulations. This building block and the known phosphoramidite derivative of 3b-(2-hydroxyethoxy)cholesterol have been exploited in standard oligonucleotide [...] Read more.

A novel phosphoramidite derivative of cholesterol, with an ether-linked hexaethylene glycol (HEG) spacer arm, has been obtained through simple and reproducible solid phase modified oligonucleotide synthesis manipulations. This building block and the known phosphoramidite derivative of 3b-(2-hydroxyethoxy)cholesterol have been exploited in standard oligonucleotide synthesis protocols for the preparation of 5'- conjugates of the G-quadruplex-forming ^5'TGGGAG³^' oligomer, known as the Hotoda’s sequence, to produce new potential anti-HIV agents. Full article

(This article belongs to the Special Issue Nucleic Acid Analogs)

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479 KiB

Open AccessArticle

Acetylated and Methylated β-Cyclodextrins as Viable Soluble Supports for the Synthesis of Short 2′-Oligodeoxyribo-nucleotides in Solution

by Alejandro Gimenez Molina, Vyacheslav Kungurtsev, Pasi Virta and Harri Lönnberg

Molecules 2012, 17(10), 12102-12120; https://doi.org/10.3390/molecules171012102 - 16 Oct 2012

Cited by 19 | Viewed by 9931

Abstract

Novel soluble supports for oligonucleotide synthesis 11a–c have been prepared by immobilizing a 5′-O-protected 3′-O-(hex-5-ynoyl)thymidine (6 or 7) to peracetylated or permethylated 6-deoxy-6-azido-β-cyclodextrins 10a or 10b by Cu(I)-promoted 1,3-dipolar cycloaddition. The applicability of the supports [...] Read more.

Novel soluble supports for oligonucleotide synthesis 11a–c have been prepared by immobilizing a 5′-O-protected 3′-O-(hex-5-ynoyl)thymidine (6 or 7) to peracetylated or permethylated 6-deoxy-6-azido-β-cyclodextrins 10a or 10b by Cu(I)-promoted 1,3-dipolar cycloaddition. The applicability of the supports to oligonucleotide synthesis by the phosphoramidite strategy has been demonstrated by assembling a 3′-TTT-5′ trimer from commercially available 5′-O-(4,4′-dimethoxytrityl)thymidine 3′-phosphoramidite. To simplify the coupling cycle, the 5′-O-(4,4′-dimethoxytrityl) protecting group has been replaced with an acetal that upon acidolytic removal yields volatile products. For this purpose, 5′-O-(1-methoxy-1-methylethyl)-protected 3′-(2-cyanoethyl-N,N-diisopropyl-phosphoramidite)s of thymidine (5a), N⁴-benzoyl-2′-deoxycytidine (5b) and N⁶-benzoyl-2′-deoxyadenosine (5c) have been synthesized and utilized in synthesis of a pentameric oligonucleotide 3′-TTCAT-5′ on the permethylated cyclodextrin support 11c. Full article

(This article belongs to the Special Issue Nucleic Acid Analogs)

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561 KiB

Open AccessArticle

Synthesis and Photophysical Study of 2′-Deoxyuridines Labeled with Fluorene Derivatives

by Hyun Yi Cho, Sang Keun Woo and Gil Tae Hwang

Molecules 2012, 17(10), 12061-12071; https://doi.org/10.3390/molecules171012061 - 15 Oct 2012

Cited by 14 | Viewed by 6486

Abstract

We examined microenvironment-sensitive fluorescent 2′-deoxyuridines labeled with fluorene derivatives that exhibited solvent-dependent photophysical properties. The high sensitivity of the fluorescence shift and the nucleoside intensity dependence on solvent polarity provided information useful for estimating the polarity of the environment surrounding the fluorescent nucleoside. [...] Read more.

