Interstrand DNA covalent binding of two dinuclear Ru(ii) complexes. Influence of the extra ring of the bridging ligand on the DNA interaction and cytotoxic activity

Abstract

In this work, we report experimental and computational evidence for the intercalation into the DNA base-pairs of the free quinones quinizarin (Q) and naphthazarin (N) and the interstrand covalent binding of their p-cymene di-ruthenium(ii) complexes (ClRuX, with X = N, Q bridging ligands). The intercalation extent for the N complex was larger than that for Q, which is in good agreement with the higher relative contour length and melting temperature for the same C/C ratio and with the computational mean stacking distances between the ligand and the nearest base-pair (3.34 Å and 3.19 Å) for N and Q, respectively. However, the apparent binding constant of Q/DNA, two orders higher than that of N/DNA, indicates that the thermal stability of the X/DNA complex is more related to the degree of intercalation than to the magnitude of the binding constant. ClRuX complexes undergo aquation, forming the aqua-derivatives [(HO)RuX]. These can further bind covalently to DNA via interstrand crosslinking, through both Ru centres and two N7 sites of consecutive guanines, to give (DNA)RuX complexes, by a mechanism similar to that of cisplatin. To the best of our knowledge, this type of interaction with dinuclear Ru(ii) complexes has not been reported hitherto. The experimental and computational results reveal that the number of rings of the aromatic moiety and the covalent binding to DNA play a key role in the behaviour of the quinones and their Ru(ii) derivatives. The cytotoxicity of the ligands and the corresponding Ru(ii) complexes was evaluated in MCF-7, A2780, A2780cis tumour cells and in the healthy cell line MRC-5. The cytotoxic activity was notable for N and negligible for Q. The IC values and the resistance (RF) and selectivity (SF) factors show that the ClRuN complex is the most promising among the four studied anticancer drugs.

Coordination of Ru(II)-Arene Fragments to Dipyridophenazine Ligands Leads to the Modulation of Their In Vitro and In Vivo Anticancer Activity

“…79, 31, and 15% respectively, in comparison with untreated cells. The improved DNA degradation of 3A in comparison with equally cytotoxic ligand A might be related to the interactions of the DNA nucleobases with an Ru center . On the other hand, DNA extracted from cells treated with 1A and A remained relatively intact, although ligand A caused some degree of DNA smearing, indicating initial fragmentation of high-molecular weight DNA.…”

“…The improved DNA degradation of 3A in comparison with equally cytotoxic ligand A might be related to the interactions of the DNA nucleobases with an Ru center. 46 On the other hand, DNA extracted from cells treated with 1A and A remained relatively intact, although ligand A caused some degree of DNA smearing, indicating initial fragmentation of highmolecular weight DNA. Since all compounds were used at equipotent concentrations, the most prominent DNA degradation caused by (cymene)Ru-dppz complex 3A might be one of the underlying causes of its highest cytotoxicity among the tested complexes.…”

Synthesis, photophysical, electrochemical and DNA binding properties of a novel ruthenium(II) N^N complex

“…The electronic absorption spectra for the ruthenium(II) N^N complex 1 is shown in Fig. 2, and its electronic absorption and the corresponding wavelength are recorded as following: λ abs / nm (ε / dm 3…”

“…Since the reports on the highly luminescent DNA light switch behaviour of [Ru(bpy) 2 (dppz)] 2+ (dppz = dipyrido[3,2-a:2',3'-c]phenazine), 1 the binding of transition metal complexes to DNA has received much attention and extensive studies in the field of spectrochemical DNA recognition have emerged. [2][3][4] These studies contribute to the design of conformation-or site-specific probes with emphasis on the use of cations with extended aromatic systems such as the dyes ethidium bromide, acridine orange cation, or proflavine, so as to enhance non-covalent binding especially through intercalation, or covalently linked bifunctional compounds for recognition of the biopolymer structure, the development of selective DNA cleaving agents for mapping or footprinting experiments, as well as rational drug design. DNA intercalation is a noncovalent binding mode by * Corresponding author: lntukjf@163.com which the dye slides between the hydrophobic base pairs of the polynucleotide duplex and is stabilized through π stacking, as well as nonspecific ion interactions.…”

Multiply Intercalator-Substituted Cu(II) Cyclen Complexes as DNA Condensers and DNA/RNA Synthesis Inhibitors

“…Moreover, certain intercalating aromatic compounds carrying alkyl ammonium groups such as mitoxantrone (1,4-dihydroxy-5,8-bis-[2-(2-hydroxyethylamino)-ethylamino]-anthracene-9,10-dione), a 9,10-anthraquinone (AQ) derivative, and YOYO-1 (1,1′-(4,4,8,8-tetramethyl-4,8-di­aza­undeca­methylene)­bis­[4-[(3-methylbenzo-1,3-oxazol-2-yl)­methylidene]-l,4-dihydroquinolinium]­tetraiodide) can act as condensing agents. However, their mechanism of action is different from that of metal complexes, since they interact not only electrostatically but also by intercalation into DNA duplexes. ,, There are a few examples reported, mainly using Pt and Ru, where cytotoxic characteristics resulted from the combination of the respective metal ion with a DNA intercalating ligand moiety as, for example, in refs − . DNA condensing agents based on such complexes are scarce. − The interaction of intercalating AQ cyclen and cyclam complexes with DNA has been exploited solely for the recognition of specific sequence patterns and the unwinding of DNA. − …”