Chemical, Biological and Antitumor Properties of Ruthenium(II) Complexes with Dimethylsulfoxide

Mestroni, G.; Alessio, Enzo; Calligaris, M.; Attia, W. M.; Quadrifoglio, Franco; Cauci, Sabina; Sava, Gianni; Zorzet, Sonia; Pacor, Sabrina; Monti‐Bragadin, C.; Tamaro, M.; Dolzani, Lucilla

doi:10.1007/978-3-642-74760-1_4

Cited by 35 publications

(21 citation statements)

References 12 publications

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“…The average S-0 bond lengths within the anions of 1 (1.46 A) -as for the Rh analogue (lo) -and within 4 (1.46 A) are, as usually in S-bondei dmso metal complexes, shorter than in crystalline dmso, 1.51 A (23), because of a resonance contribution from M +S--Ot (24). The structure of 1 has been mentioned in a review but no crystal data were presented by the authors (25). 6 The same group has recently published structural data on 4 (3); the data are in good a reement generally although our Ru-Cl distance 9f 2.432(1) a' is significantly longer than that reported, 2.402(2) A.…”

Section: Crystallographic Data On the Ru Moietiesmentioning

confidence: 78%

Ruthenium(III) complexes containing dimethylsulfoxide or dimethylsulfide ligands, and a new route to trans-dichlorotetrakis(dimethylsulfoxide)ruthenium(II)

Jaswal¹,

Rettig²,

James³

1990

Can. J. Chem.

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The new Ru(II1) complex trans-[(dm~o)~H]'[RuCl~(dmso)~]-(I) (dmso = S-bonded dimethylsulfoxide) has been synthesized. New synthetic routes are reported for rner-R~X~(dms)~ complexes (dms = dimethylsulfide, X = Cl(2) and Br (3)) and for tran~-RuCl~(dmso)~ (4). The complexes have been studied spectroscopically while 1, 2 and 4 have also been characterized crystallographically. Crystals of 1 are monoclinic, P2/n, a = 9.280(3), b = 16.518(4), c = 14.034(3) A, P = 100.78 (2) Chem. 27, 4099 (1988)), and reveals all S-bonded dmso ligands; the Ru-CI distance, 2.432(1) A, is significantly longer than that reported, 2.402(2) A. The dms complexes 2 and 3 were isolated unexpectedly from reaction of Ru salts with acidic dmso solutions.Key words: ruthenium complexes, dimethylsulfoxide, dimethylsulfide, hydrogen bonding. Inorg. Chem. 27, 4099 (1988)) et elle rkvkle tous les ligands dmso liCs par le S; la distance Ru-C1, 2,432(1) A est beaucoup plus longue que celle rapportCe, 2,402(2) A. On a Ct C surpris de pouvoir isoler les complexes 2 et 3 du dms provenant de la rkaction de sels du Ru avec des solutions acides de dmso.

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Section: Crystallographic Data On the Ru Moietiesmentioning

confidence: 78%

Ruthenium(III) complexes containing dimethylsulfoxide or dimethylsulfide ligands, and a new route to trans-dichlorotetrakis(dimethylsulfoxide)ruthenium(II)

Jaswal¹,

Rettig²,

James³

1990

Can. J. Chem.

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“…In cell lines, the number of DNA complexes of NAMI-A is far lower than that of cisplatin. 4 These results indicate that ruthenium-metal complexes represent a novel class of metal-based antitumor compounds acting by a mechanism different from classical GG and AG DNA intrastrand cross-linking (31,32,33,34). 4 Disease stabilization was observed in heavily pretreated patients with advanced NSCLC.…”

Section: Discussionmentioning

confidence: 94%

“…Results indicate that no linear relationship existed between the ruthenium concentration and the AUC of ultrafiltrable ruthenium. Binding of ruthenium complexes to DNA has been proven in vitro using calf thymus DNA and human tumor cell lines (31)(32)(33)(34). 4 At equimolar exposure of calf thymus DNA the number of ruthenium-DNA complexes from NAMI-A is the same as that of platinum-DNA complexes from cisplatin.…”

Section: Discussionmentioning

confidence: 99%

A Phase I and Pharmacological Study with Imidazolium- trans- DMSO-imidazole-tetrachlororuthenate, a Novel Ruthenium Anticancer Agent

