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Medicinal Importance of Ruthenium Compounds
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Medicinal Importance of Ruthenium Compounds

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Organometallic Chemistry".

Deadline for manuscript submissions: closed (31 May 2019) | Viewed by 21187

Special Issue Editor

Prof. Dr. Iztok Turel

E-Mail Website
Guest Editor
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Vecna pot 113, 1000 Ljubljana, Slovenia
Interests: bioinorganic chemistry; metal ions; biologically active compounds; metal based drugs; quinolones; guanine derivatives; diketonates; hydroxyquinolines; pyrithiones; ruthenium chemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Forty years ago (1978), cisplatin was approved by the FDA (Food and Drug Administration) for use in certain types of cancers and this drug is still used in clinical practice. Without any doubt, for many years platinum complexes were the most intensely studied from all potential metal-based anticancer drugs; however, in the last few decades, an increasing number of papers have been published exploring the medicinal properties of another platinum group metal—ruthenium. Some of the reasons why the alternatives for platinum complexes were explored were resistance development and the severe side effects of platinum drugs. Ruthenium(III) compounds isolated in the labs of Alessio (NAMI-A) and Keppler (KP1019, and more soluble analog KP1339) have, long ago, entered clinical trials. It is encouraging that a photodynamic therapy (PDT) agent based on Ru(II), namely TLD-1433, has also recently entered clinical trials. Several other ruthenium compounds are involved in preclinical level studies as potential chemotherapeutics. On the other hand, radiotherapy with ruthenium-106 was also found to be effective for the treatment of malignant iris melanoma.

However, ruthenium compounds were not only explored as anticancer agents, but also as potential antimicrobial drugs, as potential drugs for neurodegenerative diseases, as inhibitors of several enzymes, as immunosuppressants and as nitric oxide scavengers.

Apart from the biological activity of ruthenium complexes, their physico-chemical properties (e.g., photophysical effects) can be used for diagnostic properties. Ruthenium luminophores can be used as highly effective probes for cell imaging in microscopy. Moreover, theranostics (a combination of therapy and diagnostics) is very popular and luminescent ruthenium complexes are also tested for such types of applications.

This Special Issue will include a selection of research and review articles to collect and disseminate contributions in the field of ruthenium medicinal chemistry.

Prof. Dr. Iztok Turel
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Uses of ruthenium in:

  • metal-based drugs
  • metal–drug interactions
  • anticancer drugs
  • antimicrobial agents
  • neurodegenerative diseases
  • enzyme inhibition
  • photophysical properties
  • photodynamic therapy
  • diagnostics
  • theranostics

Published Papers (4 papers)

