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G‐quadruplex Ligands: Recent Advances
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G‐quadruplex Ligands: Recent Advances

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (20 April 2024) | Viewed by 10202

Special Issue Editors

Dr. Zizza Pasquale

E-Mail Website
Guest Editor
Oncogenomic and Epigenetic Unit, Regina Elena National Cancer Institute, via Elio Chianesi, 53, 00146 Rome, Italy
Interests: cancer; G-quadruplex; aging
Dr. Sara Iachettini

E-Mail Website
Guest Editor
IRCCS - Regina Elena National Cancer Institute, 00144 Rome, Italy
Interests: antitumor activity of G-quadruplex ligands; functions of the shelterin protein TRF2; biochemistry, molecular and cellular biology

Special Issue Information

Dear Colleagues,

G-quadruplexes (G4s) are guanine-rich non-canonical secondary structures of nucleic acids which were discovered in vitro almost a half century ago. From the early 1980s onward, these structures have also been identified in eukaryotic cells, first at the level of telomeres and more recently in regulatory regions of certain genes.

Due their involvement in numerous biological processes and in the pathogenesis of several disease, including cancer, the interest in G4s and their targeting has undergone exponential growth over the last few years. Notably, G4 ligands constitute a large family of heterogeneous molecules which exert their functions through recognition, binding and stabilization of G4 structures. In terms of anti-cancer activity, the efficacy of G4 ligands can be attributed to their capability to inhibit telomerase activity (long-term effects) and induce DNA damage and/or modulation of cancer-related genes (short-term effects). Interestingly, while the knowledge concerning the structural organization of G4s has been extensively characterized, the functions, the potential application of these structures and the development of novel G4s are still active research topics worthy of further investigation.

Dr. Zizza Pasquale
Dr. Sara Iachettini
Guest Editors

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Keywords

  • G-quadruplex
  • telomeres
  • aging
  • cancer
  • genomic stability
  • G4-ligands
  • DNA damage

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Published Papers (4 papers)

