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 High throughput screening of a new fluorescent G-quadruplex ligand having telomerase inhibitory activity in human A549 cells

2021 ◽  
Author(s):  
Sourav Ghosh ◽  
Debapriya De ◽  
Victor Banerjee ◽  
Soumyajit Biswas ◽  
Utpal Ghosh
Keyword(s):  
Dna Sequences ◽  
High Throughput Screening ◽  
A549 Cells ◽  
Telomerase Activity ◽  
Live Cells ◽  
Cancer Drug ◽  
Quadruplex Dna ◽  
Anti Cancer ◽  
G Quadruplex ◽  
Human A549

Genome-wide analysis showed that putative G-quadruplex DNA structures are prevalent in the human genome. The presence of G-quadruplex structure in the telomere and promoter region of certain oncogenes inspired people to use G-quadruplex ligand as anti-cancer agents. G-quadruplex structures, stabilized by ligand at telomere are resolved by telomerase making the cancer cells resistant to G-quadruplex ligand. So, identification of a new G-quadruplex ligand having anti-telomerase activity would be a promising strategy for cancer therapy as about 85% of human cancers are telomerase positive. A set of the drug-like compounds were screened from the ZINC database randomly and 2284 ligands were chosen following Lipinski rule of five that were docked with five different G-quadruplex DNA sequences in idock. We screened 43 potential G-quadruplex binders using Z-score as a normalization scoring function. The compound (ZINC ID- 05220992) gave the best score (average idock = -10.17 kcal/mol, average normalized idock = -3.42). We performed G4 FID assay, CD analysis to understand its binding with three different G-quadruplex DNA sequences, and checked its anti-telomerase activity in A549 cells using TRAP assay. We observed that this compound had an intrinsic fluorescence, capability to stain live cells with a blue fluorescence, and a specific affinity to only 22AG out of three different G-quadruplex DNA sequences under study. It showed cytotoxicity, good permeability to live cells, and a significant reduction of telomerase activity in human A549 cells at a very low dose. So, this compound has strong potential to be an anti-cancer drug.

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

New dimeric carbazole–benzimidazole mixed ligands for the stabilization of human telomeric G-quadruplex DNA and as telomerase inhibitors. A remarkable influence of the spacer

2015 ◽  
Vol 13 (30) ◽  
pp. 8335-8348 ◽  
Author(s):  
Basudeb Maji ◽  
Krishan Kumar ◽  
K. Muniyappa ◽  
Santanu Bhattacharya
Keyword(s):  
Dna Binding ◽  
Inhibition Activity ◽  
Telomerase Inhibition ◽  
Quadruplex Dna ◽  
Telomerase Inhibitors ◽  
Mixed Ligands ◽  
G Quadruplex

G-quadruplex DNA binding dimeric ligands and their telomerase inhibition activity are reported.

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