Differential Anticancer Activities of the Geometric Isomers of Dinuclear Iridium(III) Complexes

Pandrala, Mallesh; Sundaraneedi, Madhu K.; Ammit, Alaina J.; Woodward, Clifford E.; Wallace, L.; Keene, F. Richard; Collins, J. Grant

doi:10.1002/ejic.201501069

Cited by 7 publications

(6 citation statements)

References 39 publications

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“…Cytotoxicity assays were performed using the mitochondrial-dependent reduction of 3-(3,4-dimethylthiazol-2yl)-5-diphenyl tetrazolium bromide (MTT) to formazan as described by Pandrala et al [ 35 ]. The human bile duct cell line H69 was cultured in 96-well microtiter plates containing 0.1 ml of growth factor-supplemented media (DMEM/F12 with high glucose (4 mg/ml), 10% FCS, 1×AA, 25 μg/ml adenine, 5 μg/ml insulin, 1 μg/ml epinephrine, 8.3 μg/ml holo-transferrin, 0.62 μg/ml hydrocortisone, 13.6 ng/ml triiodo-1-thyronine (T3) and 10 ng/ml epithelial growth factor (EGF)) [ 36 ] to a cell density of 5,000 per well at 37°C in 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

Polypyridylruthenium(II) complexes exert anti-schistosome activity and inhibit parasite acetylcholinesterases

et al. 2017

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BackgroundSchistosomiasis affects over 200 million people and there are concerns whether the current chemotherapeutic control strategy (periodic mass drug administration with praziquantel (PZQ)—the only licenced anti-schistosome compound) is sustainable, necessitating the development of new drugs.Methodology/Principal findingsWe investigated the anti-schistosome efficacy of polypyridylruthenium(II) complexes and showed they were active against all intra-mammalian stages of S. mansoni. Two compounds, Rubb12-tri and Rubb7-tnl, which were among the most potent in their ability to kill schistosomula and adult worms and inhibit egg hatching in vitro, were assessed for their efficacy in a mouse model of schistosomiasis using 5 consecutive daily i.v. doses of 2 mg/kg (Rubb12-tri) and 10 mg/kg (Rubb7-tnl). Mice treated with Rubb12-tri showed an average 42% reduction (P = 0.009), over two independent trials, in adult worm burden. Liver egg burdens were not significantly decreased in either drug-treated group but ova from both of these groups showed significant decreases in hatching ability (Rubb12-tri—68%, Rubb7-tnl—56%) and were significantly morphologically altered (Rubb12-tri—62% abnormal, Rubb7-tnl—35% abnormal). We hypothesize that the drugs exerted their activity, at least partially, through inhibition of both neuronal and tegumental acetylcholinesterases (AChEs), as worms treated in vitro showed significant decreases in activity of these enzymes. Further, treated parasites exhibited a significantly decreased ability to uptake glucose, significantly depleted glycogen stores and withered tubercules (a site of glycogen storage), implying drug-mediated interference in this nutrient acquisition pathway.Conclusions/SignificanceOur data provide compelling evidence that ruthenium complexes are effective against all intra-mammalian stages of schistosomes, including schistosomula (refractory to PZQ) and eggs (agents of disease transmissibility). Further, the results of this study suggest that schistosome AChE is a target of ruthenium drugs, a finding that can inform modification of current compounds to identify analogues which are even more effective and selective against schistosomes.

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Section: Methodsmentioning

confidence: 99%

Polypyridylruthenium(II) complexes exert anti-schistosome activity and inhibit parasite acetylcholinesterases

et al. 2017

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“…The results are summarised in Table . While the ruthenium complexes show moderate cytotoxicity (5‐10 μM for a 72‐hour incubation), and are more active than cisplatin (IC 50 =19 μM against MCF‐7 cells), they are relatively inactive compared to other current clinically‐used drugs against breast cancer, e. g. adriamycin (72‐hour IC 50 =0.03 μM against MCF‐7 cells) . No general correlation between the inhibition of MKP‐1 and/or MKP‐3 activity and cytotoxicity was observed.…”

Section: Resultsmentioning

confidence: 96%

Tetranuclear Polypyridylruthenium(II) Complexes as Inhibitors and Down‐Regulators of Phosphatase Enzymes

et al. 2017

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Mitogen-activated protein kinase phosphatases (MKPs) are over-expressed in many cancers. The increased levels of MKP enzymes protect cells from apoptosis induced by anticancer drugs, and thereby decrease the efficacy of the drug. Consequently, there is considerable interest in the development of agents that can down-regulate the production of the MKP enzymes or inhibit their catalytic activities. We have examined the ability of a series of oligonuclear polypyridylruthenium(II) complexes to inhibit the activity of MKP-1 and MKP-3. The results demonstrated that two tetranuclear complexes inhibit the activity of MKP-1 and MKP-3 at 10-20 mM concentrations. The ability of the ruthenium complexes to inhibit the production of MKP-1 in live cancer cells was demonstrated through Western blotting assays, while real-time reverse transcription polymerase chain reaction assays demonstrated the tetranuclear complexes decreased the amount of mkp-1 mRNA produced in cancer cells. The results of this study suggest that tetranuclear ruthenium complexes could be used to enhance the antiproliferative effect of anticancer drugs.

