Opening the lid on piano-stool complexes: An account of ruthenium(II)–arene complexes with medicinal applications
TL;DR: The origins of the field are described, the design of compounds that inhibit enzymes are designed, the application of multinuclear systems to act as drug delivery vehicles, and the development of bioanalytical and biophysical methods are highlighted to help elucidate the mechanisms by which these compounds function.
About: This article is published in Journal of Organometallic Chemistry.The article was published on 2014-02-01. It has received 226 citations till now.
Citations
More filters
01 Jan 2008
TL;DR: The recent achievement of oxaliplatin for the treatment of colon cancer should not belie the imbalance between a plethora of investigated complexes and a very small number of clinically approved platinum drugs.
Abstract: Triggered by the resounding success of cisplatin, the past decades have seen tremendous efforts to produce clinically beneficial analogues. The recent achievement of oxaliplatin for the treatment of colon cancer should, however, not belie the imbalance between a plethora of investigated complexes and a very small number of clinically approved platinum drugs. Strategies opening up new avenues are increasingly being sought using complexes of metals other than platinum such as ruthenium or gallium. Based on the chemical differences between these metals, the spectrum of molecular mechanisms of action and potential indications can be broadened substantially. Other approaches focus on complexes with tumour-targeting properties, thereby maximizing the impact on cancer cells and minimizing the problem of adverse side effects, and complexes with biologically active ligands.
698 citations
TL;DR: It is shown here the different antitumoral approaches offered by ferrocifen derivatives, originally simple derivatives of tamoxifen, which over the course of their development have proved to possess remarkable structural and mechanistic diversity.
Abstract: Despite current developments in therapeutics focusing on biotechnologically-oriented species, the unflagging utility of small molecules or peptides in medicine is still producing strong results. In 2014 for example, of the 41 new medicines authorized for sale, 33 belonged to the category of small molecules, while in 2013 they represented 24 of 27, according to the FDA. This can be explained as the result of recent forays into new or long-neglected areas of chemistry. Medicinal organometallic chemistry can provide us with an antimalarial against resistant parasitic strains, as attested by the phase II clinical development of ferroquine, with a new framework for conceptual advances based on three-dimensional space-filling, and with redox or indeed catalytic intracellular properties. In this context, bioferrocene species with antiproliferative potential have for several years been the subject of sustained effort, based on some initial successes and on the nature of ferrocene as a stable aromatic, with low toxicity, low cost, and possessing reversible redox properties. We show here the different antitumoral approaches offered by ferrocifen derivatives, originally simple derivatives of tamoxifen, which over the course of their development have proved to possess remarkable structural and mechanistic diversity. These entities act via various targets, some of which have been identified, that are triggered according to the concentration of the products. They also act according to the nature of the cancer cells and their functionality, by mechanistic pathways that can operate either synergistically or not, in successive, concomitant or sequential ways, depending for example on newly identified signaling pathways inducing senescence or apoptosis. Here we present a first attempt to rationalize the behavior of these entities with various anticancer targets.
422 citations
TL;DR: Ruthenium(II)-arene RAPTA-type compounds have been extensively explored for their medicinal properties and a comprehensive review of this class of compounds is provided in this article.
360 citations
TL;DR: This work highlights compounds that are apparently incompatible with the more classical (platinum-derived) concepts employed in the development of metal-based anticancer drugs, with respect to both compound design and the approaches used to validate their utility.
Abstract: Cisplatin and other platinum compounds have had a huge impact in the treatment of cancers and are applied in the majority of anticancer chemotherapeutic regimens. The success of these compounds has biased the approaches used to discover new metal-based anticancer drugs. In this perspective we highlight compounds that are apparently incompatible with the more classical (platinum-derived) concepts employed in the development of metal-based anticancer drugs, with respect to both compound design and the approaches used to validate their utility. Possible design approaches for the future are also suggested.
