Toward selective anticancer metallodrugs

The field of transition-metal based chemotherapeutics are dominated by derivatives of cisplatin, but a major downside of these platinum based chemotherapeutics is their lack of selectivity that leads to undesirable side effects. In this work we present alternative strategies such as light-activation with different transition-metals such as ruthenium and palladium that have the potential to be more selective than cisplatin type of drugs. NWOMetals in Catalysis, Biomimetics & Inorganic Material

Controlling with light the interaction between trans-tetrapyridyl ruthenium complexes and an oligonucleotide

Metals in Catalysis, Biomimetics & Inorganic Material

Effects of the Bidentate Ligand on the Photophysical Properties, Cellular Uptake, and (Photo)cytotoxicity of Glycoconjugates Based on the [Ru(tpy)(NN)(L)]2+ Scaffold

Ruthenium polypyridyl complexes have received widespread attention as potential chemotherapeutics in photodynamic therapy (PDT) and in photochemotherapy (PACT). Here, we investigate a series of sixteen ruthenium polypyridyl complexes with general formula [Ru(tpy)(N−N)(L)]+/2+ (tpy=2,2′:6′,2′′‐terpyridine, N−N=bpy (2,2′‐bipyridine), phen (1,10‐phenanthroline), dpq (pyrazino[2,3‐f][1,10]phenanthroline), dppz (dipyrido[3,2‐a:2′,3′‐c]phenazine, dppn (benzo[i]dipyrido[3,2‐a:2′,3′‐c]phenazine), pmip (2‐(4‐methylphenyl)‐1H‐imidazo[4,5‐f][1,10]phenanthroline), pymi ((E)‐N‐phenyl‐1‐(pyridin‐2‐yl)methanimine), or azpy (2‐(phenylazo)pyridine), L=Cl− or 2‐(2‐(2‐(methylthio)ethoxy)ethoxy)ethyl‐β‐d‐glucopyranoside) and their potential for either PDT or PACT. We demonstrate that although increased lipophilicity is generally related to increased uptake of these complexes, it does not necessarily lead to increased (photo)cytotoxicity. However, the non‐toxic complexes are excellent candidates as PACT carriers.Metals in Catalysis, Biomimetics & Inorganic Material

Ruthenium-based PACT agents based on bisquinoline chelates: synthesis, photochemistry, and cytotoxicity

The known ruthenium complex [Ru(tpy)(bpy)(Hmte)](PF6)(2) ([1](PF6)(2), where tpy = 2,2':6',2 ''-terpyridine, bpy = 2,2'-bipyridine, Hmte = 2-(methylthio)ethanol) is photosubstitutionally active but non-toxic to cancer cells even upon light irradiation. In this work, the two analogs complexes [Ru(tpy)(NN)(Hmte)](PF6)(2), where NN = 3,3'-biisoquinoline (i-biq, [2](PF6)(2)) and di(isoquinolin-3-yl)amine (i-Hdiqa, [3](PF6)(2)), were synthesized and their photochemistry and phototoxicity evaluated to assess their suitability as photoactivated chemotherapy (PACT) agents. The increase of the aromatic surface of [2](PF6)(2) and [3](PF6)(2), compared to [1](PF6)(2), leads to higher lipophilicity and higher cellular uptake for the former complexes. Such improved uptake is directly correlated to the cytotoxicity of these compounds in the dark: while [2](PF6)(2) and [3](PF6)(2) showed low EC50 values in human cancer cells, [1](PF6)(2) is not cytotoxic due to poor cellular uptake. While stable in the dark, all complexes substituted the protecting thioether ligand upon light irradiation (520 nm), with the highest photosubstitution quantum yield found for [3](PF6)(2) (phi([3]) = 0.070). Compounds [2](PF6)(2) and [3](PF6)(2) were found both more cytotoxic after light activation than in the dark, with a photo index of 4. Considering the very low singlet oxygen quantum yields of these compounds, and the lack of cytotoxicity of the photoreleased Hmte thioether ligand, it can be concluded that the toxicity observed after light activation is due to the photoreleased aqua complexes [Ru(tpy)(NN)(OH2)](2+), and thus that [2](PF6)(2) and [3](PF6)(2) are promising PACT candidates.[GRAPHICS].Metals in Catalysis, Biomimetics & Inorganic Material