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“… 3 Recently, establishing a structure–activity relationship between isomers of the same molecule has emerged as a new frontier in bioinorganic medicinal chemistry. 4 , 5 …”

Section: Introductionmentioning

confidence: 99%

“…Overall, the anticancer properties of a metal compound can be strongly influenced by the intrinsic (stereo)chemical differences between two isomers . Recently, establishing a structure–activity relationship between isomers of the same molecule has emerged as a new frontier in bioinorganic medicinal chemistry. , …”

Section: Introductionmentioning

confidence: 99%

Rollover Cyclometalation vs Nitrogen Coordination in Tetrapyridyl Anticancer Gold(III) Complexes: Effect on Protein Interaction and Toxicity

Zhou

Carbo-Bague

Siegler

et al. 2021

JACS Au

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In this work, a pair of gold(III) complexes derived from the analogous tetrapyridyl ligands H 2 biqbpy1 and H 2 biqbpy2 was prepared: the rollover, bis-cyclometalated [Au(biqbpy1)Cl ([1]Cl) and its isomer [Au(biqbpy2)Cl ([2]Cl). In [1] + , two pyridyl rings coordinate to the metal via a Au–C bond (C ∧ N ∧ N ∧ C coordination) and the two noncoordinated amine bridges of the ligand remain protonated, while in [2] + all four pyridyl rings of the ligand coordinate to the metal via a Au–N bond (N ∧ N ∧ N ∧ N coordination), but both amine bridges are deprotonated. As a result, both complexes are monocationic, which allowed comparison of the sole effect of cyclometalation on the chemistry, protein interaction, and anticancer properties of the gold(III) compounds. Due to their identical monocationic charge and similar molecular shape, both complexes [1]Cl and [2]Cl displaced reference radioligand [ 3 H]dofetilide equally well from cell membranes expressing the K v 11.1 (hERG) potassium channel, and more so than the tetrapyridyl ligands H 2 biqbpy1 and H 2 biqbpy2. By contrast, cyclometalation rendered [1]Cl coordinatively stable in the presence of biological thiols, while [2]Cl was reduced by a millimolar concentration of glutathione into metastable Au(I) species releasing the free ligand H 2 biqbpy2 and TrxR-inhibiting Au + ions. The redox stability of [1]Cl dramatically decreased its thioredoxin reductase (TrxR) inhibition properties, compared to [2]Cl. On the other hand, unlike [2]Cl, [1]Cl aggregated into nanoparticles in FCS-containing medium, which resulted in much more efficient gold cellular uptake. [1]Cl had much more selective anticancer properties than [2]Cl and cisplatin, as it was almost 10 times more cytotoxic to human cancer cells (A549, A431, A375, and MCF7) than to noncancerous cells (MRC5). Mechanistic studies highlight the strikingly different mode of action of the two compounds: while for [1]Cl high gold cellular uptake, nuclear DNA damage, and interaction with hERG may contribute to cell killing, for [2]Cl extracellular reduction released TrxR-inhibiting Au + ions that were taken up in minute amounts in the cytosol, and a toxic tetrapyridyl ligand also capable of binding to hERG. These results demonstrate that bis-cyclometalation is an appealing method to improve the redox stability of Au(III) compounds and to develop gold-based cytotoxic compounds that do not rely on TrxR inhibition to kill cancer cells.

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Differential Anticancer Activities of the Geometric Isomers of Dinuclear Iridium(III) Complexes

Cited by 7 publications

References 39 publications

Polypyridylruthenium(II) complexes exert anti-schistosome activity and inhibit parasite acetylcholinesterases

Polypyridylruthenium(II) complexes exert anti-schistosome activity and inhibit parasite acetylcholinesterases

Tetranuclear Polypyridylruthenium(II) Complexes as Inhibitors and Down‐Regulators of Phosphatase Enzymes

Rollover Cyclometalation vs Nitrogen Coordination in Tetrapyridyl Anticancer Gold(III) Complexes: Effect on Protein Interaction and Toxicity

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