We examined microenvironment-sensitive fluorescent 2′-deoxyuridines labeled with fluorene derivatives that exhibited solvent-dependent photophysical properties. The high sensitivity of the fluorescence shift and the nucleoside intensity dependence on solvent polarity provided information useful for estimating the polarity of the environment surrounding the fluorescent nucleoside. Full article

(This article belongs to the Special Issue Nucleic Acid Analogs)

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484 KiB

Open AccessArticle

Enhancement of Gene Silencing Effect and Membrane Permeability by Peptide-Conjugated 27-Nucleotide Small Interfering RNA

by Takanori Kubo, Kazuyoshi Yanagihara, Yuichiro Sato, Yasuhiro Morita and Toshio Seyama

Molecules 2012, 17(9), 11089-11102; https://doi.org/10.3390/molecules170911089 - 14 Sep 2012

Cited by 6 | Viewed by 5784

Abstract

Two different sizes of siRNAs, of which one type was 21-nucleotide (nt) siRNA containing 2-nt dangling ends and the other type was 27-nt siRNA with blunt ends, were conjugated with a nuclear export signal peptide of HIV-1 Rev at the 5′-sense end. Processing [...] Read more.

Two different sizes of siRNAs, of which one type was 21-nucleotide (nt) siRNA containing 2-nt dangling ends and the other type was 27-nt siRNA with blunt ends, were conjugated with a nuclear export signal peptide of HIV-1 Rev at the 5′-sense end. Processing by Dicer enzyme, cell membrane permeability, and RNAi efficiency of the peptide-conjugated siRNAs were examined. Dicer cleaved the peptide-conjugated 27-nt siRNA leading to the release of 21-nt siRNA, whereas the peptide-conjugated 21-nt siRNA was not cleaved. High membrane permeability and cytoplasmic localization was found in the conjugates. Moreover, the peptide-conjugated 27-nt siRNA showed increased potency of RNAi in comparison with the nonmodified 21-nt and 27-nt siRNAs, whereas the peptide-conjugated 21-nt siRNA showed decreased RNAi efficacy. This potent RNAi efficacy is probably owing to acceleration of RISC through recognition by Dicer, as well as to the improvement of cell membrane permeability and intracellular accumulation. Full article

(This article belongs to the Special Issue Nucleic Acid Analogs)

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851 KiB

Open AccessArticle

Synthesis and Chromatography-Free Purification of PNA-PEO Conjugates for the Functionalisation of Gold Sensors

by Monica Dettin, Davide Silvestri, Roberta Danesin, Erica Cretaio, Gianluca Picariello, Elisabetta Casarin, Agnese Sonato, Filippo Romanato and Margherita Morpurgo

Molecules 2012, 17(9), 11026-11045; https://doi.org/10.3390/molecules170911026 - 13 Sep 2012

Cited by 10 | Viewed by 6285

Abstract

Peptide Nucleic Acids (PNAs) linked to high molecular weight (MW) poly(ethylene oxide) (PEO) derivatives could be useful conjugates for the direct functionalisation of gold surfaces dedicated to Surface Plasmon Resonance (SPR)-based DNA sensing. However their use is hampered by the difficulty to obtain [...] Read more.

Peptide Nucleic Acids (PNAs) linked to high molecular weight (MW) poly(ethylene oxide) (PEO) derivatives could be useful conjugates for the direct functionalisation of gold surfaces dedicated to Surface Plasmon Resonance (SPR)-based DNA sensing. However their use is hampered by the difficulty to obtain them through a convenient and economical route. In this work we compared three synthetic strategies to obtain PNA-high MW PEO conjugates composed of (a) a 15-mer PNA sequence as the probe complementary to genomic DNA of Mycobacterium tuberculosis, (b) a PEO moiety (2 or 5 KDa MW) and (c) a terminal trityl-protected thiol necessary (after acidic deprotection) for grafting to gold surfaces. The 15-mer PNA was obtained by solid-phase synthesis. Its amino terminal group was later condensed to bi-functional PEO derivatives (2 and 5 KDa MW) carrying a Trt-cysteine at one end and a carboxyl group at the other end. The reaction was carried out either in solution, using HATU or PyOxim as coupling agents, or through the solid-phase approach, with 49.6%, 100% and 5.2% yield, respectively. A differential solvent extraction strategy for product purification without the need for chromatography is described. The ability of the 5 KDa PEO conjugate to function as a probe for complementary DNA detection was demonstrated using a Grating-Coupling Surface Plasmon Resonance (GC-SPR) system. The optimized PEO conjugation and purification protocols are economical and simple enough to be reproduced also within laboratories that are not highly equipped for chemical synthesis. Full article

