Binding of anticancer drug adriamycin to parallel G‐quadruplex DNA [d‐(TTAGGGT)] 4 comprising human telomeric DNA leads to thermal stabilization: A multiple spectroscopy study

2019 ◽  
Vol 33 (2) ◽  
Author(s):  
Shailja Raje ◽  
Kumud Pandav ◽  
Ritu Barthwal
Keyword(s):  
Anticancer Drug ◽  
Thermal Stabilization ◽  
Spectroscopy Study ◽  
Telomeric Dna ◽  
Quadruplex Dna ◽  
G Quadruplex

scholarly journals Molecular Recognition of Parallel G-quadruplex [d-(TTGGGGT)]4 Containing Tetrahymena Telomeric DNA Sequence by Anticancer Drug Daunomycin: NMR-Based Structure and Thermal Stability

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2266 ◽  
Author(s):  
Ritu Barthwal ◽  
Zia Tariq
Keyword(s):  
Anticancer Drug ◽  
Topoisomerase Ii ◽  
Specific Interaction ◽  
Thermal Stabilization ◽  
Telomere Maintenance ◽  
Telomeric Dna ◽  
Groove Binding ◽  
Telomerase Inhibitors ◽  
G Quadruplex ◽  
Dynamics Simulations

The anticancer drug daunomycin exerts its influence by multiple strategies of action to interfere with gene functioning. Besides inhibiting DNA/RNA synthesis and topoisomerase-II, it affects the functional pathway of telomere maintenance by the telomerase enzyme. We present evidence of the binding of daunomycin to parallel-stranded tetramolecular [d-(TTGGGGT)]4 guanine (G)-quadruplex DNA comprising telomeric DNA from Tetrahymena thermophilia by surface plasmon resonance and Diffusion Ordered SpectroscopY (DOSY). Circular Dichroism (CD) spectra show the disruption of daunomycin dimers, suggesting the end-stacking and groove-binding of the daunomycin monomer. Proton and phosphorus-31 Nuclear Magnetic Resonance (NMR) spectroscopy show a sequence-specific interaction and a clear proof of absence of intercalation of the daunomycin chromophore between base quartets or stacking between G-quadruplexes. Restrained molecular dynamics simulations using observed short interproton distance contacts depict interaction at the molecular level. The interactions involving ring A and daunosamine protons, the stacking of an aromatic ring of daunomycin with a terminal G6 quartet by displacing the T7 base, and external groove-binding close to the T1–T2 bases lead to the thermal stabilization of 15 °C, which is likely to inhibit the association of telomerase with telomeres. The findings have implications in the structure-based designing of anthracycline drugs as potent telomerase inhibitors.

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).

Controlling anticancer drug mediated G-quadruplex formation and stabilization by a molecular container

2018 ◽  
Vol 20 (11) ◽  
pp. 7808-7818 ◽  
Author(s):  
Sagar Satpathi ◽  
Reman K. Singh ◽  
Arnab Mukherjee ◽  
Partha Hazra
Keyword(s):  
Anticancer Drug ◽  
Quadruplex Dna ◽  
Emission Color ◽  
Molecular Container ◽  
G Quadruplex ◽  
Quadruplex Formation

G-quadruplex DNA (GQ-DNA) formation has been controlled using a molecular container, cucurbit[7]uril (CB7), by means of translocating a potential anticancer drug, topotecan, from GQ-DNA to the CB7 nanocavity. Interestingly, this whole cycle can be easily monitored through the change in the emission color of the stabilizing ligand, i.e., topotecan.

