5 years ago

Telomerase Inhibition and Human Telomeric G-Quadruplex DNA Stabilization by a β-Carboline–Benzimidazole Derivative at Low Concentrations

Telomerase Inhibition and Human Telomeric G-Quadruplex DNA Stabilization by a β-Carboline–Benzimidazole Derivative at Low Concentrations
Ragampeta Srinivas, Narayana Nagesh, Bathini Nagendra Babu, Sravanthi Devi Guggilapu, Panuganti Devayani, Ahmed Kamal, Penchala Narasimha Rao Meka, Jeshma Kovvuri, Sudeshna Sadhu, Kranthikumar Yadav
Guanine rich regions in DNA, which can form highly stable secondary structures, namely, G-quadruplex or G4 DNA structures, affect DNA replication and transcription. Molecules that stabilize G4 DNA have become important in recent years. In this study, G4 DNA stabilization, inhibition of telomerase, and anticancer activity of synthetic β-carboline–benzimidazole derivatives (5a, 5d, 5h, and 5r) were studied. Among them, derivatives containing a 4-methoxyphenyl ring at C1 and a 6-methoxy-substituted benzimidazole at C3 (5a) were found to stabilize telomeric G-quadruplex DNA efficiently. The stoichiometry and interaction of a synthetic, β-carboline–benzimidazole derivative, namely, 3-(6-methoxy-1H-benzo[d]imidazol-2-yl)-1-(4-methoxyphenyl)-9H-pyrido[3,4-b]indole (5a), with human intermolecular G-quadruplex DNA at low concentrations were examined using electrospray ionization mass spectrometry. Spectroscopy techniques indicate that 5a may intercalate between the two stacks of G-quadruplex DNA. This model is supported by docking studies. When cancer cells are treated with 5a, the cell cycle arrest occurs at the sub-G1 phase. In addition, an apoptosis assay and fluorescence microscopy studies using cancer cells indicate that 5a can induce apoptosis. Results of biochemical assays such as the polymerase chain reaction stop assay and telomerase activity assay indicate that 5a has the potential to stabilize G-quadruplex DNA, and thereby, it may interfere with in vitro DNA synthesis and decrease telomerase activity. The results of this study reveal that the β-carboline–benzimidazole derivative (5a) is efficient in G-quadruplex DNA stabilization over double-stranded DNA, inhibits telomerase activity, and induces apoptosis in cancer cells.

Publisher URL: http://dx.doi.org/10.1021/acs.biochem.7b00008

DOI: 10.1021/acs.biochem.7b00008

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