(This article belongs to the Special Issue Nucleic Acid Analogs)

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439 KiB

Open AccessArticle

Synthesis of Oligonucleotides Carrying Thiol Groups Using a Simple Reagent Derived from Threoninol

by Sonia Pérez-Rentero, Santiago Grijalvo, Rubén Ferreira and Ramon Eritja

Molecules 2012, 17(9), 10026-10045; https://doi.org/10.3390/molecules170910026 - 24 Aug 2012

Cited by 9 | Viewed by 7700

Abstract

Oligonucleotides carrying thiol groups are useful intermediates for a remarkable number of applications involving nucleic acids. In this study, DNA oligonucleotides carrying tert-butylsulfanyl (t-BuS) protected thiol groups have been prepared. A building block derived from threoninol has been developed to [...] Read more.

Oligonucleotides carrying thiol groups are useful intermediates for a remarkable number of applications involving nucleic acids. In this study, DNA oligonucleotides carrying tert-butylsulfanyl (t-BuS) protected thiol groups have been prepared. A building block derived from threoninol has been developed to introduce a thiol group at any predetemined position of an oligonucleotide. The resulting thiolated oligonucleotides have been used for the preparation of oligonucleotide conjugates and for the functionalization of gold nanoparticles using the reactivity of the thiol groups. Full article

(This article belongs to the Special Issue Nucleic Acid Analogs)

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395 KiB

Open AccessArticle

Synthesis, DNA-Binding and Antiproliferative Properties of Acridine and 5-Methylacridine Derivatives

by Rubén Ferreira, Anna Aviñó, Stefania Mazzini and Ramon Eritja

Molecules 2012, 17(6), 7067-7082; https://doi.org/10.3390/molecules17067067 - 08 Jun 2012

Cited by 25 | Viewed by 6501

Abstract

Several acridine derivatives were synthesized and their anti-proliferative activity was determined. The most active molecules were derivatives of 5-methylacridine-4-carboxylic acid. The DNA binding properties of the synthesized acridines were analyzed by competitive dialysis and compared with the anti-proliferative activities. While inactive acridine derivatives [...] Read more.

Several acridine derivatives were synthesized and their anti-proliferative activity was determined. The most active molecules were derivatives of 5-methylacridine-4-carboxylic acid. The DNA binding properties of the synthesized acridines were analyzed by competitive dialysis and compared with the anti-proliferative activities. While inactive acridine derivatives showed high selectivity for G-quadruplex structures, the most active 5-methylacridine-4-carboxamide derivatives had high affinity for DNA but showed poor specificity. An NMR titration study was performed with the most active 5-methylacridine-4-carboxamide, confirming the high affinity of this compound for both duplex and quadruplex DNAs. Full article

(This article belongs to the Special Issue Nucleic Acid Analogs)

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491 KiB

Open AccessArticle

Development of Diversified Methods for Chemical Modification of the 5,6-Double Bond of Uracil Derivatives Depending on Active Methylene Compounds

by Hironao Sajiki, Yusuke Iida, Kanoko Ikawa, Yoshinari Sawama, Yasunari Monguchi, Yukio Kitade, Yoshifumi Maki, Hideo Inoue and Kosaku Hirota

Molecules 2012, 17(6), 6519-6546; https://doi.org/10.3390/molecules17066519 - 30 May 2012

Cited by 3 | Viewed by 7934

Abstract

The reaction of 5-halogenouracil and uridine derivatives 1 and 7 with active methylene compounds under basic conditions produced diverse and selective C-C bond formation products by virtue of the nature of the carbanions. Three different types of reactions such as the regioselective C-C [...] Read more.

The reaction of 5-halogenouracil and uridine derivatives 1 and 7 with active methylene compounds under basic conditions produced diverse and selective C-C bond formation products by virtue of the nature of the carbanions. Three different types of reactions such as the regioselective C-C bond formation at the 5- and 6-positions of uracil and uridine derivatives (products 2, 5, 8, 17, 20 and 21), and the formation of fused heterocycle derivatives 2,4-diazabicyclo[4.1.0]heptane (15) and 2,4-diazabicyclo-[4.1.0]nonane (16) via dual C-C bond formations at both the 5- and 6-positions were due to the different active methylene compounds used as reagents. Full article

