scholarly journals Berberrubine Phosphate: A Selective Fluorescent Probe for Quadruplex DNA

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2566
Author(s):  
Peter Jonas Wickhorst ◽  
Heiko Ihmels
Keyword(s):  
Duplex Dna ◽  
Binding Modes ◽  
Strong Fluorescence ◽  
Binding Properties ◽  
Thermally Induced ◽  
Quadruplex Dna ◽  
G4 Dna ◽  
Fluorescence Light ◽  
Dna Binders ◽  
Ct Dna

A phosphate-substituted, zwitterionic berberine derivative was synthesized and its binding properties with duplex DNA and G4-DNA were studied using photometric, fluorimetric and polarimetric titrations and thermal DNA denaturation experiments. The ligand binds with high affinity toward both DNA forms (Kb = 2–7 × 105 M−1) and induces a slight stabilization of G4-DNA toward thermally induced unfolding, mostly pronounced for the telomeric quadruplex 22AG. The ligand likely binds by aggregation and intercalation with ct DNA and by terminal stacking with G4-DNA. Thus, this compound represents one of the rare examples of phosphate-substituted DNA binders. In an aqueous solution, the title compound has a very weak fluorescence intensity (Φfl < 0.01) that increases significantly upon binding to G4-DNA (Φfl = 0.01). In contrast, the association with duplex DNA was not accompanied by such a strong fluorescence light-up effect (Φfl < 0.01). These different fluorimetric responses upon binding to particular DNA forms are proposed to be caused by the different binding modes and may be used for the selective fluorimetric detection of G4-DNA.

scholarly journals Synthesis of 10-O-aryl-substituted berberine derivatives by Chan–Evans–Lam coupling and investigation of their DNA-binding properties

2021 ◽  
Vol 17 ◽  
pp. 991-1000
Author(s):  
Peter Jonas Wickhorst ◽  
Mathilda Blachnik ◽  
Denisa Lagumdzija ◽  
Heiko Ihmels
Keyword(s):  
Dna Binding ◽  
Coupling Reaction ◽  
Spectroscopic Studies ◽  
Binding Properties ◽  
Quadruplex Dna ◽  
G4 Dna ◽  
Fluorescence Light ◽  
Berberine Derivatives ◽  
Ct Dna ◽  
Dna Binding Properties

Eleven novel 10-O-aryl-substituted berberrubine and berberine derivatives were synthesized by the Cu2+-catalyzed Chan–Evans–Lam coupling of berberrubine with arylboronic acids and subsequent 9-O-methylation. The reaction is likely introduced by the Cu2+-induced demethylation of berberrubine and subsequent arylation of the resulting 10-oxyanion functionality. Thus, this synthetic route represents the first successful Cu-mediated coupling reaction of berberine substrates. The DNA-binding properties of the 10-O-arylberberine derivatives with duplex and quadruplex DNA were studied by thermal DNA denaturation experiments, spectrometric titrations as well as CD and LD spectroscopy. Fluorimetric DNA melting analysis with different types of quadruplex DNA revealed a moderate stabilization of the telomeric quadruplex-forming oligonucleotide sequence G3(TTAG3)3. The derivatives showed a moderate affinity towards quadruplex DNA (K b = 5–9 × 105 M−1) and ct DNA (K b = 3–5 × 104 M−1) and exhibited a fluorescence light-up effect upon complexation to both DNA forms, with slightly higher intensity in the presence of the quadruplex DNA. Furthermore, the CD- and LD-spectroscopic studies revealed that the title compounds intercalate into ct DNA and bind to G4-DNA by terminal stacking.

scholarly journals Subtle structural alterations in G-quadruplex DNA regulate site specificity of fluorescence light-up probes

2020 ◽  
Vol 48 (3) ◽  
pp. 1108-1119 ◽  
Author(s):  
Rajendra Kumar ◽  
Karam Chand ◽  
Sudipta Bhowmik ◽  
Rabindra Nath Das ◽  
Snehasish Bhattacharjee ◽  
...  
Keyword(s):  
Rational Design ◽  
Dna Structure ◽  
Biological Processes ◽  
Chemical Research ◽  
Quadruplex Dna ◽  
Dna Structures ◽  
Future Studies ◽  
G4 Dna ◽  
G Quadruplex ◽  
Fluorescence Light

