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Naphthalenediimide-Linked Bisbenzimidazole Derivatives as Telomeric G-Quadruplex-Stabilizing Ligands with Improved Anticancer Activity
[Image: see text] 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 C(2)-symmetric bisubstituted bisbenzimidazole naphthalenediimide (NDI) ligands, ALI-C(3), BBZ-ARO,...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2017
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6044781/ https://www.ncbi.nlm.nih.gov/pubmed/30023623 http://dx.doi.org/10.1021/acsomega.6b00523 |
Sumario: | [Image: see text] 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 C(2)-symmetric bisubstituted bisbenzimidazole naphthalenediimide (NDI) ligands, ALI-C(3), BBZ-ARO, and BBZ-AROCH(2), 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 G(4)-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-C(3), and BBZ-AROCH(2) 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 ΔG(free) obtained from molecular mechanics Poisson–Boltzmann surface area calculations of molecular dynamics (MD) simulation studies suggest that BBZ-ARO interacted strongly with G(4)-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 (IC(50) = 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. |
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