(This article belongs to the Special Issue Nucleic Acid Analogs)

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Review

Jump to: Research

18 pages, 1283 KiB

Open AccessReview

Determining RNA Natural Modifications and Nucleoside Analog-Labeled Sites by a Chemical/Enzyme-Induced Base Mutation Principle

by Ziming Bao, Tengwei Li and Jianzhao Liu

Molecules 2023, 28(4), 1517; https://doi.org/10.3390/molecules28041517 - 04 Feb 2023

Cited by 3 | Viewed by 1966

Abstract

The natural chemical modifications of messenger RNA (mRNA) in living organisms have shown essential roles in both physiology and pathology. The mapping of mRNA modifications is critical for interpreting their biological functions. In another dimension, the synthesized nucleoside analogs can enable chemical labeling [...] Read more.

The natural chemical modifications of messenger RNA (mRNA) in living organisms have shown essential roles in both physiology and pathology. The mapping of mRNA modifications is critical for interpreting their biological functions. In another dimension, the synthesized nucleoside analogs can enable chemical labeling of cellular mRNA through a metabolic pathway, which facilitates the study of RNA dynamics in a pulse-chase manner. In this regard, the sequencing tools for mapping both natural modifications and nucleoside tags on mRNA at single base resolution are highly necessary. In this work, we review the progress of chemical sequencing technology for determining both a variety of naturally occurring base modifications mainly on mRNA and a few on transfer RNA and metabolically incorporated artificial base analogs on mRNA, and further discuss the problems and prospects in the field. Full article

(This article belongs to the Collection New Frontiers in Nucleic Acid Chemistry)

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19 pages, 3287 KiB

Open AccessReview

Single-Labeled Oligonucleotides Showing Fluorescence Changes upon Hybridization with Target Nucleic Acids

by Gil Tae Hwang

Molecules 2018, 23(1), 124; https://doi.org/10.3390/molecules23010124 - 08 Jan 2018

Cited by 23 | Viewed by 7973

Abstract

Sequence-specific detection of nucleic acids has been intensively studied in the field of molecular diagnostics. In particular, the detection and analysis of single-nucleotide polymorphisms (SNPs) is crucial for the identification of disease-causing genes and diagnosis of diseases. Sequence-specific hybridization probes, such as molecular [...] Read more.

Sequence-specific detection of nucleic acids has been intensively studied in the field of molecular diagnostics. In particular, the detection and analysis of single-nucleotide polymorphisms (SNPs) is crucial for the identification of disease-causing genes and diagnosis of diseases. Sequence-specific hybridization probes, such as molecular beacons bearing the fluorophore and quencher at both ends of the stem, have been developed to enable DNA mutation detection. Interestingly, DNA mutations can be detected using fluorescently labeled oligonucleotide probes with only one fluorophore. This review summarizes recent research on single-labeled oligonucleotide probes that exhibit fluorescence changes after encountering target nucleic acids, such as guanine-quenching probes, cyanine-containing probes, probes containing a fluorophore-labeled base, and microenvironment-sensitive probes. Full article

(This article belongs to the Collection New Frontiers in Nucleic Acid Chemistry)

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31930 KiB

Open AccessFeature PaperReview

Recent Advances in Nucleic Acid Targeting Probes and Supramolecular Constructs Based on Pyrene-Modified Oligonucleotides

by Olga A. Krasheninina, Darya S. Novopashina, Evgeny K. Apartsin and Alya G. Venyaminova

Molecules 2017, 22(12), 2108; https://doi.org/10.3390/molecules22122108 - 30 Nov 2017

Cited by 36 | Viewed by 9800

Abstract

In this review, we summarize the recent advances in the use of pyrene-modified oligonucleotides as a platform for functional nucleic acid-based constructs. Pyrene is of special interest for the development of nucleic acid-based tools due to its unique fluorescent properties (sensitivity of fluorescence [...] Read more.