Abstract G-quadruplex (G4) DNA structures are linked to key biological processes and human diseases. Small molecules that target specific G4 DNA structures and signal their presence would therefore be of great value as chemical research tools with potential to further advance towards diagnostic and therapeutic developments. However, the development of these types of specific compounds remain as a great challenge. In here, we have developed a compound with ability to specifically signal a certain c-MYC G4 DNA structure through a fluorescence light-up mechanism. Despite the compound's two binding sites on the G4 DNA structure, only one of them result in the fluorescence light-up effect. This G-tetrad selectivity proved to originate from a difference in flexibility that affected the binding affinity and tilt the compound out of the planar conformation required for the fluorescence light-up mechanism. The intertwined relation between the presented factors is likely the reason for the lack of examples using rational design to develop compounds with turn-on emission that specifically target certain G4 DNA structures. However, this study shows that it is indeed possible to develop such compounds and present insights into the molecular details of specific G4 DNA recognition and signaling to advance future studies of G4 biology.

Spectroscopic Studies on the Binding Properties of Ofloxacin and Human Telomeric G-Quadruplex DNA

2013 ◽  
Vol 634-638 ◽  
pp. 1062-1065 ◽  
Author(s):  
Xu Jian Luo ◽  
Qi Pin Qin ◽  
Yu Lan Li ◽  
Yan Yang
Keyword(s):  
Spectral Analysis ◽  
Fluorescence Emission ◽  
Spectroscopic Studies ◽  
Binding Properties ◽  
Quadruplex Dna ◽  
G4 Dna ◽  
G Quadruplex ◽  
Shoulder Peak ◽  
Binding Intensity ◽  
Dna Complex

The binding of ofloxacin with human telomeric G-quadruplex DNA, Htel-G4-DNA and Htel-3-G4-DNA were examined by Fluorescence and CD spectroscopic methods. In the Fluorescence emission spectral analysis, the addition of ofloxacin induced significant quenching on the fluorescence emission of TO-G4-DNA complex. The fluorescence spectral analysis indicated that ofloxacin exhibited higher binding affinity and binding intensity to Htel-G4-DNA than Htel-3-G4-DNA. In the CD spectral analysis, the interaction with ofloxacin did not disturb the characteristic absorption of Htel-G4-DNA at 290 nm corresponding to its antiparallel form, and only slightly increased the positive absorption at 270 nm as shoulder peak, which suggests the antiparallel structure of G-quadruplex can remain stable in the presence of ofloxacin

Studies on the Material Properties of Platinum Complex Binding to Human Telomeric G-Quadruplex DNA

2013 ◽  
Vol 700 ◽  
pp. 63-66
Author(s):  
Xu Jian Luo ◽  
Qi Pin Qin ◽  
Yu Lan Li ◽  
Yan Cheng Liu
Keyword(s):  
Binding Affinity ◽  
Material Properties ◽  
Platinum Complex ◽  
Spectroscopic Methods ◽  
Binding Properties ◽  
Quadruplex Dna ◽  
G Quadruplex ◽  
New Material ◽  
Binding Intensity ◽  
Ct Dna

A new material of cation platinum (II) complex has been synthesized and characterized. The new material binding properties with human telomeric G-quadruplex DNA (G4-Htel DNA) and ct-DNA were examined by UV-Vis and CD spectroscopic methods. The results showed that complex exhibited higher binding affinity and binding intensity to G4-Htel DNA (up to Kb = 1.54×106 M-1) and with selectivity (up to 11-fold) over duplex DNA. The CD results suggests the antiparallel structure of G-quadruplex can remain stable in the presence of platinum complex and the complex may bind to DNA by intercalation mode.

