Bioactive papaverine derivatives bind G-quadruplexes selectively

2012 ◽  
Vol 66 (2) ◽  
Author(s):  
Elzbieta Galezowska ◽  
Joanna Kosman ◽  
Agnieszka Stepien ◽  
Blazej Rubis ◽  
Maria Rybczynska ◽  
...  
Keyword(s):  
Equilibrium Dialysis ◽  
Oxidation Products ◽  
Telomeric Sequence ◽  
Telomeric Dna ◽  
Binding Selectivity ◽  
Anti Cancer ◽  
G Quadruplex ◽  
Chloride Ligand ◽  
Papaverine Derivatives ◽  
Dna Secondary Structures

AbstractG-quadruplexes are a family of DNA secondary structures resulting from the folding of a guanine-rich sequence. Targeting quadruplexes by small molecules is an approach that is currently being studied with the aim of exploring their biological roles and developing new anti-cancer agents. There is evidence that the formation of G4 structures by telomeric DNA can be used to inhibit the enzyme activity of telomerase, and thereby to activate the pathway to senescence in tumour cells. It was previously shown that the papaverine oxidation products 6a,12a-diazadibenzo-[a,g]fluorenylium derivative (ligand I) and 2,3,9,10-tetramethoxy-12-oxo-12H-indolo[2,1-a]isoquinolinium chloride (ligand II) bind to G-quadruplex representing the human telomeric sequence. These ligands possess the ability to inhibit telomerase and polymerase action at the micromolar level. Here we report a DNA binding study on these two ligands and a new derivative 2-(2-carboxy-4,5-dimethoxyphenyl0-6,7-dimethoxyisoquiloliniuminner salt (ligand III) in order to evaluate their binding selectivity to samples of nucleic acids (ssDNA, dsDNA, triplexes, and quadruplexes). Simultaneous investigations on several DNA-ligand complexes carried out using an equilibrium dialysis approach revealed pronounced binding selectivity of ligand I and ligand II to tetraplex DNA structures over the doublestranded DNA forms.

scholarly journals PhenQE8, a Novel Ligand of the Human Telomeric Quadruplex

2021 ◽  
Vol 22 (2) ◽  
pp. 749
Author(s):  
Patricia B. Gratal ◽  
Julia G. Quero ◽  
Adrián Pérez-Redondo ◽  
Zoila Gándara ◽  
Lourdes Gude
Keyword(s):  
Equilibrium Dialysis ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
The Novel ◽  
X Ray Diffraction ◽  
Telomeric Dna ◽  
Healthy Human ◽  
Quadruplex Dna ◽  
Step Procedure ◽  
G Quadruplex

A novel quadruplex ligand based on 1,10-phenanthroline and incorporating two guanyl hydrazone functionalities, PhenQE8, is reported herein. Synthetic access was gained in a two-step procedure with an overall yield of 61%. X-ray diffraction studies revealed that PhenQE8 can adopt an extended conformation that may be optimal to favor recognition of quadruplex DNA. DNA interactions with polymorphic G-quadruplex telomeric structures were studied by different techniques, such as Fluorescence resonance energy transfer (FRET) DNA melting assays, circular dichroism and equilibrium dialysis. Our results reveal that the novel ligand PhenQE8 can efficiently recognize the hybrid quadruplex structures of the human telomeric DNA, with high binding affinity and quadruplex/duplex selectivity. Moreover, the compound shows significant cytotoxic activity against a selected panel of cultured tumor cells (PC-3, HeLa and MCF-7), whereas its cytotoxicity is considerably lower in healthy human cells (HFF-1 and RPWE-1).

scholarly journals Increasing the activity of DNAzyme based on the telomeric sequence: 2’-OMe-RNA and LNA modifications

2019 ◽  
Vol 17 (1) ◽  
pp. 1157-1166
Author(s):  
J. Kosman ◽  
K. Żukowski ◽  
B. Juskowiak
Keyword(s):  
Dna Sequences ◽  
Peroxidase Activity ◽  
Telomeric Sequence ◽  
Modified Oligonucleotides ◽  
Biological Applications ◽  
Telomeric Dna ◽  
Nucleotide Analogues ◽  
Dna Oligonucleotides ◽  
G Quadruplex ◽  
Low Activity