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16 pages, 4214 KiB  
Article
Carbazole Derivatives Binding to Bcl-2 Promoter Sequence G-quadruplex
by Agata Głuszyńska, Joanna Kosman, Shang Shiuan Chuah, Marcin Hoffmann and Shozeb Haider
Pharmaceuticals 2024, 17(7), 912; https://doi.org/10.3390/ph17070912 - 9 Jul 2024
Viewed by 829
Abstract
In this study, we used ultraviolet-visible (UV-Vis), fluorescence, and circular dichroism (CD) techniques, as well as molecular modeling, to probe the interactions between carbazole derivatives and the G-quadruplex structure formed in the promoter region of gene Bcl-2. This gene is a rational [...] Read more.
In this study, we used ultraviolet-visible (UV-Vis), fluorescence, and circular dichroism (CD) techniques, as well as molecular modeling, to probe the interactions between carbazole derivatives and the G-quadruplex structure formed in the promoter region of gene Bcl-2. This gene is a rational target for anticancer therapy due to its high expression in a variety of tumors as well as resistance to chemotherapy-induced apoptosis. We employed a sequence with a specific dual G-to-T mutation that may form a mixed-type hybrid G-quadruplex structure in the Bcl-2 P1 promoter region. The three tested carbazole compounds differing in substitution on the nitrogen atom of carbazole interact with the Bcl-2 G-quadruplex by the same binding mode with the very comparable binding affinities in the order of 105 M−1. During absorption and fluorescence measurements, large changes in the ligand spectra were observed at higher G4 concentrations. The spectrophotometric titration results showed a two-step complex formation between the ligands and the G-quadruplex in the form of initial hypochromicity followed by hyperchromicity with a bathochromic shift. The strong fluorescence enhancement of ligands was observed after binding to the DNA. All of the used analytical techniques, as well as molecular modeling, suggested the π–π interaction between carbazole ligands and a guanine tetrad of the Bcl-2 G-quadruplex. Molecular modeling has shown differences in the interaction between each of the ligands and the tested G-quadruplex, which potentially had an impact on the binding strength. Full article
(This article belongs to the Special Issue G‐quadruplex Ligands: Recent Advances)
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29 pages, 3591 KiB  
Article
New 2,4-bis[(substituted-aminomethyl)phenyl]phenylquinazoline and 2,4-bis[(substituted-aminomethyl)phenyl]phenylquinoline Derivatives: Synthesis and Biological Evaluation as Novel Anticancer Agents by Targeting G-Quadruplex
by Jean Guillon, Marc Le Borgne, Vittoria Milano, Aurore Guédin-Beaurepaire, Stéphane Moreau, Noël Pinaud, Luisa Ronga, Solène Savrimoutou, Sandra Albenque-Rubio, Mathieu Marchivie, Haouraa Kalout, Charley Walker, Louise Chevallier, Corinne Buré, Eric Largy, Valérie Gabelica, Jean-Louis Mergny, Virginie Baylot, Jacky Ferrer, Yamina Idrissi, Edith Chevret, David Cappellen, Vanessa Desplat, Zsuzsanna Schelz and István Zupkóadd Show full author list remove Hide full author list
Pharmaceuticals 2024, 17(1), 30; https://doi.org/10.3390/ph17010030 - 25 Dec 2023
Viewed by 1652
Abstract
The syntheses of novel 2,4-bis[(substituted-aminomethyl)phenyl]phenylquinazolines 12 and 2,4-bis[(substituted-aminomethyl)phenyl]phenylquinolines 13 are reported here in six steps starting from various halogeno-quinazoline-2,4-(1H,3H)-diones or substituted anilines. The antiproliferative activities of the products were determined in vitro against a panel of breast (MCF-7 and [...] Read more.
The syntheses of novel 2,4-bis[(substituted-aminomethyl)phenyl]phenylquinazolines 12 and 2,4-bis[(substituted-aminomethyl)phenyl]phenylquinolines 13 are reported here in six steps starting from various halogeno-quinazoline-2,4-(1H,3H)-diones or substituted anilines. The antiproliferative activities of the products were determined in vitro against a panel of breast (MCF-7 and MDA-MB-231), human adherent cervical (HeLa and SiHa), and ovarian (A2780) cell lines. Disubstituted 6- and 7-phenyl-bis(3-dimethylaminopropyl)aminomethylphenyl-quinazolines 12b, 12f, and 12i displayed the most interesting antiproliferative activities against six human cancer cell lines. In the series of quinoline derivatives, 6-phenyl-bis(3-dimethylaminopropyl)aminomethylphenylquinoline 13a proved to be the most active. G-quadruplexes (G4) stacked non-canonical nucleic acid structures found in specific G-rich DNA, or RNA sequences in the human genome are considered as potential targets for the development of anticancer agents. Then, as small aza-organic heterocyclic derivatives are well known to target and stabilize G4 structures, their ability to bind G4 structures have been determined through FRET melting, circular dichroism, and native mass spectrometry assays. Finally, telomerase inhibition ability has been also assessed using the MCF-7 cell line. Full article
(This article belongs to the Special Issue G‐quadruplex Ligands: Recent Advances)
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11 pages, 1794 KiB  
Article
Taq-Polymerase Stop Assay to Determine Target Selectivity of G4 Ligands in Native Promoter Sequences of MYC, TERT, and KIT Oncogenes
by Galina V. Chashchina, Liana L. Tevonyan, Artemy D. Beniaminov and Dmitry N. Kaluzhny
Pharmaceuticals 2023, 16(4), 544; https://doi.org/10.3390/ph16040544 - 5 Apr 2023
Cited by 2 | Viewed by 2475
Abstract
Computational and high-throughput experimental methods predict thousands of potential quadruplex sequences (PQSs) in the human genome. Often these PQSs contain more than four G-runs, which introduce additional uncertainty into the conformational polymorphism of the G4 DNA. G4-specific ligands, which are currently being actively [...] Read more.
Computational and high-throughput experimental methods predict thousands of potential quadruplex sequences (PQSs) in the human genome. Often these PQSs contain more than four G-runs, which introduce additional uncertainty into the conformational polymorphism of the G4 DNA. G4-specific ligands, which are currently being actively developed as potential anticancer agents or tools for studying G4 structures in genomes, may preferentially bind to specific G4 structures over the others that can be potentially formed in the extended G-rich genomic region. We propose a simple technique that identifies the sequences that tend to form G4 in the presence of potassium ions or a specific ligand. Thermostable DNA Taq-polymerase stop assay can detect the preferential position of the G4 –ligand binging within a long PQS-rich genomic DNA fragment. This technique was tested for four G4 binders PDS, PhenDC3, Braco-19, and TMPyP4 at three promoter sequences of MYC, KIT, and TERT that contain several PQSs each. We demonstrate that the intensity of polymerase pausing reveals the preferential binding of a ligand to particular G4 structures within the promoter. However, the strength of the polymerase stop at a specific site does not always correlate with the ligand-induced thermodynamic stabilization of the corresponding G4 structure. Full article
(This article belongs to the Special Issue G‐quadruplex Ligands: Recent Advances)
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11 pages, 1463 KiB  
Perspective
Therapeutic Use of G4-Ligands in Cancer: State-of-the-Art and Future Perspectives
by Sara Iachettini, Annamaria Biroccio and Pasquale Zizza
Pharmaceuticals 2024, 17(6), 771; https://doi.org/10.3390/ph17060771 - 13 Jun 2024
Cited by 3 | Viewed by 4597
Abstract
G-quadruplexes (G4s) are guanine-rich non-canonical secondary structures of nucleic acids that were identified in vitro almost half a century ago. Starting from the early 1980s, these structures were also observed in eukaryotic cells, first at the telomeric level and later in regulatory regions [...] Read more.
G-quadruplexes (G4s) are guanine-rich non-canonical secondary structures of nucleic acids that were identified in vitro almost half a century ago. Starting from the early 1980s, these structures were also observed in eukaryotic cells, first at the telomeric level and later in regulatory regions of cancer-related genes, in regulatory RNAs and within specific cell compartments such as lysosomes, mitochondria, and ribosomes. Because of the involvement of these structures in a large number of biological processes and in the pathogenesis of several diseases, including cancer, the interest in G4 targeting has exponentially increased in the last few years, and a great number of novel G4 ligands have been developed. Notably, G4 ligands represent a large family of heterogeneous molecules that can exert their functions by recognizing, binding, and stabilizing G4 structures in multiple ways. Regarding anti-cancer activity, the efficacy of G4 ligands was originally attributed to the capability of these molecules to inhibit the activity of telomerase, an enzyme that elongates telomeres and promotes endless replication in cancer cells. Thereafter, novel mechanisms through which G4 ligands exert their antitumoral activities have been defined, including the induction of DNA damage, control of gene expression, and regulation of metabolic pathways, among others. Here, we provided a perspective on the structure and function of G4 ligands with particular emphasis on their potential role as antitumoral agents. In particular, we critically examined the problems associated with the clinical translation of these molecules, trying to highlight the main aspects that should be taken into account during the phases of drug design and development. Indeed, taking advantage of the successes and failures, and the more recent technological progresses in the field, it would be possible to hypothesize the development of these molecules in the future that would represent a valid option for those cancers still missing effective therapies. Full article
(This article belongs to the Special Issue G‐quadruplex Ligands: Recent Advances)
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