Synthesis, biophysical and biological evaluation of 3,6-bis-amidoacridines with extended 9-anilino substituents as potent G-quadruplex-binding telomerase inhibitors

Guanine-rich nucleic acid sequences can adopt G-quadruplex structures stabilized by layers of four Hoogsteen-paired guanine residues. Quadruplex-prone sequences are found in many regions of human genome and in the telomeres of all eukaryotic organisms. Since small molecules that target G-quadruplexes have been found to be effective telomerase inhibitors, the identification of new specific ligands for G-quadruplexes is emerging as a promising approach to develop new anticancer drugs. Distamycin A is known to bind to AT-rich sequences of duplex DNA, but it has recently been shown to interact also with G-quadruplexes. Here, isothermal titration calorimetry (ITC) and NMR techniques have been employed to characterize the interaction between a dicationic derivative of distamycin A (compound1) and the [d(TGGGGT)]4quadruplex. Additionally, to compare the binding behaviour of netropsin and compound1to the same target, a calometric study of the interaction between netropsin and [d(TGGGGT)]4has been performed. Experiments show that netropsin and compound1are able to bind to [d(TGGGGT)]4with good affinity and comparable thermodynamic profiles. In both cases the interactions are entropically driven processes with a small favourable enthalpic contribution. Interestingly, the structural modifications of compound1decrease the affinity of the ligand toward the duplex, enhancing the selectivity.

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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

Organic & Biomolecular Chemistry ◽

10.1039/c5ob00675a ◽

2015 ◽

Vol 13 (30) ◽

pp. 8335-8348 ◽

Cited By ~ 19

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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Synthesis, biological evaluation, 3D-QSAR studies of novel aryl-2H-pyrazole derivatives as telomerase inhibitors

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2012.12.010 ◽

2013 ◽

Vol 23 (4) ◽

pp. 1091-1095 ◽

Cited By ~ 17

Author(s):

Yin Luo ◽

Shuai Zhang ◽

Ke-Ming Qiu ◽

Zhi-Jun Liu ◽

Yu-Shun Yang ◽

...

Keyword(s):

3D Qsar ◽

Biological Evaluation ◽

Pyrazole Derivatives ◽

Qsar Studies ◽

Telomerase Inhibitors

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Selective recognition of c-MYC G-quadruplex DNA using prolinamide derivatives

Organic & Biomolecular Chemistry ◽

10.1039/c6ob00177g ◽

2016 ◽

Vol 14 (24) ◽

pp. 5761-5767 ◽

Cited By ~ 15

Author(s):

Ajay Chauhan ◽

Sushovan Paladhi ◽

Manish Debnath ◽

Jyotirmayee Dash

Keyword(s):

Biological Evaluation ◽

Selective Recognition ◽

Design Synthesis ◽

Quadruplex Dna ◽

G Quadruplex

Herein we report the design, synthesis, biophysical and biological evaluation of triazole containing prolinamide derivatives as selectivec-MYCG-quadruplex binding ligands.

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Novel platinum complexes as efficient G-quadruplex DNA binders and telomerase inhibitors

International Journal of Biological Macromolecules ◽

10.1016/j.ijbiomac.2013.01.004 ◽

2013 ◽

Vol 55 ◽

pp. 185-192 ◽

Cited By ~ 5

Author(s):

Chunying Wei ◽

Ye Wen ◽

Junhong Wang

Keyword(s):

Platinum Complexes ◽

Quadruplex Dna ◽

Telomerase Inhibitors ◽

G Quadruplex ◽

Dna Binders

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Structural properties and anticoagulant/cytotoxic activities of heterochiral enantiomeric thrombin binding aptamer (TBA) derivatives

Nucleic Acids Research ◽

10.1093/nar/gkaa1109 ◽

2020 ◽

Vol 48 (22) ◽

pp. 12556-12565

Author(s):

Antonella Virgilio ◽

Veronica Esposito ◽

Annalisa Pecoraro ◽

Annapina Russo ◽

Valentina Vellecco ◽

...

Keyword(s):

Anticoagulant Activity ◽

Biological Evaluation ◽

Structure Characteristic ◽

Resonance Spectroscopy ◽

Cytotoxic Activities ◽

Structural Investigations ◽

Left Handedness ◽

Loop Region ◽

G Quadruplex ◽

Derivatives Of

Abstract The thrombin binding aptamer (TBA) possesses promising antiproliferative properties. However, its development as an anticancer agent is drastically impaired by its concomitant anticoagulant activity. Therefore, suitable chemical modifications in the TBA sequence would be required in order to preserve its antiproliferative over anticoagulant activity. In this paper, we report structural investigations, based on circular dichroism (CD) and nuclear magnetic resonance spectroscopy (NMR), and biological evaluation of four pairs of enantiomeric heterochiral TBA analogues. The four TBA derivatives of the d-series are composed by d-residues except for one l-thymidine in the small TT loops, while their four enantiomers are composed by l-residues except for one d-thymidine in the same TT loop region. Apart from the left-handedness for the l-series TBA derivatives, CD and NMR measurements have shown that all TBA analogues are able to adopt the antiparallel, monomolecular, ‘chair-like’ G-quadruplex structure characteristic of the natural D-TBA. However, although all eight TBA derivatives are endowed with remarkable cytotoxic activities against colon and lung cancer cell lines, only TBA derivatives of the l-series show no anticoagulant activity and are considerably resistant in biological environments.

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