Dinuclear Ruthenium(II) Triple‐Stranded Helicates: Luminescent Supramolecular Cylinders That Bind and Coil DNA and Exhibit Activity against Cancer Cell Lines

Abstract

Synthetic agents that bind to DNA and affect its processing are attractive targets in molecular design. Small molecules can regulate specific gene expression [1] and remain at the forefront of clinical application as anticancer and antiviral drugs.[2] Clinical drugs can intercalate (anthracycline antibiotics), [3] minor groove bind (berenil), [4] or form coordination bonds to DNA (cisplatin). [5] To create different spectra of activity and circumvent cross-resistance, it is important to explore drugs that interact with DNA in new and distinct ways.We have previously described synthetic metallo-supramolecular cylinders of a similar size and shape to protein zinc fingers. These tetracationic cylinders contain three bis(pyridylimine) ligand strands wrapped in a helical fashion about two iron(II) centers. The cylinders not only can bind strongly and noncovalently in the major groove of DNA, inducing dramatic and unprecedented intramolecular DNA coiling in natural polymeric DNAs, [2,6] but also can bind at the heart of Y-shaped DNA junctions, an unparalleled and hitherto unexpected mode of DNA recognition. [7] Combining these striking DNA binding features with the fact that ruthenium compounds represent a new and promising class of anticancer drugs [8][9][10] led to the aim of developing a triple-stranded ruthenium cylinder that would be one of the few noncovalent DNA recognition metal compounds studied for its biological activity. This design was still more attractive because of the potential for luminescence (from MLCT states), [11] which might be used to probe the DNA binding. We describe herein the synthesis of the luminescent ruthenium(II) triple-stranded helicate of ligand L (Scheme 1) and explore its DNA binding and activity against cancer cells.Although the synthesis of triple-stranded helicates with labile first-row transition metals is well established, [12] the synthesis of triple-stranded helicates with an inert metal such as ruthenium(II) represents a considerable challenge and prior to this work had not been achieved. Coordinate bond formation with labile metals is reversible and the assembly is under thermodynamic control. With inert metals this is not the case and the metals and ligands can become trapped in alternative polymeric structures that are not pathways to the assembly of the helicate; in illustration we note that of the three isomeric dinuclear double-stranded unsaturated ruthenium(II) helicates we recently described, none has the correct conformation at any of their metal centers needed for triple-helicate formation.[13] It is striking that, despite the great interest in the photophysical and redox properties of ruthenium(II) tris(diimine) centers, [14] no diruthenium(II) triple-stranded helicate has been prepared. [15] To try to prepare the triple-stranded diruthenium(II) complex, we initially explored different ruthenium starting materials ([{Ru(cod)Cl 2 } n ], RuCl 3 , and [Ru(CH 3 CN) 6 ](PF 6 ) 2 ; cod = 1,5-cyclooctodiene), which we heated under reflux with the ligand in a variety of o...

Os2–Os4 Switch Controls DNA Knotting and Anticancer Activity

“…The unusual behavior of 1 and 2 differs considerably from the DNA cross-linking caused by Ru II -arene m-Hoxonato tetramers [15] or the DNA full-coiling induced by metallocylinders. [12] Experiments carried out at a lower DNA:2 mol ratio (2.5:1) showed the formation of similar knotted aggregates ( Figure S14f), characterized by a higher surface density and a slightly larger cross-sectional height (Supporting Information), confirming a higher linear density of 2 bound to the DNA strands. Conversely, a lower density of bridging tetramers 2 was observed on incubating 5:1 DNA:2 samples for 24 h at 310 K (Figures 3 d and S14e, detailed discussion in the Supporting Information).…”

“…The anticancer activity of 2·[PF 6 ] 4 is comparable to some reported dinuclear Ru II cylinders. [12] Metallosupramolecules are also known to bind in the grooves of DNA.[13] Therefore, binding of complexes 1 and 2 to calf thymus DNA (ct-DNA) was also investigated (Figures S11 and S13). The characteristic circular dichroism (CD) bands of ct-DNA ( Figure S11) and the negative linear dichroism (LD) band arising from the DNA bases (Figure S13) decreased in intensity with increasing concentrations of 1 or 2, even at low Os loading.…”

“…The anticancer activity of 2·[PF 6 ] 4 is comparable to some reported dinuclear Ru II cylinders. [12] Metallosupramolecules are also known to bind in the grooves of DNA.…”

“…The anticancer activity of 2·[PF 6 ] 4 is comparable to some reported dinuclear Ru II cylinders. [12] Metallosupramolecules are also known to bind in the grooves of DNA. [13] Therefore, binding of complexes 1 and 2 to calf thymus DNA (ct-DNA) was also investigated (Figures S11 and S13).…”

Molecular architecture of redox-active half-sandwich Ru(ii) cyclic assemblies. Interactions with biomolecules and anticancer activity

“…2). 20 The ability of 2a to interact with DNA and to induce conformational changes is a probable result of a mixture of electrostatic interactions with polyanionic DNA and size and shape complementarity of this system with the DNA major groove.…”