Cellular and cell-free studies of catalytic DNA cleavage by ruthenium polypyridyl complexes containing redox-active intercalating ligands

Griffith, Cynthia Ann; Dayoub, Adam S.; Jaranatne, Thamara; Alatrash, Nagham; Mohamedi, Ali H; Abayan, Kenneth; Breitbach, Zachary S.; Armstrong, Daniel W.; MacDonnell, Frederick M.

doi:10.1039/c6sc04094b

Cited by 41 publications

(49 citation statements)

References 137 publications

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“…determined the cytotoxicity of 12h in H358, HCC2998, HOP-62, Hs766t cells, in vitro , under normoxia (18% O 2 ) and hypoxia (1.1% O 2 ). 207 The cytotoxicity of 12h was increased in Hs766t and HOP-62 cells under hypoxia compared to normoxia; however, neither H358 and HCC2998 cells were significantly affected by 12h . The authors hypothesized that a mechanistic model where single-strand cleavage of the DNA-bound complex was due to redox-cycling mediated by the concentration of GSH and O 2 in a low O 2 environment.…”

Section: Ruthenium(ii) Polypyridyl Complexesmentioning

confidence: 91%

The development of anticancer ruthenium(ii) complexes: from single molecule compounds to nanomaterials

et al. 2017

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Cancer is rapidly becoming the top killer in the world. Most of the FDA approved anticancer drugs are organic molecules, while metallodrugs are very scarce. The advent of first metal based therapeutic agent, cisplatin, launched a new era in the application of transition metal complexes for therapeutic design. Due to their unique and versatile biochemical properties, ruthenium-based compounds have emerged as promising anti-cancer agents that serve as alternatives to cisplatin and its derivertives. The ruthenium(III) complexes have successfully been used in clinical research and their mechanisms of anticancer action have been reported in large volumes over the past few decades. Ruthenium(II) complexes have also attracted significant attention as anticancer candidates; however, only few of them have been reported comprehensively. In this review, we discuss the development of ruthenium(II) complexes as anticancer candidates and biocatalysts, including arene ruthenium complexes, polypyridyl ruthenium complexes, and ruthenium nanomaterial complexes. This review focuses on the likely mechanisms of action of ruthenium(II)-based anticancer drugs and the relationship between their chemical structures and biological properties. This review also highlights the catalytic activity and the photoinduced activation of ruthenium(II) complexes, their targeted delivery, and their activity in nanomaterial systems.

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Section: Ruthenium(ii) Polypyridyl Complexesmentioning

confidence: 91%

The development of anticancer ruthenium(ii) complexes: from single molecule compounds to nanomaterials

et al. 2017

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“…164 In 2017, MacDonnell and co-workers proposed a mechanistic model to explain the dependency of the DNA cleavage on oxygen concentration. 165 In more detail, they performed cell-free experiments, whose data supported the mechanistic pathway shown in Figure 27. The mechanism exhibits a multistep pathway by in Figure 28).…”

Section: Dinuclear Ru(ii) Complexes Targeting Dnamentioning

confidence: 99%

Monomeric and dimeric coordinatively saturated and substitutionally inert Ru(ii) polypyridyl complexes as anticancer drug candidates

2017

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Due to the increasing impact of cancer on worldwide mortality, more and more attention is being devoted to the investigation of novel anticancer strategies. Among these, chemotherapy plays a key role in fighting cancer. This explains the increasing engagement of both pharmaceutical industry and academia towards the discovery of new chemotherapeutic agents. Over the recent years, metal-based drugs have attracted much attention due to their atypical physico-chemical properties compared to organic molecules. After the approval of cisplatin as a chemotherapeutic agent in 1978, several types of metal-based drugs have been explored. Among them, Ru-based anticancer drug candidates have become a central subject in this research field. However, most of the Ru-based compounds investigated over the last two decades express their cytotoxicity with a mechanism of action involving, among others, a ligand-exchange mechanism. In this Review, we give a complete overview of a specific class of antiproliferative ruthenium complexes, namely coordinatively saturated and substitutionally inert Ru(II) polypyridyl complexes. This implies that the cytotoxicity observed comes from the entire complex and not from a ligand-exchange. In this Review, we are presenting monomeric and dimeric Ru(II) polypyridyl complexes, which have been found to be toxic to cancer cells. More specifically, the monomeric Ru(II) polypyridyl complexes are analysed considering their direct interaction or not with DNA as cause of cell death, while dimeric Ru(II) polypyridyl complexes, are classified according to their biological targets. Very importantly, the cellular targets of these complexes are discussed in detail. Indeed, several targets were identified and different mechanisms of action were suggested.

