Dinuclear Double‐Stranded Metallosupramolecular Ruthenium Complexes: Potential Anticancer Drugs

Abstract

Platinum metallodrugs are among the most effective clinical agents for the treatment of cancer, and three such agents (cisplatin, carboplatin, and oxaliplatin) are in widespread use. These agents are believed to act by binding to DNA and to have similar molecular-level actions.[1] Clinical problems include acquired cisplatin resistance the limited spectrum of cancers that can be treated. To address these issues, alternative metallodrug designs that are distinct from cisplatin and have different molecular-level interactions are being explored. Recently, some ruthenium compounds have been shown to have antitumor [2][3][4] and antimetastatic [5] actions; two such compounds are currently in clinical trials and have a different spectrum of activity to the platinum drugs. [2,5] Polynuclear drugs in which the metal centers are linked by an alkyl chain have also been designed. [6][7][8] Some of these show very high activity and overcome both acquired and intrinsic cisplatin resistance as a result of their ability to form long-range inter-and intrastrand DNA cross-links. [6] Rather than using a flexible alkyl chain to link the metal centers, we were interested in exploring whether activity could be obtained by positioning the metal centers within a more-rigid metallosupramolecular architecture. The architecture would impose the relative spatial positions of the two metal centers and the ligands, and their structural conformations might afford additional effects. Our reasoning was informed by our observations that the external surfaces of metallosupramolecular helicates can impart unprecedented noncovalent DNA-binding properties, such as the recognition of unusual DNA junction structures and remarkable intramolecular DNA coiling effects. [9,10] In most helicates (such as those used in our previous DNA-binding studies [9,10] ), the metal centers are fully coordinated by the helical ligands; these are termed "saturated" [11] helicates. The focus of our design herein is on "unsaturated" [12] helicates, in which there are vacant coordination sites that offer the additional possibility of the metal center interacting directly with DNA. We selected ruthenium, rather than platinum, as our metal center of choice for its higher coordination number and because mononuclear azopyridine ruthenium(II) complexes with two vacant coordination sites have been shown to exhibit cytotoxic activity.[3] There are only a few previous reports of helicates based on ruthenium, and their properties have not been explored.[13] We describe herein three isomeric dinuclear unsaturated ruthenium(II) complexes each with a different double-stranded supramolecular architecture and report their activity in cell lines, thus presenting the first direct biomedical application of metallosupramolecular helical arrays.The investigated complexes [Ru 2 Cl 4 L 2 ] are based on a dinucleating bisazopyridine ligand with a di(4-phenyl)methane spacer (Scheme 1), which is the azo analogue of the bispyridylimine ligand systems [9] whose DNA binding we have previously descri...

New trends for metal complexes with anticancer activity

“…Related unsaturated dinuclear ruthenium double helicates, capable of classic coordinative binding to DNA, show greatly improved cytotoxicity towards the same cell lines (30-fold more active than cisplatin). These complexes illustrate the many possibilities of using metallosupramolecular architectures in anticancer drug design [35].…”

“…Related unsaturated dinuclear ruthenium double helicates, capable of classic coordinative binding to DNA, show greatly improved cytotoxicity towards the same cell lines (30-fold more active than cisplatin). These complexes illustrate the many possibilities of using metallosupramolecular architectures in anticancer drug design [35].These examples not only illustrate the role of noncovalent DNA interactions, but also the newly emerging trend of using the metal in a scaffold, rather than as the reactive centre. In a highly modular approach, the use of a metal centre as a building block allows for the spatial orientation of other functionalities (as part of the ligands), which in turn interact favourably with the target via, for instance, hydrogen bonds (phosphate clamps) or p-stacking interactions (helicates).…”

DNA Interactions Mediated by Cyclopentadienidoruthenium(II) Complexes Containing Water‐Soluble Phosphanes

“…Ruthenium complexes have shown important biological activity and are becoming increasingly important in both bioinorganic chemistry and anticancer chemotherapy. [1][2][3][4][5] The water solubility of ruthenium compounds has been greatly increased by using dialkyl sulfoxide derivatives such as in [trans-RuCl 4 …”

Polypyridyl Metal Complexes with Biological Activity

“…[33] The flexible 23 and 24 (Scheme 10) were designed to induce DNA binding modes analogous to other metallosupramolecular cylinders developed by the same group. [34] Although it was not possible to obtain the absolute IC 50 value for these complexes for solubility reasons, it was observed that 23 and 24 would have an IC 50 of approximately 80-100 μm for HBL100 cells. No significant difference in cytotoxicity is present between the mixture and the enantiopure complexes.…”