In this review, we summarize the recent advances in the use of pyrene-modified oligonucleotides as a platform for functional nucleic acid-based constructs. Pyrene is of special interest for the development of nucleic acid-based tools due to its unique fluorescent properties (sensitivity of fluorescence to the microenvironment, ability to form excimers and exciplexes, long fluorescence lifetime, high quantum yield), ability to intercalate into the nucleic acid duplex, to act as a π-π-stacking (including anchoring) moiety, and others. These properties of pyrene have been used to construct novel sensitive fluorescent probes for the sequence-specific detection of nucleic acids and the discrimination of single nucleotide polymorphisms (SNPs), aptamer-based biosensors, agents for binding of double-stranded DNAs, and building blocks for supramolecular complexes. Special attention is paid to the influence of the design of pyrene-modified oligonucleotides on their properties, i.e., the structure-function relationships. The perspectives for the applications of pyrene-modified oligonucleotides in biomolecular studies, diagnostics, and nanotechnology are discussed. Full article

(This article belongs to the Collection New Frontiers in Nucleic Acid Chemistry)

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2434 KiB

Open AccessReview

Evolution of Complex Target SELEX to Identify Aptamers against Mammalian Cell-Surface Antigens

by Prabodhika Mallikaratchy

Molecules 2017, 22(2), 215; https://doi.org/10.3390/molecules22020215 - 30 Jan 2017

Cited by 74 | Viewed by 9467

Abstract

The demand has increased for sophisticated molecular tools with improved detection limits. Such molecules should be simple in structure, yet stable enough for clinical applications. Nucleic acid aptamers (NAAs) represent a class of molecules able to meet this demand. In particular, aptamers, a [...] Read more.

The demand has increased for sophisticated molecular tools with improved detection limits. Such molecules should be simple in structure, yet stable enough for clinical applications. Nucleic acid aptamers (NAAs) represent a class of molecules able to meet this demand. In particular, aptamers, a class of small nucleic acid ligands that are composed of single-stranded modified/unmodified RNA/DNA molecules, can be evolved from a complex library using Systematic Evolution of Ligands by EXponential enrichment (SELEX) against almost any molecule. Since its introduction in 1990, in stages, SELEX technology has itself undergone several modifications, improving selection and broadening the repertoire of targets. This review summarizes these milestones that have pushed the field forward, allowing researchers to generate aptamers that can potentially be applied as therapeutic and diagnostic agents. Full article

(This article belongs to the Collection New Frontiers in Nucleic Acid Chemistry)

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346 KiB

Open AccessReview

Therapeutic Applications of Nucleic Acids and Their Analogues in Toll-like Receptor Signaling

by Vijayakumar Gosu, Shaherin Basith, O-Pil Kwon and Sangdun Choi

Molecules 2012, 17(11), 13503-13529; https://doi.org/10.3390/molecules171113503 - 14 Nov 2012

Cited by 53 | Viewed by 8736

Abstract

Toll-like receptors (TLRs) belong to a family of innate immune receptors that detect and clear invading microbial pathogens. Specifically intracellular TLRs such as TLR3, TLR7, TLR8 and TLR9 recognize nucleic acids such as double-stranded RNA, single-stranded RNA and CpG DNA respectively derived from [...] Read more.

Toll-like receptors (TLRs) belong to a family of innate immune receptors that detect and clear invading microbial pathogens. Specifically intracellular TLRs such as TLR3, TLR7, TLR8 and TLR9 recognize nucleic acids such as double-stranded RNA, single-stranded RNA and CpG DNA respectively derived from microbial components. Upon infection, nucleic acid sensing TLRs signal within endosomal compartment triggering the induction of essential proinflammatory cytokines and type I interferons to initiate innate immune responses thereby leading to a critical role in the development of adaptive immune responses. Thus, stimulation of TLRs by nucleic acids is a promising area of research for the development of novel therapeutic strategies against pathogenic infection, allergies, malignant neoplasms and autoimmunity. This review summarizes the therapeutic applications of nucleic acids or nucleic acid analogues through the modulation of TLR signaling pathways. Full article

(This article belongs to the Special Issue Nucleic Acid Analogs)

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418 KiB

Open AccessReview

Structural Probes in Quadruplex Nucleic Acid Structure Determination by NMR

by Andreas Ioannis Karsisiotis and Mateus Webba da Silva

Molecules 2012, 17(11), 13073-13086; https://doi.org/10.3390/molecules171113073 - 05 Nov 2012

Cited by 17 | Viewed by 9204

Abstract

Traditionally, isotope-labelled DNA and RNA have been fundamental to nucleic acid structural studies by NMR. Four-stranded nucleic acid architectures studies increasingly benefit from a plethora of nucleotide conjugates for resonance assignments, the identification of hydrogen bond alignments, and improving the population of preferred [...] Read more.