Abstract2’-OMe-RNA analogues and LNA point modifications of DNA oligonucleotides were applied for the modulation of the G-quadruplex topology and enhancement of peroxidase activity of the resulting DNAzymes. The effect of the 2’-OMe-RNA analogue was studied for full length modified oligonucleotides with various sequences. In the case of LNA-point modification, we have chosen a telomeric DNA sequence and investigated various numbers of modifications. Our main goal was to prove that the application of these modifications can influence the activity of DNAzyme, especially those, which normally form poor DNAzymes. As an example, we have chosen the telomeric HT22 sequence which is known to form DNAzyme characterized by low activity. In all cases, the DNAzymes formed by a telomeric sequence with the application of the 2’-OMe-RNA analogue as well as LNA-point modification, showed significantly higher peroxidase activity. We were also able to shift the formation of hybrid or antiparallel topology to parallel topology. These results are important for the development of probes for biological applications as well as for the design of probes based on DNA sequences that normally form DNAzymes with low activity. This paper also provides information on how the application of nucleotide analogues can transform the topology of G-quadruplexes.

scholarly journals G-QUADRUPLEX LIGANDS AS STABILIZER TARGETING TELOMERASE ENZYME AS ANTI CANCER AGENTS

2017 ◽  
Vol 10 (8) ◽  
pp. 50
Author(s):  
Hemalatha Cn ◽  
Vijey Aanandhi M ◽  
Vijey Aanandhi M
Keyword(s):  
Basic Research ◽  
The Novel ◽  
Telomeric Dna ◽  
Inhibitor Activity ◽  
Quadruplex Dna ◽  
Biological Studies ◽  
Anti Cancer ◽  
G Quadruplex ◽  
Biophysical Studies ◽  
Lagging Strand

The human telomere stabilization with G-Quadruplex DNA tends to induce apoptosis. The molecular target of telomere cascade with a rigid molecular may show efficacious to treat cancer. The study of intercalation to human telomeric DNA with proposed ligand can be evaluated by the help of biophysical studies and biological studies. G-Quadruplex is one of the key epigenetic episodes of eukaryotes and prokaryotes, generally found in the telomeric end region, immunoglobulin switch recombination and the lagging strand of the DNA. These chemotherapeutic advances are not enough to maintain a life expectancy of cancer affected patients. A number of G-Quadruplex ligands such as acridine, perylene, and anthraquinones have been synthesized reported and evaluated them for the inhibitor activity. Therefore, translational research can pave the novel prospect to treat cancer in a fundamental way. In that connection, basic research showed G-Quadruplex phenomenon of DNA, which is having a great impact in this chemotherapy.

scholarly journals Telomeric DNA sequences in beetle taxa vary with species richness

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Daniela Prušáková ◽  
Vratislav Peska ◽  
Stano Pekár ◽  
Michal Bubeník ◽  
Lukáš Čížek ◽  
...  
Keyword(s):  
Species Richness ◽  
Dna Sequences ◽  
Genome Instability ◽  
Telomeric Sequence ◽  
Dna Repeats ◽  
Telomeric Dna ◽  
Common Pattern ◽  
Telomeric Sequences ◽  
Genomic Changes ◽  
Protective Structures

AbstractTelomeres are protective structures at the ends of eukaryotic chromosomes, and disruption of their nucleoprotein composition usually results in genome instability and cell death. Telomeric DNA sequences have generally been found to be exceptionally conserved in evolution, and the most common pattern of telomeric sequences across eukaryotes is (TxAyGz)n maintained by telomerase. However, telomerase-added DNA repeats in some insect taxa frequently vary, show unusual features, and can even be absent. It has been speculated about factors that might allow frequent changes in telomere composition in Insecta. Coleoptera (beetles) is the largest of all insect orders and based on previously available data, it seemed that the telomeric sequence of beetles varies to a great extent. We performed an extensive mapping of the (TTAGG)n sequence, the ancestral telomeric sequence in Insects, across the main branches of Coleoptera. Our study indicates that the (TTAGG)n sequence has been repeatedly or completely lost in more than half of the tested beetle superfamilies. Although the exact telomeric motif in most of the (TTAGG)n-negative beetles is unknown, we found that the (TTAGG)n sequence has been replaced by two alternative telomeric motifs, the (TCAGG)n and (TTAGGG)n, in at least three superfamilies of Coleoptera. The diversity of the telomeric motifs was positively related to the species richness of taxa, regardless of the age of the taxa. The presence/absence of the (TTAGG)n sequence highly varied within the Curculionoidea, Chrysomeloidea, and Staphylinoidea, which are the three most diverse superfamilies within Metazoa. Our data supports the hypothesis that telomere dysfunctions can initiate rapid genomic changes that lead to reproductive isolation and speciation.