247 citations
TL;DR: A review of the recent developments of arene ruthenium complexes towards both supramolecular chemistry and biology can be found in this paper, where the authors focus on the recent development of these compounds towards both biology and chemistry.
175 citations
References
More filters
TL;DR: In E. coli, the presence of certain group VIIIb transition metal compounds in concentrations of about 1–10 parts per million of the metal in the culture medium causes an inhibition of the cell division process, which implies that the growth process is not markedly affected.
Abstract: IN an investigation of the possible effects of an electric field on growth processes in bacteria, we have discovered a new and interesting effect. In E. coli, the presence of certain group VIIIb transition metal compounds in concentrations of about 1–10 parts per million of the metal in the culture medium causes an inhibition of the cell division process. The bacteria form long filaments, up to 300 times the normal length, which implies that the growth process is not markedly affected.
2,728 citations
TL;DR: In this article, the same authors compared their results with available data on arene exchange in arenetricarbonylchromium complexes and discussed in terms of electronic and steric effects on metal-arene bonding.
Abstract: Arenedi-µ-chloro-ruthenium complexes [RuCl2(arene)]2 have been prepared by dehydrogenation of the appropriate cyclohexa-1,3-diene or cyclohexa-1,4-diene with ethanolic ruthenium(III) trichloride. They react with ligands (L) such as pyridine, tertiary phosphines, or tertiary arsines to give monomeric complexes [RuCl2(arene)L], which are formally analogous to the arenetricarbonylchromium complexes. Analogous dibromo-, di-iodo-, halogeno-(methyl), and dimethyl derivatives have also been prepared; the latter are thermally unstable and air-sensitive. Reaction of the complexes [RuCl2(arene)]2(arene = benzene or p-cymene) with water gives binuclear tri-µ-chloro-cationic species [Ru2C13(arene)2]+, and reaction with silver(I) tetrafluoroborate in acetonitrile gives monomeric [Ru(arene)(MeCN)3]2+. I.r. and n.m.r. data for the new complexes are given. The complexes [RuCl2(arene)L](L = PBun3 or PPh3) undergo partial or complete arene exchange on heating or on u.v. irradiation in an aromatic solvent, co-ordinated p-cymene being the most easily displaced. The exchange method can be used to prepare hexamethylbenzene complexes, e.g.[RuCl2(C6Me6)(PBun3)]. The results are compared with available data on arene exchange in arenetricarbonylchromium complexes and discussed in terms of electronic and steric effects on metal–arene bonding.
939 citations
TL;DR: The preclinical and early clinical development of KP1019 - from bench to bedside - is recapitulated and promising activity against certain types of tumors is observed.
875 citations
TL;DR: The maximum-tolerated dose (MTD), profile of adverse events, and dose-limiting toxicity of NAMI-A in patients with solid tumors were determined and the ruthenium pharmacokinetic analysis revealed a linear relationship between dose and area under the concentration-time curve (AUC) of total and unbound rUThenium.
Abstract: 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.
751 citations
[...]
TL;DR: In the fight against cancer cisplatin, one of the world's best selling anticancer drugs, is being joined by other platinum, titanium, and ruthenium complexes, and metal-targeted organic agents show exciting clinical potential.
Abstract: Not only the 24 or so essential elements, but also nonessential and even radioactive elements have enormous potential for applications in medicine. In the fight against cancer cisplatin, one of the world's best selling anticancer drugs, is being joined by other platinum, titanium, and ruthenium complexes. Gadolinium(III) complexes can be safely injected as magnetic resonance imaging contrast agents, and ligand design allows targeting of paramagnetic ions as well as radiodiagnostic (e.g. 99mTc) and radiotherapeutic isotopes (e.g. 186Re). Manganese superoxide dismutase mimics, vanadium insulin mimics, ruthenium nitric oxide scavengers, lanthanide-based photosensitizers, and metal-targeted organic agents show exciting clinical potential.
740 citations