Traditionally, isotope-labelled DNA and RNA have been fundamental to nucleic acid structural studies by NMR. Four-stranded nucleic acid architectures studies increasingly benefit from a plethora of nucleotide conjugates for resonance assignments, the identification of hydrogen bond alignments, and improving the population of preferred species within equilibria. In this paper, we review their use for these purposes. Most importantly we identify reasons for the failure of some modifications to result in quadruplex formation. Full article

(This article belongs to the Special Issue Nucleic Acid Analogs)

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784 KiB

Open AccessReview

Chemical Architecture and Applications of Nucleic Acid Derivatives Containing 1,2,3-Triazole Functionalities Synthesized via Click Chemistry

by Tim Efthymiou, Wei Gong and Jean-Paul Desaulniers

Molecules 2012, 17(11), 12665-12703; https://doi.org/10.3390/molecules171112665 - 26 Oct 2012

Cited by 44 | Viewed by 14061

Abstract

There is considerable attention directed at chemically modifying nucleic acids with robust functional groups in order to alter their properties. Since the breakthrough of copper-assisted azide-alkyne cycloadditions (CuAAC), there have been several reports describing the synthesis and properties of novel triazole-modified nucleic acid [...] Read more.

There is considerable attention directed at chemically modifying nucleic acids with robust functional groups in order to alter their properties. Since the breakthrough of copper-assisted azide-alkyne cycloadditions (CuAAC), there have been several reports describing the synthesis and properties of novel triazole-modified nucleic acid derivatives for potential downstream DNA- and RNA-based applications. This review will focus on highlighting representative novel nucleic acid molecular structures that have been synthesized via the “click” azide-alkyne cycloaddition. Many of these derivatives show compatibility for various applications that involve enzymatic transformation, nucleic acid hybridization, molecular tagging and purification, and gene silencing. The details of these applications are discussed. In conclusion, the future of nucleic acid analogues functionalized with triazoles is promising. Full article

(This article belongs to the Special Issue Nucleic Acid Analogs)

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718 KiB

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Recent Advances in Cyclonucleosides: C-Cyclonucleosides and Spore Photoproducts in Damaged DNA

by Yuichi Yoshimura and Hiroki Takahata

Molecules 2012, 17(10), 11630-11654; https://doi.org/10.3390/molecules171011630 - 28 Sep 2012

Cited by 9 | Viewed by 5100

Abstract

Cyclonucleosides which are fixed in a specific conformation around the glycosyl bond by a carbon and heteroatom chain constitute a unique category of nucleoside derivatives. Because they are structural analogs, cyclonucleosides and oligodeoxynucleotides containing them would be useful tools for investigating the biological [...] Read more.

Cyclonucleosides which are fixed in a specific conformation around the glycosyl bond by a carbon and heteroatom chain constitute a unique category of nucleoside derivatives. Because they are structural analogs, cyclonucleosides and oligodeoxynucleotides containing them would be useful tools for investigating the biological functions and conformations of DNA, RNA as well as their steric interactions with proteins. C-Cyclonucleosides bridged by a carbon chain between the base and sugar moieties are the most attractive from the synthetic points of view as well as for use as biological tools. In this review, recent progress of the synthesis of C-cyclonucleosides is surveyed. Among the C-cyclonucleosides, 5′,8-C-cyclodeoxyadenosine is one of the well-known derivatives of which the first practical synthesis was reported over 30 years ago. Recently, 5′,8-C-cyclodeoxyadenosine has attracted considerable interest as a biomarker, since its formation in oxidatively-damaged DNA is considered to be related to various diseases and aging. Another important analogue of cyclonucleosides is a unique thymidine phosphate dimer, a so-called spore photoproduct, which has been found in photo-damaged DNA. Recent advances in the synthesis, mechanism-studies, and stereochemical preference of repairing enzymes related to 5′,8-C-cyclodeoxyadenosine and spore photoproducts are also reviewed. Full article

(This article belongs to the Special Issue Nucleic Acid Analogs)

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