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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 2009

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 19 | Viewed by 5012

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 13 | Viewed by 5873

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 4904

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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8 pages, 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 15 | Viewed by 5832

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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11 pages, 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 5131

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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16 pages, 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 19 | Viewed by 7889

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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11 pages, 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 5 | Viewed by 8139

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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16 pages, 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 4 | Viewed by 8010

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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9 pages, 105 KiB

Open AccessArticle

Thermus thermophilus Strains Active in Purine Nucleoside Synthesis

by Marcos Almendros, José-Vicente Sinisterra Gago and José Berenguer Carlos

Molecules 2009, 14(3), 1279-1287; https://doi.org/10.3390/molecules14031279 - 24 Mar 2009

Cited by 9 | Viewed by 12402

Abstract

Several strains of Thermus thermophilus were tested in order to detect purine nucleoside synthase activity using pyrimidine nucleosides as the sugar-donor and adenine or hypoxanthine as bases. High productivity values (t =1 hr) were obtained while completely avoiding adenosine-deaminase degradation of the products. [...] Read more.

Several strains of Thermus thermophilus were tested in order to detect purine nucleoside synthase activity using pyrimidine nucleosides as the sugar-donor and adenine or hypoxanthine as bases. High productivity values (t =1 hr) were obtained while completely avoiding adenosine-deaminase degradation of the products. N-2-deoxy-ribosyltransferase activity is described for the first time in hyperthermophilic bacteria. Full article

(This article belongs to the Special Issue Nucleic Acids)

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11 pages, 962 KiB

Open AccessArticle

Differential Cytotoxicity of MEX: a Component of Neem Oil Whose Action Is Exerted at the Cell Membrane Level

by Francesca Ricci, Valerio Berardi and Gianfranco Risuleo

Molecules 2009, 14(1), 122-132; https://doi.org/10.3390/molecules14010122 - 31 Dec 2008

Cited by 35 | Viewed by 15026

Abstract

Neem oil is obtained from the seeds of the tree Azadirachta indica. Its chemical composition is very complex, being rich in terpenoids and limonoids, as well as volatile sulphur modified compounds. This work focused on the evaluation of a component of the [...] Read more.

Neem oil is obtained from the seeds of the tree Azadirachta indica. Its chemical composition is very complex, being rich in terpenoids and limonoids, as well as volatile sulphur modified compounds. This work focused on the evaluation of a component of the whole Neem oil obtained by methanolic extraction and defined as MEX. Cytotoxicity was assessed on two different cell populations: a stabilized murine fibroblast line (3T6) and a tumor cell line (HeLa). The data presented here suggest a differential sensitivity of these two populations, the tumor line exhibiting a significantly higher sensitivity to MEX. The data strongly suggest that its toxic target is the cell membrane. In addition the results presented here imply that MEX may contain one or more agents that could find a potential use in anti-proliferative therapy. Full article

(This article belongs to the Special Issue Nucleic Acids)

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20 pages, 390 KiB

Open AccessArticle

The Inhibitory Action of Kohamaic Acid A Derivatives on Mammalian DNA Polymerase β

by Yoshiyuki Mizushina, Daisuke Manita, Toshifumi Takeuchi, Fumio Sugawara, Yuko Kumamoto-Yonezawa, Yuki Matsui, Masaharu Takemura, Mitsuru Sasaki, Hiromi Yoshida and Hirosato Takikawa

Molecules 2009, 14(1), 102-121; https://doi.org/10.3390/molecules14010102 - 29 Dec 2008

Cited by 18 | Viewed by 14199

Abstract

We previously isolated a novel natural product, designated kohamaic acid A (KA-A, compound 1), as an inhibitor of the first cleavage of fertilized sea urchin eggs, and found that this compound could selectively inhibit the activities of mammalian DNA polymerases (pols). In this [...] Read more.

