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Divalent Naphthalene Diimide Ligands Display High Selectivity for the Human Telomeric G-quadruplex in K+ Buffer.

ABSTRACT: Selective G-quadruplex ligands offer great promise for the development of anti-cancer therapies. A novel series of divalent cationic naphthalene diimide ligands that selectively bind to the hybrid form of the human telomeric G-quadruplex in K+ buffer are described herein. We demonstrate that an imidazolium-bearing mannoside-conjugate is the most selective ligand to date for this quadruplex against several other quadruplex and duplex structures. We also show that a similarly selective methylpiperazine-bearing ligand was more toxic to HeLa cancer cells than doxorubicin, whilst exhibiting three times less toxicity towards fetal lung fibroblasts WI-38.

SUBMITTER: Street STG

PROVIDER: S-EPMC5485019 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Divalent Naphthalene Diimide Ligands Display High Selectivity for the Human Telomeric G-quadruplex in K<sup>+</sup> Buffer.

Street Steven T G STG Chin Donovan N DN Hollingworth Gregory J GJ Berry Monica M Morales Juan C JC Galan M Carmen MC

Chemistry (Weinheim an der Bergstrasse, Germany) 20170330 29

Selective G-quadruplex ligands offer great promise for the development of anti-cancer therapies. A novel series of divalent cationic naphthalene diimide ligands that selectively bind to the hybrid form of the human telomeric G-quadruplex in K<sup>+</sup> buffer are described herein. We demonstrate that an imidazolium-bearing mannoside-conjugate is the most selective ligand to date for this quadruplex against several other quadruplex and duplex structures. We also show that a similarly selective ...[more]

PMID: 28257554

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Mechanism of the antiproliferative activity of some naphthalene diimide G-quadruplex ligands.

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G-Quadruplex Identification in the Genome of Protozoan Parasites Points to Naphthalene Diimide Ligands as New Antiparasitic Agents.

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G-quadruplex DNA as a target for pathogenic bacteria: efficacy of an extended naphthalene diimide ligand and mode of action

Project description:Guanidine DNA quadruplex (G4-DNA) structures convey a distinctive layer of epigenetic information that is critical for the regulation of key biological activities and processes as genome transcription regulation, replication and repair. Despite several works that have been published recently, the information regarding their role and possible use as therapeutic drug targets in bacteria is still scarce. Here, we tested the biological activity of a small G4-DNA ligand library based on the naphthalene diimide (NDI) pharmacophore, against both Gram-positive and Gram-negative bacteria. For the best compound identified, NDI-10, the action mechanism was further characterized. Gram-negative bacteria were more resistant altogether due to the presence of the outer membrane, although the activity of the G4-Ligand was generally bactericidal, while it was bacteriostatic for Gram-positive bacteria. This asymmetric activity could be related to the different prevalence of putative G4-DNA structures in each group, the influence that they can exert on the gene expression (which was found more severe for the Gram-negative bacteria) and the role of the G4 structures in these bacteria, that seems to be more related to promote transcription in Gram-positive bacteria and repress transcription in Gram-negative.

2022-12-10 | GSE178890 | GEO

DNA Binding Mode Analysis of a Core-Extended Naphthalene Diimide as a Conformation-Sensitive Fluorescent Probe of G-Quadruplex Structures.

Project description:G-quadruplex existence was proved in cells by using both antibodies and small molecule fluorescent probes. However, the G-quadruplex probes designed thus far are structure- but not conformation-specific. Recently, a core-extended naphthalene diimide (cex-NDI) was designed and found to provide fluorescent signals of markedly different intensities when bound to G-quadruplexes of different conformations or duplexes. Aiming at evaluating how the fluorescence behaviour of this compound is associated with specific binding modes to the different DNA targets, cex-NDI was here studied in its interaction with hybrid G-quadruplex, parallel G-quadruplex, and B-DNA duplex models by biophysical techniques, molecular docking, and biological assays. cex-NDI showed different binding modes associated with different amounts of stacking interactions with the three DNA targets. The preferential binding sites were the groove, outer quartet, or intercalative site of the hybrid G-quadruplex, parallel G-quadruplex, and B-DNA duplex, respectively. Interestingly, our data show that the fluorescence intensity of DNA-bound cex-NDI correlates with the amount of stacking interactions formed by the ligand with each DNA target, thus providing the rationale behind the conformation-sensitive properties of cex-NDI and supporting its use as a fluorescent probe of G-quadruplex structures. Notably, biological assays proved that cex-NDI mainly localizes in the G-quadruplex-rich nuclei of cancer cells.

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Naphthalenediimide-Linked Bisbenzimidazole Derivatives as Telomeric G-Quadruplex-Stabilizing Ligands with Improved Anticancer Activity.

Project description:Human telomeric G-quadruplex DNA stabilization has emerged as an exciting novel approach for anticancer drug development. In the present study, we have designed and synthesized three C2-symmetric bisubstituted bisbenzimidazole naphthalenediimide (NDI) ligands, ALI-C3 , BBZ-ARO, and BBZ-AROCH2 , which stabilize human telomeric G-quadruplex DNA with high affinity. Herein, we have studied the binding affinities and thermodynamic contributions of each of these molecules with G-quadruplex DNA and compared the same to those of the parent NDI analogue, BMSG-SH-3. Results of fluorescence resonance energy transfer and surface plasmon resonance demonstrate that these ligands have a higher affinity for G4-DNA over duplex DNA and induce the formation of a G-quadruplex. The binding equilibrium constants obtained from the microcalorimetry studies of BBZ-ARO, ALI-C3 , and BBZ-AROCH2 were 8.47, 6.35, and 3.41 μM, respectively, with h-telo 22-mer quadruplex. These showed 10 and 100 times lower binding affinity with h-telo 12-mer and duplex DNA quadruplexes, respectively. Analysis of the thermodynamic parameters obtained from the microcalorimetry study suggests that interactions were most favorable for BBZ-ARO among all of the synthesized compounds. The ΔGfree obtained from molecular mechanics Poisson-Boltzmann surface area calculations of molecular dynamics (MD) simulation studies suggest that BBZ-ARO interacted strongly with G4-DNA. MD simulation results showed the highest hydrogen bond occupancy and van der Waals interactions were between the side chains of BBZ-ARO and the DNA grooves. A significant inhibition of telomerase activity (IC50 = 4.56 μM) and induced apoptosis in cancer cell lines by BBZ-ARO suggest that this molecule has the potential to be developed as an anticancer agent.

| S-EPMC6044781 | biostudies-literature

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