Editorial

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4 pages, 204 KiB

Open AccessEditorial

Selective Ligands for Non-Canonical DNA Structures: Do They Have a Future in Medicinal Chemistry?

by Manlio Palumbo and Claudia Sissi

Int. J. Mol. Sci. 2022, 23(19), 11984; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911984 - 09 Oct 2022

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Abstract

Winning the war against cancer represents a major goal currently [...] Full article

(This article belongs to the Special Issue Selective Ligands for Non-canonical DNA Structures: Do They Have a Future in Medicinal Chemistry?)

Research

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29 pages, 3750 KiB

Open AccessArticle

Synthesis and Characterization of Bis-Triazolyl-Pyridine Derivatives as Noncanonical DNA-Interacting Compounds

by Anna Di Porzio, Ubaldina Galli, Jussara Amato, Pasquale Zizza, Sara Iachettini, Nunzia Iaccarino, Simona Marzano, Federica Santoro, Diego Brancaccio, Alfonso Carotenuto, Stefano De Tito, Annamaria Biroccio, Bruno Pagano, Gian Cesare Tron and Antonio Randazzo

Int. J. Mol. Sci. 2021, 22(21), 11959; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111959 - 04 Nov 2021

Cited by 5 | Viewed by 2702

Abstract

Besides the well-known double-helical conformation, DNA is capable of folding into various noncanonical arrangements, such as G-quadruplexes (G4s) and i-motifs (iMs), whose occurrence in gene promoters, replication origins, and telomeres highlights the breadth of biological processes that they might regulate. Particularly, previous studies [...] Read more.

Besides the well-known double-helical conformation, DNA is capable of folding into various noncanonical arrangements, such as G-quadruplexes (G4s) and i-motifs (iMs), whose occurrence in gene promoters, replication origins, and telomeres highlights the breadth of biological processes that they might regulate. Particularly, previous studies have reported that G4 and iM structures may play different roles in controlling gene transcription. Anyway, molecular tools able to simultaneously stabilize/destabilize those structures are still needed to shed light on what happens at the biological level. Herein, a multicomponent reaction and a click chemistry functionalization were combined to generate a set of 31 bis-triazolyl-pyridine derivatives which were initially screened by circular dichroism for their ability to interact with different G4 and/or iM DNAs and to affect the thermal stability of these structures. All the compounds were then clustered through multivariate data analysis, based on such capability. The most promising compounds were subjected to a further biophysical and biological characterization, leading to the identification of two molecules simultaneously able to stabilize G4s and destabilize iMs, both in vitro and in living cells. Full article

(This article belongs to the Special Issue Selective Ligands for Non-canonical DNA Structures: Do They Have a Future in Medicinal Chemistry?)

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16 pages, 3572 KiB

Open AccessArticle

Interaction of 9-Methoxyluminarine with Different G-Quadruplex Topologies: Fluorescence and Circular Dichroism Studies

by Joanna Nowak-Karnowska, Agata Głuszyńska, Joanna Kosman, Grażyna Neunert and Anna Dembska

Int. J. Mol. Sci. 2021, 22(19), 10399; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910399 - 27 Sep 2021

Cited by 3 | Viewed by 2013

Abstract

The interactions of G–quadruplexes of different topologies with highly fluorescent 9-methoxyluminarine ligand 9-MeLM were investigated by fluorescence and circular dichroism spectroscopy. The results showed that 9-methoxyluminarine was able to interact and did not destabilize any investigated molecular targets. The studied compound was selectively [...] Read more.

The interactions of G–quadruplexes of different topologies with highly fluorescent 9-methoxyluminarine ligand 9-MeLM were investigated by fluorescence and circular dichroism spectroscopy. The results showed that 9-methoxyluminarine was able to interact and did not destabilize any investigated molecular targets. The studied compound was selectively quenched by parallel c-MYC G-quadruplex DNA, whereas hybrid and antiparallel G4 topology caused only a negligible decrease in the fluorescence of the ligand. A high decrease of fluorescence of the ligand after binding with c-MYC G-quadruplex suggests that this molecule can be used as a selective probe for parallel G-quadruplexes. Full article

(This article belongs to the Special Issue Selective Ligands for Non-canonical DNA Structures: Do They Have a Future in Medicinal Chemistry?)