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“…[6] RPCs were under examination as potential drugs as early as the 1950s, when Dwyer and co-workerse xamined the virostatic,m ammalian cell cytotoxicity,a nd even antitumor properties of simple metal complexes [M(diimine) 3 ] 2 + ,i ncluding ruthenium(II) and related complexes. Ta rgets as varied as the DNA, [9] mitochondria, protein kinases, [10] and the endoplasmicr eticulum [6] have all been implicated for various RPCs and it is becoming increasingly cleart hat natureo ft he ligands can drastically alter their cellular target and response. [8] It is increasingly common to see the cytotoxicity of new RPCs reported againstn umerous cultured cell lines, including human cell lines.…”

Section: Introductionmentioning

confidence: 99%

“…[7] By far the biggest efforts to advance RPCs as therapeutics have been in the realm of anticancer drugs,w here it is hoped that these inorganic pharmaceuticals may match the tremendous successo ft he platinum drugs:c isplatin, oxaliplatin, and carboplatin. [6,9] While demonstrable cytotoxicity and progress in identifying cellulart argets are critical for the subsequentd evelopment of RPCs as drugs, complementary information aboutt heir toxicity at the organism level is needed. Moreover,t here are growingr eports on the cellular transport and distribution in the cell, and the action of RPCs in againstv arious organelles.…”

Section: Introductionmentioning

confidence: 99%

“…[3] These complexes inducem ultiple DNA double-strand breaks (DSBs) in the nuclei of tumor cells in as little as 2hpost-administration [9] and induce apoptosis in cultured malignant human cells lines at low micromolar doses. [3] These complexes inducem ultiple DNA double-strand breaks (DSBs) in the nuclei of tumor cells in as little as 2hpost-administration [9] and induce apoptosis in cultured malignant human cells lines at low micromolar doses.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis, DNA Cleavage Activity, Cytotoxicity, Acetylcholinesterase Inhibition, and Acute Murine Toxicity of Redox‐Active Ruthenium(II) Polypyridyl Complexes

et al. 2017

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Four mononuclear [(L-L) Ru(tatpp)] and two dinuclear [(L-L) Ru(tatpp)Ru(L-L) ] ruthenium(II) polypyridyl complexes (RPCs) containing the 9,11,20,22-tetraazatetrapyrido[3,2-a:2',3'-c:3'',2''-l:2''',3'''-n]pentacene (tatpp) ligand were synthesized, in which L-L is a chelating diamine ligand such as 2,2'-bipyridine (bpy), 1,10-phenanthroline (phen), 3,4,7,8-tetramethyl-1,10-phenanthroline (Me phen) or 4,7-diphenyl-1,10-phenanthroline (Ph phen). These Ru-tatpp analogues all undergo reduction reactions with modest reducing agents, such as glutathione (GSH), at pH 7. These, plus several structurally related but non-redox-active RPCs, were screened for DNA cleavage activity, cytotoxicity, acetylcholinesterase (AChE) inhibition, and acute mouse toxicity, and their activities were examined with respect to redox activity and lipophilicity. All of the redox-active RPCs show single-strand DNA cleavage in the presence of GSH, whereas none of the non-redox-active RPCs do. Low-micromolar cytotoxicity (IC ) against malignant H358, CCL228, and MCF7 cultured cell lines was mainly restricted to the redox-active RPCs; however, they were substantially less toxic toward nonmalignant MCF10 cells. The IC values for AChE inhibition in cell-free assays and the acute toxicity of RPCs in mice revealed that whereas most RPCs show potent inhibitory action against AChE (IC values <15 μm), Ru-tatpp complexes as a class are surprisingly well tolerated in animals relative to other RPCs.

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Cellular and cell-free studies of catalytic DNA cleavage by ruthenium polypyridyl complexes containing redox-active intercalating ligands

Abstract: Yellow foci show time dependent DNA double strand breaks in the nuclei of H358 cells treated with IC50 concentration of [(phen)2Ru(tatpp)Ru(Phen)2]Cl4.

Cited by 41 publications

References 137 publications

The development of anticancer ruthenium(ii) complexes: from single molecule compounds to nanomaterials

The development of anticancer ruthenium(ii) complexes: from single molecule compounds to nanomaterials

Monomeric and dimeric coordinatively saturated and substitutionally inert Ru(ii) polypyridyl complexes as anticancer drug candidates

Synthesis, DNA Cleavage Activity, Cytotoxicity, Acetylcholinesterase Inhibition, and Acute Murine Toxicity of Redox‐Active Ruthenium(II) Polypyridyl Complexes

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