Synthesis and investigation of quadruplex-DNA-binding, 9-O-substituted berberine derivatives

A small series of five novel berberine derivatives was synthesized by the Cu-catalyzed click reaction of 9-propargyladenine with 9-O-(azidoalkyl)berberine derivatives. The association of the resulting berberine–adenine conjugates with representative quadruplex-forming oligonucleotides 22AG dA(G3TTA)3G3 and a2 d(ACAG4TGTG4)2 was examined with photometric and fluorimetric titrations, thermal DNA denaturation analysis, and CD spectroscopy. The results from the spectrometric titrations indicated the formation of 2:1 or 1:1 complexes (ligand:G4-DNA) with log K b values of 10–11 (2:1) and 5–6 (1:1), which are typical for berberine derivatives. Notably, a clear relationship between the binding affinity of the ligands with the length of the alkyl linker chain, n, was not observed. However, depending on the structure, the ligands exhibited different effects when bound to the G4-DNA, such as fluorescent light-up effects and formation of ICD bands, which are mostly pronounced with a linker length of n = 4 (with a2) and n = 5 (with 22AG), thus indicating that each ligand–G4-DNA complex has a specific structure with respect to relative alignment and conformational flexibility of the ligand in the binding site. It was shown exemplarily with one representative ligand from the series that such berberine–adenine conjugates exhibit a selective binding, specifically a selectivity to quadruplex DNA in competition with duplex DNA, and a preferential thermal stabilization of the G4-DNA forms 22AG and KRAS. Notably, the experimental data do not provide evidence for a significant effect of the adenine unit on the binding affinity of the ligands, for example, by additional association with the loops, presumably because the adenine residue is sterically shielded by the neighboring triazole unit.

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

Advanced Materials Research ◽

10.4028/www.scientific.net/amr.634-638.1062 ◽

2013 ◽

Vol 634-638 ◽

pp. 1062-1065 ◽

Cited By ~ 1

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

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Binding Study of the Fluorescent Carbazole Derivative with Human Telomeric G-Quadruplexes

Molecules ◽

10.3390/molecules23123154 ◽

2018 ◽

Vol 23 (12) ◽

pp. 3154 ◽

Cited By ~ 4

Author(s):

Agata Głuszyńska ◽

Bernard Juskowiak ◽

Błażej Rubiś

Keyword(s):

Binding Constants ◽

Binding Mode ◽

Cd Spectroscopy ◽

Telomeric Sequence ◽

Potassium Ions ◽

Carbazole Derivative ◽

Quadruplex Dna ◽

G4 Dna ◽

G Quadruplex ◽

Sodium And Potassium

The carbazole ligand 3 was synthesized, characterized and its binding interactions with human telomeric (22HT) G-quadruplex DNA in Na+ and K+-containing buffer were investigated by ultraviolet-visible (UV-Vis) spectrophotometry, fluorescence, circular dichroism (CD) spectroscopy, and DNA melting. The results showed that the studied carbazole ligand interacted and stabilized the intramolecular G-quadruplexes formed by the telomeric sequence in the presence of sodium and potassium ions. In the UV-Vis titration experiments a two-step complex formation between ligand and G-quadruplex was observed. Very low fluorescence intensity of the carbazole derivative in Tris HCl buffer in the presence of the NaCl or KCl increased significantly after addition of the 22HT G4 DNA. Binding stoichiometry of the ligand/G-quadruplex was investigated with absorbance-based Job plots. Carbazole ligand binds 22HT with about 2:1 stoichiometry in the presence of sodium and potassium ions. The binding mode appeared to be end-stacking with comparable binding constants of ~105 M−1 as determined from UV-Vis and fluorescence titrations data. The carbazole ligand is able to induce formation of G4 structure of 22HT in the absence of salt, which was proved by CD spectroscopy and melting studies. The derivative of carbazole 3 shows significantly higher cytotoxicity against breast cancer cells then for non-tumorigenic breast epithelial cells. The cytotoxic activity of ligand seems to be not associated with telomerase inhibition.

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

Beilstein Journal of Organic Chemistry ◽

10.3762/bjoc.17.81 ◽

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.

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

Nature Communications ◽

10.1038/s41467-021-24206-5 ◽

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.

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

Nucleic Acids Research ◽

10.1093/nar/gkz1205 ◽

2020 ◽

Vol 48 (3) ◽

pp. 1108-1119 ◽

Cited By ~ 5

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.