We previously isolated a novel natural product, designated kohamaic acid A (KA-A, compound 1), as an inhibitor of the first cleavage of fertilized sea urchin eggs, and found that this compound could selectively inhibit the activities of mammalian DNA polymerases (pols). In this paper, we investigated the structure and bioactivity of KA-A and its chemically synthesized 11 derivatives (i.e., compounds 2–12), including KA-A - fatty acid conjugates. The pol inhibitory activity of compound 11 [(1S*,4aS*,8aS*)-17-(1,4,4a,5,6,7,8,8a-octahydro-2,5,5,8a-tetramethyl-naphthalen-1-yl)heptadecanoic acid] was the strongest among the synthesized compounds, and the range of IC₅₀ values for mammalian pols was 3.22 to 8.76 µM; therefore, the length of the fatty acid side chain group of KA-A is important for pol inhibition. KA-A derivatives could prevent human cancer cell (promyelocytic leukemia cell line, HL-60) growth with the same tendency as the inhibition of mammalian pols. Since pol β is the smallest molecule, we used it to analyze the biochemical relationship with KA-A derivatives. From computer modeling analysis (i.e., docking simulation analysis), these compounds bound selectively to four amino acid residues (Leu11, Lys35, His51 and Thr79) of the N-terminal 8-kDa domain of pol β, and the binding energy between compound 11 and pol β was largest in the synthesized compounds. The relationship between the three-dimensional molecular structures of KA-A-related compounds and these inhibitory activities is discussed. Full article

(This article belongs to the Special Issue Nucleic Acids)

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9 pages, 175 KiB

Open AccessArticle

A New Method for the Determination of Nucleic Acid Using an Eu³⁺– nicotinic Acid Complex as a Resonance Light Scattering Probe

by Meng Guo, Lin-Tong Wang, Xia Wu, Wei Xu and Jing-He Yang

Molecules 2009, 14(1), 10-18; https://doi.org/10.3390/molecules14010010 - 23 Dec 2008

Cited by 8 | Viewed by 16304

Abstract

This study found that in Tris-HCl buffer, the resonance light scattering (RLS) intensity of the Eu³⁺-nicotinic acid system can be greatly enhanced by nucleic acids and the enhanced intensity is proportional to the concentration of nucleic acid in the range of [...] Read more.

This study found that in Tris-HCl buffer, the resonance light scattering (RLS) intensity of the Eu³⁺-nicotinic acid system can be greatly enhanced by nucleic acids and the enhanced intensity is proportional to the concentration of nucleic acid in the range of 7×10^-8-1×10^-5g∙mL^-1 for fsDNA, and its detection limit is 2×10^-8g∙mL^-1. Based on this, a new method for the determination of nucleic acids is proposed. Synthetic and actual samples are determined satisfactorily. The interaction mechanism is also studied. It is thought that nucleic acid can bind with the Eu³⁺-nicotinic acid complex through electrostatic attraction and thus form a large Eu³⁺-nicotinic acid-nucleic acid complex. Full article

(This article belongs to the Special Issue Nucleic Acids)

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12 pages, 294 KiB

Open AccessArticle

Binding of Cationic Bis-porphyrins Linked with p- or m-Xylylenediamine and Their Zinc(II) Complexes to Duplex DNA

by Yoshinobu Ishikawa, Naoki Yamakawa and Tadayuki Uno

Molecules 2008, 13(12), 3117-3128; https://doi.org/10.3390/molecules13123117 - 15 Dec 2008

Cited by 10 | Viewed by 12516

Abstract

Spectroscopic, viscometric, and molecular docking analysis of binding of cationic bis-porphyrins linked with p- or m-xylylenediamine (H₂pXy and H₂mXy) and their zinc(II) complexes (ZnpXy and ZnmXy) to duplex DNA are described. H₂pXy and H₂mXy [...] Read more.

Spectroscopic, viscometric, and molecular docking analysis of binding of cationic bis-porphyrins linked with p- or m-xylylenediamine (H₂pXy and H₂mXy) and their zinc(II) complexes (ZnpXy and ZnmXy) to duplex DNA are described. H₂pXy and H₂mXy bound to calf thymus DNA (CTDNA) stronger than unichromophoric H₂TMPyP, and showed exciton-type induced circular dichroism spectra of their Soret bands. The H₂TMPyP-like units of the metal-free bis-porphyrins did not intercalate into CTDNA, and thus the binding mode is outside binding with intramolecular stacking. ZnpXy showed favorable binding to A·T over G·C region, and should lie in the major groove of A·T region. Full article

