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...

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

“…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 organic solvents (such as different alcohols, ethylene glycol, acetonitrile, acetone) for various reaction times (days to weeks).…”

Heterodimetall‐Dreistranghelicate mit direktionalen Benzol‐o‐dithiolat/Brenzcatechinat‐Liganden

“…Eine erste Anwendung für derartige Komplexe wurde für ein dreisträngiges Fe II -Dimetall-Helicat beschrieben, das selektiv in der großen Furche der DNA bindet und eine intramolekulare Windung des DNA-Doppelstrangs induziert. [4] Weit weniger ist über supramolekulare Komplexe mit der Benzol-o-dithiolat-Donorgruppe bekannt.…”

“…Dagegen zeigen {Mo(bdt) 3 }-Polyeder (bdt = Benzolo-dithiolat-Dianion) eine Abhängigkeit des Koordinationsmodus von der Oxidationsstufe des Metallzentrums, wobei {Mo VI (bdt) 3 }-Polyeder trigonal-prismatisch und {Mo V (bdt) 3 }-Polyeder verzerrt oktaedrisch sind. [12] Die Reaktion von drei ¾quivalenten H 4 [7] die bereits mehrmals für Helicate mit Dibrenzcatechinat-Liganden beschrieben worden sind. [13] Die Bildung des {Mo IV (bdt) 3 }-Polyeders in 2 a ermöglicht erstmals die Bildung von NÀH···S-Wasserstoffbrücken.…”

“…[7] Wir haben nun begonnen, die unterschiedlichen Bindungspräferenzen der Donorgruppen in gemischten Benzolo-dithiolat/Brenzcatechinat-Liganden zum selektiven Aufbau helicaler Heterodimetall-Komplexe zu nutzen. Hier berichten wir über die Synthese der dreisträngigen HeterodimetallHelicate (PNP) 4 [TiMo(1) 3 ] (2 a; PNP = Bis(triphenylphosphoranyliden)ammonium) und Li 1.5 Na 0.5 (PNP) 2 [TiMo (1) …”

Catechol Oxidase, Phosphatase-Like Activity, DNA/BSA Binding Studies of RuII Complexes of S-Allyldithiocarbazate: Synthesis and Spectral Studies

“…Among ruthenium-based complexes, [HIm][trans-RuCl 4 (DMSO)(Im)] (NAMI-A) and [ImH][trans-RuCl 4 (Im) 2 ] (KP1019) have progressed into clinical trials with very promising results. [5][6][7] The mechanism of above ruthenium complexes has been most widely studied in order to establish the basis for their unique properties, whch three relevant main features are: (i) they have the ability to interact with serum proteins, such as albumin and transferrin that endows to have tumor seeking properties; 8 (ii) activation of ruthenium(III) through intracellular reduction to allow generation of toxic ruthenium(II) species 9 and (iii) tumor site reactions prefer protein binding instead of DNA binding, it gives contrast to the behavior of platinum(II) complexes, such as cisplatin. 10 Recent research on anticancer ruthenium(II) complexes as drugs bind not only to the primary target DNA, but also with the serum albumin proteins, such as bovine serum albumin (BSA) and human serum albumin (has).…”