Anticancer Activity of Platinum (II) Complex as G-Quadruplex DNA Binders

2013 ◽  
Vol 781-784 ◽  
pp. 1130-1133
Author(s):  
Qi Pin Qin ◽  
Yu Lan Li ◽  
Yan Cheng Liu ◽  
Xu Jian Luo
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Normal Cell ◽  
Cancer Cell Lines ◽  
Cytotoxic Activities ◽  
Binding Properties ◽  
Quadruplex Dna ◽  
Quadruplex Structure ◽  
G Quadruplex ◽  
Dna Binders

A platinum (II) complex has been synthesized and characterized. The complex binding properties with G-quadruplex DNA and ds26 were examined by FID and CD spectroscopic methods. The results revealed that the platinum (II) complex can induce the antiparallel G-quadruplex structure of HTG21 conformation in the absence of added K+ with selectivity over other G-quadruplex DNA and duplex DNA. The cytotoxicity of the platinum (II) was screened against four cancer cell lines and normal cells of HL-7702 in comparison to cisplatin and it showed a higher activity than cisplatin, with inhibition rates ranging from (40.06±1.65)% to (89.47±1.14)%. Furthermore, the platinum (II) complex displayed lower cytotoxic activities to HL-7702 (normal cell) compared with the cancer cell lines.

scholarly journals Small-Molecule Interaction with G-Quadruplex DNA

2019 ◽  
Vol 92 (1) ◽  
pp. 43-57
Author(s):  
Petar M. Mitrasinovic
Keyword(s):  
Binding Free Energy ◽  
Cancer Disease ◽  
Quadruplex Dna ◽  
Myc Oncogene ◽  
G4 Dna ◽  
G Quadruplex ◽  
Potential Strategy ◽  
Dna Binders ◽  
Domain Motions ◽  
Modes Of Interaction

Targeting G-quadruplex (G4) DNA structures by small molecules is a potential strategy for directing gene therapy of cancer disease. Herein, novel insights into non-covalent interactions between a structurally diversified spectrum of ligands and a G-quadruplex DNA (formed in the c-Myc oncogene promoter region) are reported. Solvation-induced effects on and entropic contributions to the binding free energy are explored. In addition, the correlation of G4 domain motions and active site rearrangements with the binding of highest affinity ligands, being associated with the fundamentally distinguishable modes of interaction (external stacking: BRACO-19, TMPyP4, and CX-3543; groove binding: Sanguinarine, Tetrahydropalmatine, and Hoechst 33258), is quantitatively evaluated and elaborated by observing thermodynamic consequences of the receptor conformational flexibility changes in the asymptotic regime (t → ∞) of molecular dynamics (MD) simulation. BRACO-19 and Tetrahydropalmatine are identified as unique (thermodynamically favorable and highly selective) G4-DNA binders. Implications of the present study for experimental research are elucidated.

scholarly journals G-quadruplex binding properties of a potent PARP-1 inhibitor derived from 7-azaindole-1-carboxamide

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sabrina Dallavalle ◽  
Loana Musso ◽  
Roberto Artali ◽  
Anna Aviñó ◽  
Leonardo Scaglioni ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Parp Inhibition ◽  
Inhibition Mechanism ◽  
Binding Properties ◽  
Dna Oligomers ◽  
Quadruplex Dna ◽  
G Quadruplex ◽  
Molecular Bases ◽  
Dna Binding Properties ◽  
Parp 1

AbstractPoly ADP-ribose polymerases (PARP) are key proteins involved in DNA repair, maintenance as well as regulation of programmed cell death. For this reason they are important therapeutic targets for cancer treatment. Recent studies have revealed a close interplay between PARP1 recruitment and G-quadruplex stabilization, showing that PARP enzymes are activated upon treatment with a G4 ligand. In this work the DNA binding properties of a PARP-1 inhibitor derived from 7-azaindole-1-carboxamide, (2-[6-(4-pyrrolidin-1-ylmethyl-phenyl)-pyrrolo[2,3-b]pyridin-1-yl]-acetamide, compound 1) with model duplex and quadruplex DNA oligomers were studied by NMR, CD, fluorescence and molecular modelling. We provide evidence that compound 1 is a strong G-quadruplex binder. In addition we provide molecular details of the interaction of compound 1 with two model G-quadruplex structures: the single repeat of human telomeres, d(TTAGGGT)4, and the c-MYC promoter Pu22 sequence. The formation of defined and strong complexes with G-quadruplex models suggests a dual G4 stabilization/PARP inhibition mechanism of action for compound 1 and provides the molecular bases of its therapeutic potential.