(This article belongs to the Special Issue Nucleic Acids)

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15 pages, 194 KiB

Open AccessArticle

Synthesis of Novel Homo-N-Nucleoside Analogs Composed of a Homo-1,4-Dioxane Sugar Analog and Substituted 1,3,5-Triazine Base Equivalents

by Qiang Yu, Dirk Schwidom, Alexander Exner and Per Carlsen

Molecules 2008, 13(12), 3092-3106; https://doi.org/10.3390/molecules13123092 - 10 Dec 2008

Cited by 5 | Viewed by 12901

Abstract

Enantioselective syntheses from dimethyl tartrate of 1,3,5-triazine homo-N-nucleoside analogs, containing a 1,4-dioxane moiety replacing the sugar unit in natural nucleosides, were accomplished. The triazine heterocycle in the nucleoside analogs was further substituted with combinations of NH₂, OH and Cl [...] Read more.

Enantioselective syntheses from dimethyl tartrate of 1,3,5-triazine homo-N-nucleoside analogs, containing a 1,4-dioxane moiety replacing the sugar unit in natural nucleosides, were accomplished. The triazine heterocycle in the nucleoside analogs was further substituted with combinations of NH₂, OH and Cl in the 2,4-triazine positions. Full article

(This article belongs to the Special Issue Nucleic Acids)

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13 pages, 301 KiB

Open AccessArticle

Enantioselective Synthesis of Homo-N-Nucleosides Containing a 1,4-Dioxane Sugar Analog

by Qiang Yu and Per Carlsen

Molecules 2008, 13(12), 2962-2974; https://doi.org/10.3390/molecules13122962 - 3 Dec 2008

Cited by 5 | Viewed by 9829

Abstract

A dioxane homo-sugar analog, (2S,5S)-and (2R,5S)-5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-iodomethyl-1,4-dioxane was prepared from (2R,3R)-dimethyl tartrate, and further elaborated into the corresponding homo-N-nucleoside analogs by its reactions with uracil and adenine, respectively. Full article

(This article belongs to the Special Issue Nucleic Acids)

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14 pages, 799 KiB

Open AccessArticle

Effect of Dehydroaltenusin-C12 Derivative, a Selective DNA Polymerase α Inhibitor, on DNA Replication in Cultured Cells

by Isoko Kuriyama, Takeshi Mizuno, Keishi Fukudome, Kouji Kuramochi, Kazunori Tsubaki, Takeo Usui, Naoko Imamoto, Kengo Sakaguchi, Fumio Sugawara, Hiromi Yoshida and Yoshiyuki Mizushina

Molecules 2008, 13(12), 2948-2961; https://doi.org/10.3390/molecules13122948 - 1 Dec 2008

Cited by 13 | Viewed by 12870

Abstract

Dehydroaltenusin is a selective inhibitor of mammalian DNA polymerase α (pol α) from a fungus (Alternaria tennuis). We have designed, synthesized, and characterized a derivative of dehydroaltenusin conjugated with a C12-alkyl side chain (dehydroaltenusin-C12 [C12]). C12 was the strongest pol α [...] Read more.

Dehydroaltenusin is a selective inhibitor of mammalian DNA polymerase α (pol α) from a fungus (Alternaria tennuis). We have designed, synthesized, and characterized a derivative of dehydroaltenusin conjugated with a C12-alkyl side chain (dehydroaltenusin-C12 [C12]). C12 was the strongest pol α inhibitor in vitro. We introduced C12 into NIH3T3 cells with the help of a hypotonic shift, that is, a transient exposure of cultured cells in hypotonic buffer with small molecules which can not penetrate cells. The cells that took in C12 by hypotonic shift showed cell growth inhibition. At a low concentration (5 μM), DNA replication was inhibited and several large replication protein A (RPA) foci, which is different from dUTP foci. Furthermore, when C12 was incubated with aphidicolin, RPA foci were not observed in cells. Finally, these findings suggest that C12 inhibited DNA replication through pol α inhibition, and generated single-stranded DNA, resulted in uncoupling of the leading strand and lagging strand synthesis. These findings suggest that C12 could be more interesting as a molecule probe or anticancer agent than aphidicolin. C12 might provide novel markers for the development of antiproliferative drugs. Full article