Rademaker-Lakhai

Bongard²,

Pluim³

et al. 2004

Clinical Cancer Research

807

471

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Purpose: NAMI-A {H 2 Im[trans-RuCl 4 (DMSO)HIm] or imidazolium-trans-DMSO-imidazole-tetrachlororuthenate} is a novel ruthenium-containing compound that has demonstrated antimetastatic activity in preclinical studies. This Phase I study was designed to determine the maximum-tolerated dose (MTD), profile of adverse events, and dose-limiting toxicity of NAMI-A in patients with solid tumors. Furthermore, the ruthenium pharmacokinetics (PK) after NAMI-A administration and preliminary antitumor activity were evaluated.Patients and Methods: Adult patients with solid tumors received NAMI-A as an i.v. infusion over 3 h daily for 5 days every 3 weeks. PK of total and unbound ruthenium was determined during the first and second treatment using noncompartmental pharmacokinetic analysis. The total accumulation of ruthenium in WBCs was also quantified.Results: Twenty-four patients were treated at 12 dose levels (2.4 -500 mg/m 2 /day). At 400 mg/m 2 /day, blisters developed on the hands, fingers, and toes. At 500 mg/m 2 /day, blisters persisted from weeks to months and slowly regressed. Although no formal common toxicity criteria (CTC) grade 3 developed, painful blister formation was considered dose limiting. Because the first signs developed at 400 mg/ m 2 /day, the advised dose for further testing of NAMI-A was determined to be 300 mg/m 2 /day on this schedule. PK analysis revealed a linear relationship between dose and area under the concentration-time curve (AUC) of total and unbound ruthenium (R 2 ‫؍‬ 0.75 and 0.96, respectively) over the whole dose range. Plasma clearance of total ruthenium was 0.17 ؎ 0.09 liter/h, and terminal half-life was 50 ؎ 19 h. The volume of distribution at steady state of total ruthenium was 10.1 ؎ 2.8 liters. The accumulation of ruthenium in WBC was not directly proportional to the increasing total exposure to ruthenium. One patient with pretreated and progressive nonsmall cell lung cancer had stable disease for 21 weeks.Conclusion: NAMI-A can be administered safely as a 3-h i.v. infusion at a dose of 300 mg/m 2 /day for 5 days, every 3 weeks.

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“…The Ru-based anti-metastatic agent NAMI-A was initially thought to act through DNA interactions but it is now accepted that its activity is due to a combination of angiogenesis control [17,71] and anti-invasive properties toward tumor cell blood vessels. On the other hand, DNA has been shown to be a primary target for other Ru(III) and Ru(II) compounds, such as pentaamine(purine)ruthenium(III) complexes [72], cis - and trans -RuCl 2 (dmso) 4 [73,74] or KP1019 [23]. [Ru(η 6 -arene)(X)(Y–Z)] compounds are activated by replacement of a monoanionic X ligand by water, followed by nucleophilic attack by the nucleotide bases of DNA to form covalent monofunctional adducts [26,27,30,31].…”

Section: Resultsmentioning

confidence: 99%

Arene–Ru(II)–chloroquine complexes interact with DNA, induce apoptosis on human lymphoid cell lines and display low toxicity to normal mammalian cells

Martínez

Rajapakse

Sánchez‐Delgado

et al. 2010

Journal of Inorganic Biochemistry

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The complexes [Ru(η6-p-cymene)(CQ)Cl2] (1), [Ru(η6-benzene)(CQ)Cl2] (2), [Ru(η6-p-cymene)(CQ)(H2O)2][BF4]2 (3), [Ru(η6- p-cymene)(en)(CQ)][PF6]2 (4), [Ru(η6-p-cymene)(η6-CQDP)][BF4]2 (5) (CQ = chloroquine base; CQDP = chloroquine diphosphate; en = ethylenediamine) interact with DNA to a comparable extent to that of CQ and in analogous intercalative manner with no evidence for any direct contribution of the metal, as shown by spectrophotometric and fluorimetric titrations, thermal denaturation measurements, circular dichroism spectroscopy and electrophoresis mobility shift assays. Complexes 1–5 induced cytotoxicity in Jurkat and SUP-T1 cancer cells primarily via apoptosis. Despite the similarities in the DNA binding behavior of complexes 1–5 with those of CQ the antitumor properties of the metal drugs do not correlate with those of CQ, indicating that DNA is not the principal target in the mechanism of cytotoxicity of these compounds. Importantly, the Ru-CQ complexes are generally less toxic toward normal mouse splenocytes and human foreskin fibroblast cells than the standard antimalarial drug CQDP and therefore this type of compound shows promise for drug development.

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Chemical, Biological and Antitumor Properties of Ruthenium(II) Complexes with Dimethylsulfoxide

Cited by 35 publications

References 12 publications

Ruthenium(III) complexes containing dimethylsulfoxide or dimethylsulfide ligands, and a new route to trans-dichlorotetrakis(dimethylsulfoxide)ruthenium(II)

Ruthenium(III) complexes containing dimethylsulfoxide or dimethylsulfide ligands, and a new route to trans-dichlorotetrakis(dimethylsulfoxide)ruthenium(II)

A Phase I and Pharmacological Study with Imidazolium- trans- DMSO-imidazole-tetrachlororuthenate, a Novel Ruthenium Anticancer Agent

Arene–Ru(II)–chloroquine complexes interact with DNA, induce apoptosis on human lymphoid cell lines and display low toxicity to normal mammalian cells

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