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20 pages, 2556 KiB

Open AccessArticle

Targeting of Telomeric Repeat-Containing RNA G-Quadruplexes: From Screening to Biophysical and Biological Characterization of a New Hit Compound

by Simona Marzano, Bruno Pagano, Nunzia Iaccarino, Anna Di Porzio, Stefano De Tito, Eleonora Vertecchi, Erica Salvati, Antonio Randazzo and Jussara Amato

Int. J. Mol. Sci. 2021, 22(19), 10315; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910315 - 24 Sep 2021

Cited by 8 | Viewed by 2686

Abstract

DNA G-quadruplex (G4) structures, either within gene promoter sequences or at telomeres, have been extensively investigated as potential small-molecule therapeutic targets. However, although G4s forming at the telomeric DNA have been extensively investigated as anticancer targets, few studies focus on the telomeric repeat-containing [...] Read more.

DNA G-quadruplex (G4) structures, either within gene promoter sequences or at telomeres, have been extensively investigated as potential small-molecule therapeutic targets. However, although G4s forming at the telomeric DNA have been extensively investigated as anticancer targets, few studies focus on the telomeric repeat-containing RNA (TERRA), transcribed from telomeres, as potential pharmacological targets. Here, a virtual screening approach to identify a library of drug-like putative TERRA G4 binders, in tandem with circular dichroism melting assay to study their TERRA G4-stabilizing properties, led to the identification of a new hit compound. The affinity of this compound for TERRA RNA and some DNA G4s was analyzed through several biophysical techniques and its biological activity investigated in terms of antiproliferative effect, DNA damage response (DDR) activation, and TERRA RNA expression in high vs. low TERRA-expressing human cancer cells. The selected hit showed good affinity for TERRA G4 and no binding to double-stranded DNA. In addition, biological assays showed that this compound is endowed with a preferential cytotoxic effect on high TERRA-expressing cells, where it induces a DDR at telomeres, probably by displacing TERRA from telomeres. Our studies demonstrate that the identification of TERRA G4-targeting drugs with potential pharmacological effects is achievable, shedding light on new perspectives aimed at discovering new anticancer agents targeting these G4 structures. Full article

(This article belongs to the Special Issue Selective Ligands for Non-canonical DNA Structures: Do They Have a Future in Medicinal Chemistry?)

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15 pages, 3246 KiB

Open AccessArticle

Exploring the Interaction of Curaxin CBL0137 with G-Quadruplex DNA Oligomers

by Sabrina Dallavalle, Luce M. Mattio, Roberto Artali, Loana Musso, Anna Aviñó, Carme Fàbrega, Ramon Eritja, Raimundo Gargallo and Stefania Mazzini

Int. J. Mol. Sci. 2021, 22(12), 6476; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126476 - 17 Jun 2021

Cited by 9 | Viewed by 2645

Abstract

Curaxins and especially the second-generation derivative curaxin CBL0137 have important antitumor activities in multiple cancers such as glioblastoma, melanoma and others. Although most of the authors suggest that their mechanism of action comes from the activation of p53 and inactivation of NF-kB by [...] Read more.

Curaxins and especially the second-generation derivative curaxin CBL0137 have important antitumor activities in multiple cancers such as glioblastoma, melanoma and others. Although most of the authors suggest that their mechanism of action comes from the activation of p53 and inactivation of NF-kB by targeting FACT, there is evidence supporting the involvement of DNA binding in their antitumor activity. In this work, the DNA binding properties of curaxin CBL0137 with model quadruplex DNA oligomers were studied by ¹H NMR, CD, fluorescence and molecular modeling. We provided molecular details of the interaction of curaxin with two G-quadruplex structures, the single repeat of human telomere d(TTAGGGT)₄ and the c-myc promoter Pu22 sequence. We also performed ¹H and ³¹P NMR experiments were also performed in order to investigate the interaction with duplex DNA models. Our data support the hypothesis that the interaction of curaxin with G-quadruplex may provide a novel insight into the DNA-binding properties of CBL0137, and it will be helpful for the design of novel selective DNA-targeting curaxin analogues. Full article

(This article belongs to the Special Issue Selective Ligands for Non-canonical DNA Structures: Do They Have a Future in Medicinal Chemistry?)