(This article belongs to the Special Issue Nucleic Acids)

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15 pages, 412 KiB

Open AccessArticle

Overexpression of the Pdx-1 Homeodomain Transcription Factor Impairs Glucose Metabolism in Cultured Rat Hepatocytes

by Rudolf Tito Pillich, Gianfranco Scarsella and Gianfranco Risuleo

Molecules 2008, 13(10), 2659-2673; https://doi.org/10.3390/molecules13102659 - 28 Oct 2008

Cited by 2 | Viewed by 10997

Abstract

The Pdx-1 transcription factor plays crucial functions both during pancreas development and in the adult β cells. Previous studies have indicated that ectopic Pdx-1 expression in liver or intestinal primary and immortalized cells is sufficient to promote activation of insulin gene expression. This [...] Read more.

The Pdx-1 transcription factor plays crucial functions both during pancreas development and in the adult β cells. Previous studies have indicated that ectopic Pdx-1 expression in liver or intestinal primary and immortalized cells is sufficient to promote activation of insulin gene expression. This work is focused on the molecular and physiological consequences of Pdx-1 overexpression in liver cells. We present evidence that Pdx-1 affects the level of expression of one of the four mammalian hexokinase isozymes. These are glucose phosphorylating enzymes involved in essential cellular functions such as glucose sensing, metabolic energy production and apoptosis. Specifically, our data show that over-expression of Pdx-1 in cultured hepatocytes is able to repress the expression of hexokinase 2 (Hxk 2) and the phenomenon is mediated via binding of Pdx-1 to a specific sequence on the Hxk 2 gene promoter. As a consequence, liver cells over-expressing Pdx-1 present interesting alterations concerning glucose metabolism. Full article

(This article belongs to the Special Issue Nucleic Acids)

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Review

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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 - 4 Feb 2023

Cited by 4 | Viewed by 3766

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 - 8 Jan 2018

Cited by 27 | Viewed by 9236

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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48 pages, 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 41 | Viewed by 11141

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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12 pages, 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 77 | Viewed by 10646

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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22 pages, 236 KiB

Open AccessReview

Recent Developments in the Chemistry of Deoxyribonucleic Acid (DNA) Intercalators: Principles, Design, Synthesis, Applications and Trends

by Brenno A. D. Neto and Alexandre A. M. Lapis

Molecules 2009, 14(5), 1725-1746; https://doi.org/10.3390/molecules14051725 - 7 May 2009

Cited by 125 | Viewed by 19657

Abstract

In the present overview, we describe the bases of intercalation of small molecules (cationic and polar neutral compounds) in DNA. We briefly describe the importance of DNA structure and principles of intercalation. Selected syntheses, possibilities and applications are shown to exemplify the importance, [...] Read more.

In the present overview, we describe the bases of intercalation of small molecules (cationic and polar neutral compounds) in DNA. We briefly describe the importance of DNA structure and principles of intercalation. Selected syntheses, possibilities and applications are shown to exemplify the importance, drawbacks and challenges in this pertinent, new, and exciting research area. Additionally, some clinical applications (molecular processes, cancer therapy and others) and trends are described. Full article

(This article belongs to the Special Issue Nucleic Acids)

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17 pages, 703 KiB

Open AccessReview

The Shorter the Better: Reducing Fixed Primer Regions of Oligonucleotide Libraries for Aptamer Selection

by Weihua Pan and Gary A. Clawson

Molecules 2009, 14(4), 1353-1369; https://doi.org/10.3390/molecules14041353 - 27 Mar 2009

Cited by 45 | Viewed by 18002

Abstract

Oligonucleotide aptamers are highly structured DNA or RNA molecules, or modified versions thereof, that can bind to targets with specific affinities comparable to antibodies. They are identified through an in vitro selection process termed SELEX (Systematic Evolution of Ligands by EXponential enrichment) to [...] Read more.