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Research

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19 pages, 3190 KiB  
Article
Interaction with Blood Proteins of a Ruthenium(II) Nitrofuryl Semicarbazone Complex: Effect on the Antitumoral Activity
by Bruno Demoro, Andreia Bento-Oliveira, Fernanda Marques, João Costa Pessoa, Lucía Otero, Dinorah Gambino, Rodrigo F. M. de Almeida and Ana Isabel Tomaz
Molecules 2019, 24(16), 2861; https://doi.org/10.3390/molecules24162861 - 07 Aug 2019
Cited by 14 | Viewed by 2763
Abstract
The steady rise in the cancer burden and grim statistics set a vital need for new therapeutic solutions. Given their high efficiency, metallodrugs are quite appealing in cancer chemotherapy. This work examined the anticancer activity of an anti-trypanosomal ruthenium-based compound bearing the 5-nitrofuryl [...] Read more.
The steady rise in the cancer burden and grim statistics set a vital need for new therapeutic solutions. Given their high efficiency, metallodrugs are quite appealing in cancer chemotherapy. This work examined the anticancer activity of an anti-trypanosomal ruthenium-based compound bearing the 5-nitrofuryl pharmacophore, [RuII(dmso)2(5-nitro-2-furaldehyde semicarbazone)] (abbreviated as RuNTF; dmso is the dimethyl sulfoxide ligand). The cytotoxicity of RuNTF was evaluated in vitro against ovarian adenocarcinoma, hormone-dependent breast adenocarcinoma, prostate carcinoma (grade IV) and V79 lung fibroblasts human cells. The activity of RuNTF was similar to the benchmark metallodrug cisplatin for the breast line and inactive against the prostate line and lung fibroblasts. Given the known role of serum protein binding in drug bioavailability and the distribution via blood plasma, this study assessed the interaction of RuNTF with human serum albumin (HSA) by circular dichroism (CD) and fluorescence spectroscopy. The fluorescence emission quenching from the HSA-Trp214 residue and the lifetime data upon RuNTF binding evidenced the formation of a 1:1 {RuNTF-albumin} adduct with log Ksv = (4.58 ± 0.01) and log KB = (4.55 ± 0.01). This is supported by CD data with an induced CD broad band observed at ~450 nm even after short incubation times. Importantly, the binding to either HSA or human apo-transferrin is beneficial to the cytotoxicity of the complex towards human cancer cells by enhancing the cytotoxic activity of RuNTF. Full article
(This article belongs to the Special Issue Medicinal Importance of Ruthenium Compounds)
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15 pages, 1672 KiB  
Article
Fine-Tuning the Activation Mode of an 1,3-Indandione-Based Ruthenium(II)-Cymene Half-Sandwich Complex by Variation of Its Leaving Group
by Stephan Mokesch, Daniela Schwarz, Michaela Hejl, Matthias H. M. Klose, Alexander Roller, Michael A. Jakupec, Wolfgang Kandioller and Bernhard K. Keppler
Molecules 2019, 24(13), 2373; https://doi.org/10.3390/molecules24132373 - 27 Jun 2019
Cited by 7 | Viewed by 3264
Abstract
Fine-tuning of the properties of a recently reported 1,3-indandione-based organoruthenium complex is attempted to optimize the stability under physiological conditions. Previous work has shown its capacity of inhibiting topoisomerase IIα; however, fast aquation leads to undesired reactions and ligand cleavage in the blood [...] Read more.
Fine-tuning of the properties of a recently reported 1,3-indandione-based organoruthenium complex is attempted to optimize the stability under physiological conditions. Previous work has shown its capacity of inhibiting topoisomerase IIα; however, fast aquation leads to undesired reactions and ligand cleavage in the blood stream before the tumor tissue is reached. Exchange of the chlorido ligand for six different N-donor ligands resulted in new analogs that were stable at pH 7.4 and 8.5. Only a lowered pH level, as encountered in the extracellular space of the tumor tissue, was capable of aquating the complexes. The 50% inhibitory concentration (IC50) values in three human cancer cell lines differed only slightly, and their dependence on the utilized leaving group was smaller than what would be expected from their differences in cellular accumulation, but in accordance with the very minor variation revealed in measurements of the complexes’ lipophilicity. Full article
(This article belongs to the Special Issue Medicinal Importance of Ruthenium Compounds)
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16 pages, 3049 KiB  
Article
New Heteroleptic Ruthenium(II) Complexes with Sulfamethoxypyridazine and Diimines as Potential Antitumor Agents
by Ariane C.C. de Melo, Jaime M.S.V.P. Santana, Kelen J.R.C. Nunes, Bernardo L. Rodrigues, Nathalia Castilho, Philipe Gabriel, Adolfo H. Moraes, Mayra de A. Marques, Guilherme A.P. de Oliveira, Ívina P. de Souza, Hernán Terenzi and Elene C. Pereira-Maia
Molecules 2019, 24(11), 2154; https://doi.org/10.3390/molecules24112154 - 07 Jun 2019
Cited by 9 | Viewed by 3405
Abstract
Two new complexes of Ru(II) with mixed ligands were prepared: [Ru(bpy)2smp](PF6) (1) and [Ru(phen)2smp](PF6) (2), in which smp = sulfamethoxypyridazine; bpy = 2,2′-bipyridine; phen = 1,10-phenanthroline. The complexes have been characterized [...] Read more.
Two new complexes of Ru(II) with mixed ligands were prepared: [Ru(bpy)2smp](PF6) (1) and [Ru(phen)2smp](PF6) (2), in which smp = sulfamethoxypyridazine; bpy = 2,2′-bipyridine; phen = 1,10-phenanthroline. The complexes have been characterized by elemental and conductivity analyses; infrared, NMR, and electrospray ionization mass spectroscopies; and X-ray diffraction of single crystal. Structural analyses reveal a distorted octahedral geometry around Ru(II) that is bound to two bpy (in 1) or two phen (in 2) via their two heterocyclic nitrogens and to two nitrogen atoms from sulfamethoxypyridazine—one of the methoxypyridazine ring and the sulfonamidic nitrogen, which is deprotonated. Both complexes inhibit the growth of chronic myelogenous leukemia cells. The interaction of the complexes with bovine serum albumin and DNA is described. DNA footprinting using an oligonucleotide as substrate showed the complexes’ preference for thymine base rich sites. It is worth notifying that the complexes interact with the Src homology SH3 domain of the Abl tyrosine kinase protein. Abl protein is involved in signal transduction and implicated in the development of chronic myelogenous leukemia. Nuclear magnetic resonance (NMR) studies of the interaction of complex 2 with the Abl-SH3 domain showed that the most affected residues were T79, G97, W99, and Y115. Full article
(This article belongs to the Special Issue Medicinal Importance of Ruthenium Compounds)
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Review

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20 pages, 2057 KiB  
Review
NAMI-A and KP1019/1339, Two Iconic Ruthenium Anticancer Drug Candidates Face-to-Face: A Case Story in Medicinal Inorganic Chemistry
by Enzo Alessio and Luigi Messori
Molecules 2019, 24(10), 1995; https://doi.org/10.3390/molecules24101995 - 24 May 2019
Cited by 242 | Viewed by 10880
Abstract
NAMI-A ((ImH)[trans-RuCl4(dmso-S)(Im)], Im = imidazole) and KP1019/1339 (KP1019 = (IndH)[trans-RuCl4(Ind)2], Ind = indazole; KP1339 = Na[trans-RuCl4(Ind)2]) are two structurally related ruthenium(III) coordination compounds that have attracted a [...] Read more.
NAMI-A ((ImH)[trans-RuCl4(dmso-S)(Im)], Im = imidazole) and KP1019/1339 (KP1019 = (IndH)[trans-RuCl4(Ind)2], Ind = indazole; KP1339 = Na[trans-RuCl4(Ind)2]) are two structurally related ruthenium(III) coordination compounds that have attracted a lot of attention in the medicinal inorganic chemistry scientific community as promising anticancer drug candidates. This has led to a considerable amount of studies on their respective chemico-biological features and to the eventual admission of both to clinical trials. The encouraging pharmacological performances qualified KP1019 mainly as a cytotoxic agent for the treatment of platinum-resistant colorectal cancers, whereas the non-cytotoxic NAMI-A has gained the reputation of being a very effective antimetastatic drug. A critical and strictly comparative analysis of the studies conducted so far on NAMI-A and KP1019 allows us to define the state of the art of these experimental ruthenium drugs in terms of the respective pharmacological profiles and potential clinical applications, and to gain some insight into the inherent molecular mechanisms. Despite their evident structural relatedness, deeply distinct biological and pharmacological profiles do emerge. Overall, these two iconic ruthenium complexes form an exemplary and unique case in the field of medicinal inorganic chemistry. Full article
(This article belongs to the Special Issue Medicinal Importance of Ruthenium Compounds)
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