scholarly journals Human Rev1 relies on insert-2 to promote selective binding and accurate replication of stabilized G-quadruplex motifs

2021 ◽  
Author(s):  
Amit Ketkar ◽  
Lane Smith ◽  
Callie Johnson ◽  
Alyssa Richey ◽  
Makayla Berry ◽  
...  
Keyword(s):  
Amino Acids ◽  
Mutation Frequency ◽  
Control Sequence ◽  
Wild Type ◽  
Binding Properties ◽  
High Affinity ◽  
G4 Dna ◽  
G Quadruplex ◽  
Forward Mutagenesis

Abstract We previously reported that human Rev1 (hRev1) bound to a parallel-stranded G-quadruplex (G4) from the c-MYC promoter with high affinity. We have extended those results to include other G4 motifs, finding that hRev1 exhibited stronger affinity for parallel-stranded G4 than either anti-parallel or hybrid folds. Amino acids in the αE helix of insert-2 were identified as being important for G4 binding. Mutating E466 and Y470 to alanine selectively perturbed G4 binding affinity. The E466K mutant restored wild-type G4 binding properties. Using a forward mutagenesis assay, we discovered that loss of hRev1 increased G4 mutation frequency &gt;200-fold compared to the control sequence. Base substitutions and deletions occurred around and within the G4 motif. Pyridostatin (PDS) exacerbated this effect, as the mutation frequency increased &gt;700-fold over control and deletions upstream of the G4 site more than doubled. Mutagenic replication of G4 DNA (±PDS) was partially rescued by wild-type and E466K hRev1. The E466A or Y470A mutants failed to suppress the PDS-induced increase in G4 mutation frequency. These findings have implications for the role of insert-2, a motif conserved in vertebrates but not yeast or plants, in Rev1-mediated suppression of mutagenesis during G4 replication.

scholarly journals ATRX promotes heterochromatin formation to protect cells from G-quadruplex DNA-mediated stress

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yu-Ching Teng ◽  
Aishwarya Sundaresan ◽  
Ryan O’Hara ◽  
Vincent U. Gant ◽  
Minhua Li ◽  
...  
Keyword(s):  
Dna Sequences ◽  
Genome Stability ◽  
Helicase Domain ◽  
Quadruplex Dna ◽  
Heterochromatin Formation ◽  
Replicative Stress ◽  
G4 Dna ◽  
Mutation Burden ◽  
G Quadruplex ◽  
Dna Replication Stress

AbstractATRX is a tumor suppressor that has been associated with protection from DNA replication stress, purportedly through resolution of difficult-to-replicate G-quadruplex (G4) DNA structures. While several studies demonstrate that loss of ATRX sensitizes cells to chemical stabilizers of G4 structures, the molecular function of ATRX at G4 regions during replication remains unknown. Here, we demonstrate that ATRX associates with a number of the MCM replication complex subunits and that loss of ATRX leads to G4 structure accumulation at newly synthesized DNA. We show that both the helicase domain of ATRX and its H3.3 chaperone function are required to protect cells from G4-induced replicative stress. Furthermore, these activities are upstream of heterochromatin formation mediated by the histone methyltransferase, ESET, which is the critical molecular event that protects cells from G4-mediated stress. In support, tumors carrying mutations in either ATRX or ESET show increased mutation burden at G4-enriched DNA sequences. Overall, our study provides new insights into mechanisms by which ATRX promotes genome stability with important implications for understanding impacts of its loss on human disease.

An in Silico Investigation of Binding Modes and Pathway of APTO-253 on c-KIT G-Quadruplex DNA

2020 ◽  
Author(s):  
Saikat Pal ◽  
Sandip Paul
Keyword(s):  
Cancer Therapy ◽  
In Silico ◽  
Binding Modes ◽  
Quadruplex Dna ◽  
G Quadruplex ◽  
The Stability

The stability of c-KIT G-quadruplex DNA by ligands has been a significant concern in the growing field of cancer therapy. Thus, it is very important to understand the mechanism behind...

Sign in / Sign up

Export Citation Format

Share Document