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14 pages, 2275 KiB

Open AccessArticle

Towards Profiling of the G-Quadruplex Targeting Drugs in the Living Human Cells Using NMR Spectroscopy

by Daniel Krafčík, Eva Ištvánková, Šimon Džatko, Pavlína Víšková, Silvie Foldynová-Trantírková and Lukáš Trantírek

Int. J. Mol. Sci. 2021, 22(11), 6042; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22116042 - 03 Jun 2021

Cited by 18 | Viewed by 3321

Abstract

Recently, the ¹H-detected in-cell NMR spectroscopy has emerged as a unique tool allowing the characterization of interactions between nucleic acid-based targets and drug-like molecules in living human cells. Here, we assess the application potential of ¹H and ¹⁹F-detected in-cell NMR [...] Read more.

Recently, the ¹H-detected in-cell NMR spectroscopy has emerged as a unique tool allowing the characterization of interactions between nucleic acid-based targets and drug-like molecules in living human cells. Here, we assess the application potential of ¹H and ¹⁹F-detected in-cell NMR spectroscopy to profile drugs/ligands targeting DNA G-quadruplexes, arguably the most studied class of anti-cancer drugs targeting nucleic acids. We show that the extension of the original in-cell NMR approach is not straightforward. The severe signal broadening and overlap of ¹H in-cell NMR spectra of polymorphic G-quadruplexes and their complexes complicate their quantitative interpretation. Nevertheless, the ¹H in-cell NMR can be used to identify drugs that, despite strong interaction in vitro, lose their ability to bind G-quadruplexes in the native environment. The in-cell NMR approach is adjusted to a recently developed 3,5-bis(trifluoromethyl)phenyl probe to monitor the intracellular interaction with ligands using ¹⁹F-detected in-cell NMR. The probe allows dissecting polymorphic mixture in terms of number and relative populations of individual G-quadruplex species, including ligand-bound and unbound forms in vitro and in cellulo. Despite the probe’s discussed limitations, the ¹⁹F-detected in-cell NMR appears to be a promising strategy to profile G-quadruplex–ligand interactions in the complex environment of living cells. Full article

(This article belongs to the Special Issue Selective Ligands for Non-canonical DNA Structures: Do They Have a Future in Medicinal Chemistry?)

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Review

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19 pages, 3639 KiB

Open AccessReview

G-Quadruplex Targeting in the Fight against Viruses: An Update

by Emanuela Ruggiero, Irene Zanin, Marianna Terreri and Sara N. Richter

Int. J. Mol. Sci. 2021, 22(20), 10984; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222010984 - 12 Oct 2021

Cited by 42 | Viewed by 4088

Abstract

G-quadruplexes (G4s) are noncanonical nucleic acid structures involved in the regulation of key cellular processes, such as transcription and replication. Since their discovery, G4s have been mainly investigated for their role in cancer and as targets in anticancer therapy. More recently, exploration of [...] Read more.