Research Progress in the Typical Structure of Human Telomeric G-Quadruplex

2014 ◽  
Vol 955-959 ◽  
pp. 419-422
Author(s):  
Gui Lin Liu ◽  
Yan Ping Ding ◽  
Yan Ling Wu ◽  
Wen Zhang
Keyword(s):  
Cell Cycle ◽  
Dna Sequences ◽  
Research Progress ◽  
Human Chromosomes ◽  
Telomeric Dna ◽  
Typical Structure ◽  
Special Sequence ◽  
Physiological Processes ◽  
G Quadruplex ◽  
Small Molecule Ligands

Telomeric DNA of human chromosomes plays a significant role in physiological processes such as cell cycle, aging, cancer and genetic stability due to its special sequence and structure. The research on small molecule ligands targeting G-quadruplex formed by such special sequence has attracted considerable attention, and has achieved great breakthrough. In this paper, we summarize the DNA sequences and structures of three kinds of typical human telomeric G-quadruplex, providing an important reference for further research.

Targeting G-quadruplex DNA as Potential Anti-cancer Therapy

2017 ◽  
pp. 129-162
Author(s):  
Riccardo Bonsignore ◽  
Elisa Trippodo ◽  
Giampaolo Barone
Keyword(s):  
Cancer Therapy ◽  
Quadruplex Dna ◽  
Anti Cancer ◽  
G Quadruplex

scholarly journals Telomeric G-Quadruplexes: From Human to Tetrahymena Repeats

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Erika Demkovičová ◽  
Ľuboš Bauer ◽  
Petra Krafčíková ◽  
Katarína Tlučková ◽  
Petra Tóthova ◽  
...  
Keyword(s):  
Life Cycle ◽  
Base Substitution ◽  
Telomeric Dna ◽  
Purine Base ◽  
Telomeric Sequences ◽  
G Quadruplex ◽  
The Stability ◽  
Scientific Value ◽  
The Relationship ◽  
Adenine Base

The human telomeric and protozoal telomeric sequences differ only in one purine base in their repeats; TTAGGG in telomeric sequences; and TTGGGG in protozoal sequences. In this study, the relationship between G-quadruplexes formed from these repeats and their derivatives is analyzed and compared. The human telomeric DNA sequence G3(T2AG3)3 and related sequences in which each adenine base has been systematically replaced by a guanine were investigated; the result is Tetrahymena repeats. The substitution does not affect the formation of G-quadruplexes but may cause differences in topology. The results also show that the stability of the substituted derivatives increased in sequences with greater number of substitutions. In addition, most of the sequences containing imperfections in repeats which were analyzed in this study also occur in human and Tetrahymena genomes. Generally, the presence of G-quadruplex structures in any organism is a source of limitations during the life cycle. Therefore, a fuller understanding of the influence of base substitution on the structural variability of G-quadruplexes would be of considerable scientific value.

scholarly journals Pif1 is essential for efficient replisome progression through lagging strand G-quadruplex DNA secondary structures

2018 ◽  
Vol 46 (22) ◽  
pp. 11847-11857 ◽  
Author(s):  
Danielle Dahan ◽  
Ioannis Tsirkas ◽  
Daniel Dovrat ◽  
Melanie A Sparks ◽  
Saurabh P Singh ◽  
...  
Keyword(s):  
Secondary Structures ◽  
Quadruplex Dna ◽  
G Quadruplex ◽  
Dna Secondary Structures ◽  
Lagging Strand

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

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2162 ◽  
Author(s):  
Filippo Doria ◽  
Valentina Pirota ◽  
Michele Petenzi ◽  
Marie-Paule Teulade-Fichou ◽  
Daniela Verga ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Structural Transition ◽  
Binding Mode ◽  
Telomeric Sequence ◽  
Recognition Element ◽  
New Family ◽  
G Quadruplex ◽  
Preferential Binding ◽  
High Cytotoxicity ◽  
Nucleic Acid Structures

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.

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