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Triazolyl Dibenzo[a,c]phenazines Stabilize Telomeric G-quadruplex and Inhibit Telomerase.

ABSTRACT: We herein report the synthesis and biophysical evaluation of triazolyl dibenzo[a,c]phenazine derivatives as a novel class of G-quadruplex ligands. The aromatic core facilitates π-π interaction and the flexible, protonatable side chains interact with the phosphate backbone of DNA via electrostatic interactions. Förster resonance energy transfer (FRET) melting assay and isothermal titration calorimetry (ITC) studies suggest that these ligands show binding preference for the hTELO G-quadruplex over G-quadruplexes found in the promoter region of various oncogenes and duplex DNA. The in vitro telomeric repeat amplification protocol (Q-TRAP) assay reveals that these ligands reduce telomerase activity in cancer cells.

SUBMITTER: Pal S

PROVIDER: S-EPMC7614908 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Triazolyl Dibenzo[a,c]phenazines Stabilize Telomeric G-quadruplex and Inhibit Telomerase.

Pal Sarmistha S Fatma Khushnood K Ravichandiran Velayutham V Dash Jyotirmayee J

Asian journal of organic chemistry 20211101 11

We herein report the synthesis and biophysical evaluation of triazolyl dibenzo[a,c]phenazine derivatives as a novel class of G-quadruplex ligands. The aromatic core facilitates π-π interaction and the flexible, protonatable side chains interact with the phosphate backbone of DNA via electrostatic interactions. Förster resonance energy transfer (FRET) melting assay and isothermal titration calorimetry (ITC) studies suggest that these ligands show binding preference for the hTELO< ...[more]

PMID: 37823002

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Project description:GW-2974 is a potent tyrosine kinase receptor inhibitor while SCH-442416 is a potent adenosine receptors' antagonist with high selectivity towards human adenosine A2A receptor over other adenosine receptors. The two compounds were reported to possess anti-cancer properties. This study aimed to investigate whether stabilization of human telomeric G-quadruplex DNA by GW-2974- and SCH-442416 is a plausible fundamental mechanism underlying their anti-cancer effects. Human telomeric G-quadruplex DNA with sequence AG3(TTAGGG)3 was used. The study used ultraviolet-visible (UV-Vis), fluorescence, fluorescence quenching, circular dichroism (CD), melting temperatures (Tm) and molecular docking techniques to evaluate interactions. The results showed that GW-2974 and SCH-442416 interacted with G-quadruplex DNA through intercalation binding into two types of dependent binding sites. Binding affinities of 1.3 × 108-1.72 × 106 M-1 and 1.55 × 107-3.74 × 105 M-1 were obtained for GW-2974 and SCH-442416, respectively. An average number of binding sites between 1 and 2 was obtained. Additionally, the melting temperature curves indicated that complexation of both compounds to G-quadruplex DNA provided more stability (ΔTm = 9.9°C and 9.6°C, respectively) compared to non-complexed G-quadruplex DNA. Increasing the molar ratios over 1:1 (drug:G-quadruplex) showed less stabilization effect on DNA. Furthermore, GW-2974 and SCH-442516 have proven ≥ 4.0 folds better selective towards G-quadruplex over double-stranded ct-DNA. In silico molecular docking and dynamics revealed favorable exothermic binding for the two compounds into two sites of parallel and hybrid G-quadruplex DNA structures. The results supported the hypothesis that GW-2974 and SCH-442416 firmly stabilize human telomeric G-quadruplex DNA in additions to modulating tyrosine kinase and adenosine receptors. Consequently, stabilizing G-quadruplex DNA could be a mechanism underlying their anti-cancer activity.

Dataset Information

Triazolyl Dibenzo[a,c]phenazines Stabilize Telomeric G-quadruplex and Inhibit Telomerase.

Publications

Triazolyl Dibenzo[<i>a,c</i>]phenazines Stabilize Telomeric G-quadruplex and Inhibit Telomerase.

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