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Tuning the ring strain effect in acridine derivatives on binding affinity with G-quadruplex-DNA: A computational and experimental study

International Journal of Biological Macromolecules ◽

10.1016/j.ijbiomac.2018.12.019 ◽

2019 ◽

Vol 124 ◽

pp. 1177-1185 ◽

Cited By ~ 1

Author(s):

Mrinal Kanti Si ◽

Sumit Kumar Pramanik ◽

Bishwajit Ganguly

Keyword(s):

Experimental Study ◽

Binding Affinity ◽

Strain Effect ◽

Ring Strain ◽

Quadruplex Dna ◽

Acridine Derivatives ◽

G Quadruplex

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G-quadruplex DNA drives genomic instability and represents a targetable molecular abnormality in ATRX-deficient malignant glioma

10.1101/347542 ◽

2018 ◽

Author(s):

Yuxiang Wang ◽

Jie Yang ◽

Wei Wu ◽

Rachna Shah ◽

Carla Danussi ◽

...

Keyword(s):

Dna Damage ◽

Malignant Glioma ◽

Model Systems ◽

Copy Number Alterations ◽

Molecular Alteration ◽

Quadruplex Dna ◽

G4 Dna ◽

G Quadruplex

AbstractMutational inactivation of ATRX (α-thalassemia mental retardation X-linked) represents a defining molecular alteration in large subsets of malignant glioma. Yet the pathogenic consequences of ATRX deficiency remain unclear, as do tractable mechanisms for its therapeutic targeting. Here we report that ATRX loss in isogenic glioma model systems induces replication stress and DNA damage by way of G-quadruplex (G4) DNA secondary structure. Moreover, these effects are associated with the acquisition of disease-relevant copy number alterations over time. We then demonstrate, both in vitro and in vivo, that ATRX deficiency selectively enhances DNA damage and cell death following chemical G4 stabilization. Finally, we show that G4 stabilization synergizes with other DNA-damaging therapies, including ionizing radiation, in the ATRX-deficient context. Our findings reveal novel pathogenic mechanisms driven by ATRX deficiency in glioma, while also pointing to tangible strategies for drug development.

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Binding of anticancer drug daunomycin to parallel G-quadruplex DNA [d-(TTGGGGT)]4 leads to thermal stabilization: A multispectroscopic investigation

International Journal of Biological Macromolecules ◽

10.1016/j.ijbiomac.2018.09.154 ◽

2018 ◽

Vol 120 ◽

pp. 1965-1974 ◽

Cited By ~ 6

Author(s):

Zia Tariq ◽

Ritu Barthwal

Keyword(s):

Anticancer Drug ◽

Thermal Stabilization ◽

Quadruplex Dna ◽

G Quadruplex

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Investigation of the Binding Affinity of a Broad Array of l-Fucosides with Six Fucose-Specific Lectins of Bacterial and Fungal Origin

Molecules ◽

10.3390/molecules24122262 ◽

2019 ◽

Vol 24 (12) ◽

pp. 2262 ◽

Cited By ~ 2

Author(s):

Son Thai Le ◽

Lenka Malinovska ◽

Michaela Vašková ◽

Erika Mező ◽

Viktor Kelemen ◽

...

Keyword(s):

Binding Affinity ◽

Functional Group ◽

Click Reaction ◽

Inhibition Assay ◽

Promising Candidate ◽

Hemagglutination Inhibition Assay ◽

Broad Array ◽

Amine Functional Group ◽

Potential Inhibitors ◽

Better Than

Series of multivalent α-l-fucoside containing glycoclusters and variously decorated l-fucosides were synthesized to find potential inhibitors of fucose-specific lectins and study the structure-binding affinity relationships. Tri- and tetravalent fucoclusters were built using copper-mediated azide-alkyne click chemistry. Series of fucoside monomers and dimers were synthesized using various methods, namely glycosylation, an azide-alkyne click reaction, photoinduced thiol-en addition, and sulfation. The interactions between compounds with six fucolectins of bacterial or fungal origin were tested using a hemagglutination inhibition assay. As a result, a tetravalent, α-l-fucose presenting glycocluster showed to be a ligand that was orders of magnitude better than a simple monosaccharide for tested lectins in most cases, which can nominate it as a universal ligand for studied lectins. This compound was also able to inhibit the adhesion of Pseudomonas aeruginosa cells to human epithelial bronchial cells. A trivalent fucocluster with a protected amine functional group also seems to be a promising candidate for designing glycoconjugates and chimeras.

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