Oligonucleotide aptamers are highly structured DNA or RNA molecules, or modified versions thereof, that can bind to targets with specific affinities comparable to antibodies. They are identified through an in vitro selection process termed SELEX (Systematic Evolution of Ligands by EXponential enrichment) to recognize a wide variety of targets, from small molecules to proteins, and from cultured cells to whole organisms. Aptamers possess a number of desirable properties, such as ease of synthesis, stability, robustness, and lack of immunogenicity. Standard SELEX libraries require two primers, one on each side of a central random domain, to amplify the target-bound sequences via PCR or RT-PCR. However, these primer sequences cause non-specific binding by their nature, and have been reported to lead to large numbers of false-positive binding sequences, or to interfere with binding of sequences within the random regions. This review is focused on methods which have been developed to eliminate fixed primer interference during the SELEX process. Full article

(This article belongs to the Special Issue Nucleic Acids)

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20 pages, 97 KiB

Open AccessReview

Gene Knockdowns in Adult Animals: PPMOs and Vivo-Morpholinos

by Jon D. Moulton and Shan Jiang

Molecules 2009, 14(3), 1304-1323; https://doi.org/10.3390/molecules14031304 - 25 Mar 2009

Cited by 97 | Viewed by 30811

Abstract

Antisense molecules do not readily cross cell membranes. This has limited the use of antisense to systems where techniques have been worked out to introduce the molecules into cells, such as embryos and cell cultures. Uncharged antisense bearing a group of guanidinium moieties [...] Read more.

Antisense molecules do not readily cross cell membranes. This has limited the use of antisense to systems where techniques have been worked out to introduce the molecules into cells, such as embryos and cell cultures. Uncharged antisense bearing a group of guanidinium moieties on either a linear peptide or dendrimer scaffold can enter cells by endocytosis and subsequently escape from endosomes into the cytosol/nuclear compartment of cells. These technologies allow systemic administration of antisense, making gene knockdowns and splice modification feasible in adult animals; this review presents examples of such animal studies. Techniques developed with PPMOs, which are an arginine-rich cell-penetrating peptide linked to a Morpholino oligo, can also be performed using commercially available Vivo-Morpholinos, which are eight guanidinium groups on a dendrimeric scaffold linked to a Morpholino oligo. Antisense-based techniques such as blocking translation, modifying pre-mRNA splicing, inhibiting miRNA maturation and inhibiting viral replication can be conveniently applied in adult animals by injecting PPMOs or Vivo-Morpholinos. Full article

(This article belongs to the Special Issue Nucleic Acids)

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44 pages, 456 KiB

Open AccessReview

Current Status of Older and New Purine Nucleoside Analogues in the Treatment of Lymphoproliferative Diseases

by Tadeusz Robak, Anna Korycka, Ewa Lech-Maranda and Pawel Robak

Molecules 2009, 14(3), 1183-1226; https://doi.org/10.3390/molecules14031183 - 23 Mar 2009

Cited by 68 | Viewed by 18456

Abstract

For the past few years more and more new cytotoxic agents active in the treatment of hematological malignancies have been synthesized and become available for either in vitro studies or clinical trials. Among them the class of antineoplastic drugs belonging to the purine [...] Read more.

For the past few years more and more new cytotoxic agents active in the treatment of hematological malignancies have been synthesized and become available for either in vitro studies or clinical trials. Among them the class of antineoplastic drugs belonging to the purine nucleoside analogues group (PNAs) plays an important role. Three of them: pentostatin (DCF), cladribine (2-CdA) and fludarabine (FA) were approved by Food and Drug Administration (FDA) for the treatment of hematological malignancies. Recently three novel PNAs: clofarabine (CAFdA), nelarabine (ara-G) and forodesine (immucillin H, BCX-1777) have been synthesized and introduced into preclinical studies and clinical trials. These agents seem to be useful mainly for the treatment of human T-cell proliferative disorders and they are currently undergoing clinical trials in lymphoid malignancies. However, there are also several studies suggesting the role of these drugs in B-cell malignancies. This review will summarize current knowledge concerning the mechanism of action, pharmacologic properties, clinical activity and toxicity of PNAs accepted for use in clinical practice, as well as new agents available for clinical trials. Full article

(This article belongs to the Special Issue Nucleic Acids)

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