Alkyne Functionalization of a Photoactivated Ruthenium Polypyridyl Complex for Click-Enabled Serum Albumin Interaction Studies

Studying metal-protein interactions is key for understanding the fate of metallodrugs in biological systems. When a metal complex is not emissive and too weakly bound for mass spectrometry analysis, however, it may become challenging to study such interactions. In this work a synthetic procedure was developed for the alkyne functionalization of a photolabile ruthenium polypyridyl complex, [Ru(tpy)(bpy)(Hmte)](PF6)2, where tpy = 2,2′:6′,2′′-terpyridine, bpy = 2,2′-bipyridine, and Hmte = 2-(methylthio)ethanol. In the functionalized complex [Ru(HCC-tpy)(bpy)(Hmte)](PF6)2, where HCC-tpy = 4′-ethynyl-2,2′:6′,2′′-terpyridine, the alkyne group can be used for bioorthogonal ligation to an azide-labeled fluorophore using copper-catalyzed “click” chemistry. We developed a gel-based click chemistry method to study the interaction between this ruthenium complex and bovine serum albumin (BSA). Our results demonstrate that visualization of the interaction between the metal complex and the protein is possible, even when this interaction is too weak to be studied by conventional means such as UV–vis spectroscopy or ESI mass spectrometry. In addition, the weak metal complex-protein interaction is controlled by visible light irradiation, i.e., the complex and the protein do not interact in the dark, but they do interact via weak van der Waals interactions after light activation of the complex, which triggers photosubstitution of the Hmte ligand.Metals in Catalysis, Biomimetics & Inorganic MaterialsBio-organic Synthesi

Induction of a Four‐Way Junction Structure in the DNA Palindromic Hexanucleotide 5′‐d(CGTACG)‐3′ by a Mononuclear Platinum Complex

Four‐way junctions (4WJs) are supramolecular DNA assemblies comprising four interacting DNA strands that in biology are involved in DNA‐damage repair. In this study, a new mononuclear platinum(II) complex 1 was prepared that is capable of driving the crystallization of the DNA oligomer 5′‐d(CGTACG)‐3′ specifically into a 4WJ‐like motif. In the crystal structure of the 1–CGTACG adduct, the distorted‐square‐planar platinum complex binds to the core of the 4WJ‐like motif through π–π stacking and hydrogen bonding, without forming any platinum–nitrogen coordination bonds. Our observations suggest that the specific molecular properties of the metal complex are crucially responsible for triggering the selective assembly of this peculiar DNA superstructure.Metals in Catalysis, Biomimetics & Inorganic Material

Induction of a four-way junction structure in the DNA palindromic hexanucleotide 5 '-d(CGTACG)-3 ' by a mononuclear platinum complex

Four-way junctions (4WJs) are supramolecular DNA assemblies comprising four interacting DNA strands that in biology are involved in DNA-damage repair. In this study, a new mononuclear platinum(II) complex 1 was prepared that is capable of driving the crystallization of the DNA oligomer 5 '-d(CGTACG)-3 ' specifically into a 4WJ-like motif. In the crystal structure of the 1-CGTACG adduct, the distorted-square-planar platinum complex binds to the core of the 4WJ-like motif through pi-pi stacking and hydrogen bonding, without forming any platinum-nitrogen coordination bonds. Our observations suggest that the specific molecular properties of the metal complex are crucially responsible for triggering the selective assembly of this peculiar DNA superstructure.Metals in Catalysis, Biomimetics & Inorganic Material

Preparation, stability, and photoreactivity of thiolato ruthenium polypyridyl complexes: Can cysteine derivatives protect ruthenium-based anticancer complexes?

Metals in Catalysis, Biomimetics & Inorganic Material

Green light-induced apoptosis in cancer cells by a tetrapyridyl ruthenium prodrug offering two trans coordination sites

Metals in Catalysis, Biomimetics & Inorganic Material

Chemical Swarming: Depending on Concentration, an Amphiphilic Ruthenium Polypyridyl Complex Induces Cell Death via Two Different Mechanisms

The crystal structure and in vitro cytotoxicity of the amphiphilic ruthenium complex [3](P