Molecular recognition of parallel quadruplex [d-(TTGGGGT)]4 by mitoxantrone: binding with 1 : 4 stoichiometry leads to telomerase inhibition

RSC Advances ◽  
2016 ◽  
Vol 6 (75) ◽  
pp. 71652-71661 ◽  
Author(s):  
Tarikere Palakshan Pradeep ◽  
Sweta Tripathi ◽  
Ritu Barthwal
Keyword(s):  
Molecular Recognition ◽  
Thermal Stabilization ◽  
Cancer Drug ◽  
Telomerase Inhibition ◽  
Quadruplex Dna ◽  
Anti Cancer ◽  
G Quadruplex ◽  
Cd Studies

NMR and CD studies show that anti-cancer drug mitoxantrone (MTX) binds to parallel G-quadruplex DNA [d-(TTGGGGT)4] as stacked dimer at grooves leading to increase in thermal stabilization of DNA by ~25 °C and inhibits telomerase with IC50 = 2 μM.

scholarly journals Pif1 helicase unfolding of G-quadruplex DNA is highly dependent on sequence and reaction conditions

2018 ◽  
Vol 293 (46) ◽  
pp. 17792-17802 ◽  
Author(s):  
Alicia K. Byrd ◽  
Matthew R. Bell ◽  
Kevin D. Raney
Keyword(s):  
Dna Sequences ◽  
Atp Hydrolysis ◽  
Monovalent Cation ◽  
Product Formation ◽  
Telomeric Dna ◽  
Reaction Conditions ◽  
Specific Sequence ◽  
Quadruplex Dna ◽  
G Quadruplex ◽  
Pif1 Helicase

In addition to unwinding double-stranded nucleic acids, helicase activity can also unfold noncanonical structures such as G-quadruplexes. We previously characterized Pif1 helicase catalyzed unfolding of parallel G-quadruplex DNA. Here we characterized unfolding of the telomeric G-quadruplex, which can fold into antiparallel and mixed hybrid structures and found significant differences. Telomeric DNA sequences are unfolded more readily than the parallel quadruplex formed by the c-MYC promoter in K+. Furthermore, we found that under conditions in which the telomeric quadruplex is less stable, such as in Na+, Pif1 traps thermally melted quadruplexes in the absence of ATP, leading to the appearance of increased product formation under conditions in which the enzyme is preincubated with the substrate. Stable telomeric G-quadruplex structures were unfolded in a stepwise manner at a rate slower than that of duplex DNA unwinding; however, the slower dissociation from G-quadruplexes compared with duplexes allowed the helicase to traverse more nucleotides than on duplexes. Consistent with this, the rate of ATP hydrolysis on the telomeric quadruplex DNA was reduced relative to that on single-stranded DNA (ssDNA), but less quadruplex DNA was needed to saturate ATPase activity. Under single-cycle conditions, telomeric quadruplex was unfolded by Pif1, but for the c-MYC quadruplex, unfolding required multiple helicase molecules loaded onto the adjacent ssDNA. Our findings illustrate that Pif1-catalyzed unfolding of G-quadruplex DNA is highly dependent on the specific sequence and the conditions of the reaction, including both the monovalent cation and the order of addition.

scholarly journals Enantiomeric copper based anticancer agents promoting sequence-selective cleavage of G-quadruplex telomeric DNA and non-random cleavage of plasmid DNA

Metallomics ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 988-999 ◽  
Author(s):  
Sabiha Parveen ◽  
J. A. Cowan ◽  
Zhen Yu ◽  
Farukh Arjmand
Keyword(s):  
Anticancer Agents ◽  
Plasmid Dna ◽  
Telomeric Dna ◽  
Quadruplex Dna ◽  
Dna Cleaving ◽  
G Quadruplex

Copper-based enantiomeric anticancer agents (1S and 1R) were synthesized and studied as sequence-selective G-quadruplex DNA cleaving agents.

Interactions of selected gold(iii) complexes with DNA G quadruplexes

2015 ◽  
Vol 44 (8) ◽  
pp. 3633-3639 ◽  
Author(s):  
P. Gratteri ◽  
L. Massai ◽  
E. Michelucci ◽  
R. Rigo ◽  
L. Messori ◽  
...  
Keyword(s):  
Dna Sequences ◽  
Dna Conformation ◽  
Telomeric Dna ◽  
Quadruplex Dna ◽  
G Quadruplex

The interactions of three Au(iii) complexes with human telomeric DNA sequences: Auoxo6 turned out to be very effective in inducing and binding the G-quadruplex DNA conformation.

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