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. 2021 May 20;13(5):764.
doi: 10.3390/pharmaceutics13050764.

DNA-Binding and Cytotoxicity of Copper(I) Complexes Containing Functionalized Dipyridylphenazine Ligands

Sammar Alsaedi  1 , Bandar A Babgi  1 , Magda H Abdellattif  2 , Muhammad N Arshad  3 , Abdul-Hamid M Emwas  4 , Mariusz Jaremko  5 , Mark G Humphrey  6 , Abdullah M Asiri  1   3 , Mostafa A Hussien  1   7
Affiliations

DNA-Binding and Cytotoxicity of Copper(I) Complexes Containing Functionalized Dipyridylphenazine Ligands

Sammar Alsaedi et al. Pharmaceutics. .

Abstract

A set of copper(I) coordination compounds with general formula [CuBr(PPh3)(dppz-R)] (dppz-R = dipyrido[3,2-a:2',3'-c]phenazine (Cu-1), 11-nitrodipyrido[3,2-a:2',3'-c]phenazine (Cu-2), 11-cyanodipyrido[3,2-a:2',3'-c]phenazine (Cu-3), dipyrido[3,2-a:2',3'-c]phenazine-11-phenone (Cu-4), 11,12-dimethyldipyrido[3,2-a:2',3'-c]phenazine (Cu-5)) have been prepared and characterized by elemental analysis, 1H-NMR and 31P-NMR spectroscopies as well as mass spectrometry. The structure of Cu-1 was confirmed by X-ray crystallography. The effect of incorporating different functional groups on the dppz ligand on the binding into CT-DNA was evaluated by absorption spectroscopy, fluorescence quenching of EtBr-DNA adducts, and viscosity measurements. The functional groups affected the binding modes and hence the strength of binding affinities, as suggested by the changes in the relative viscosity. The differences in the quenching constants (Ksv) obtained from the fluorescence quenching assay highlight the importance of the functional groups in altering the binding sites on the DNA. The molecular docking data support the DNA-binding studies, with the sites and mode of interactions against B-DNA changing with the different functional groups. Evaluation of the anticancer activities of the five copper compounds against two different cancer cell lines (M-14 and MCF-7) indicated the importance of the functional groups on the dppz ligand on the anticancer activities. Among the five copper complexes, the cyano-containing complex (Cu-3) has the best anticancer activities.

Keywords: Copper(I); DNA-binding; anticancer properties; dipyridophenazine; molecular docking.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
General structures of copper(I) complexes employed in chemotherapy.
Figure 2
Figure 2
Copper(I) complexes studied in this work.
Scheme 1
Scheme 1
Synthetic route to the copper(I) complexes.
Figure 3
Figure 3
ORTEP diagram of Cu-1 with thermal ellipsoids drawn at the 50% probability level.
Figure 4
Figure 4
Unit cell packing diagram for Cu-1.
Figure 5
Figure 5
Overlaid absorption (left) and emission (right) spectra of complexes Cu-1–Cu-5.
Figure 6
Figure 6
Quenching of EtBr-DNA adduct by Cu-1 (A), Cu-2 (B), and Cu-3 (C) (red solid lines are emission spectra of the EtBr-DNA adduct, while the blue lines are the emission spectra with increasing concentrations of the complexes. (a,b,c) Stern-Volmer plots of the quenching process of EtBr-DNA by Cu-1, Cu-2, and Cu-3.
Figure 7
Figure 7
Determination of the binding modes of the compounds to DNA by viscosity assay.
Figure 8
Figure 8
Cartoon illustration of the possible binding sites of the Cu-compounds as estimated by molecular docking modeling.
Figure 9
Figure 9
Illustration of the non-covalent interactions (2D and 3D) of Cu-compounds with B-DNA as estimated by MOE.
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