G-quadruplexes (G4s) are noncanonical nucleic acid structures involved in the regulation of key cellular processes, such as transcription and replication. Since their discovery, G4s have been mainly investigated for their role in cancer and as targets in anticancer therapy. More recently, exploration of the presence and role of G4s in viral genomes has led to the discovery of G4-regulated key viral pathways. In this context, employment of selective G4 ligands has helped to understand the complexity of G4-mediated mechanisms in the viral life cycle, and highlighted the possibility to target viral G4s as an emerging antiviral approach. Research in this field is growing at a fast pace, providing increasing evidence of the antiviral activity of old and new G4 ligands. This review aims to provide a punctual update on the literature on G4 ligands exploited in virology. Different classes of G4 binders are described, with emphasis on possible antiviral applications in emerging diseases, such as the current COVID-19 pandemic. Strengths and weaknesses of G4 targeting in viruses are discussed. Full article

(This article belongs to the Special Issue Selective Ligands for Non-canonical DNA Structures: Do They Have a Future in Medicinal Chemistry?)

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23 pages, 4514 KiB

Open AccessReview

Non-Canonical Helical Structure of Nucleic Acids Containing Base-Modified Nucleotides

by Thananjeyan Balasubramaniyam, Kwnag-Im Oh, Ho-Seong Jin, Hye-Bin Ahn, Byeong-Seon Kim and Joon-Hwa Lee

Int. J. Mol. Sci. 2021, 22(17), 9552; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179552 - 02 Sep 2021

Cited by 9 | Viewed by 5268

Abstract

Chemically modified nucleobases are thought to be important for therapeutic purposes as well as diagnosing genetic diseases and have been widely involved in research fields such as molecular biology and biochemical studies. Many artificially modified nucleobases, such as methyl, halogen, and aryl modifications [...] Read more.

Chemically modified nucleobases are thought to be important for therapeutic purposes as well as diagnosing genetic diseases and have been widely involved in research fields such as molecular biology and biochemical studies. Many artificially modified nucleobases, such as methyl, halogen, and aryl modifications of purines at the C8 position and pyrimidines at the C5 position, are widely studied for their biological functions. DNA containing these modified nucleobases can form non-canonical helical structures such as Z-DNA, G-quadruplex, i-motif, and triplex. This review summarizes the synthesis of chemically modified nucleotides: (i) methylation, bromination, and arylation of purine at the C8 position and (ii) methylation, bromination, and arylation of pyrimidine at the C5 position. Additionally, we introduce the non-canonical structures of nucleic acids containing these modifications. Full article

(This article belongs to the Special Issue Selective Ligands for Non-canonical DNA Structures: Do They Have a Future in Medicinal Chemistry?)

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23 pages, 2147 KiB

Open AccessReview

On the Road to Fight Cancer: The Potential of G-Quadruplex Ligands as Novel Therapeutic Agents

by Irene Alessandrini, Marta Recagni, Nadia Zaffaroni and Marco Folini

Int. J. Mol. Sci. 2021, 22(11), 5947; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115947 - 31 May 2021

Cited by 47 | Viewed by 3774

Abstract

Nucleic acid sequences able to adopt a G-quadruplex conformation are overrepresented within the human genome. This evidence strongly suggests that these genomic regions have been evolutionary selected to play a pivotal role in several aspects of cell biology. In the present review article, [...] Read more.

Nucleic acid sequences able to adopt a G-quadruplex conformation are overrepresented within the human genome. This evidence strongly suggests that these genomic regions have been evolutionary selected to play a pivotal role in several aspects of cell biology. In the present review article, we provide an overview on the biological impact of targeting G-quadruplexes in cancer. A variety of small molecules showing good G-quadruplex stabilizing properties has been reported to exert an antitumor activity in several preclinical models of human cancers. Moreover, promiscuous binders and multiple targeting G-quadruplex ligands, cancer cell defense responses and synthetic lethal interactions of G-quadruplex targeting have been also highlighted. Overall, evidence gathered thus far indicates that targeting G-quadruplex may represent an innovative and fascinating therapeutic approach for cancer. The continued methodological improvements, the development of specific tools and a careful consideration of the experimental settings in living systems will be useful to deepen our knowledge of G-quadruplex biology in cancer, to better define their role as therapeutic targets and to help design and develop novel and reliable G-quadruplex-based anticancer strategies. Full article

(This article belongs to the Special Issue Selective Ligands for Non-canonical DNA Structures: Do They Have a Future in Medicinal Chemistry?)

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