Organometallic Anticancer Compounds
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The quest for alternative drugs to the well-known cisplatin and its derivatives, which are still used in more than 50% of the treatment regimes for patients suffering from cancer, is highly needed, and organometallic compounds have recently been found to be promising anticancer drug candidates.Abstract:
The quest for alternative drugs to the well-known cisplatin and its derivatives, which are still used in more than 50% of the treatment regimes for patients suffering from cancer, is highly needed.1,2 Despite their tremendous success, these platinum compounds suffer from two main disadvantages: they are inefficient against platinum-resistant tumors, and they have severe side effects such as nephrotoxicity. The latter drawback is the consequence of the fact that the ultimate target of these drugs is ubiquitous: It is generally accepted that Pt anticancer drugs target DNA, which is present in all cells.3,4 Furthermore, as a consequence of its particular chemical structure, cisplatin in particular offers little possibility for rational improvements to increase its tumor specificity and thereby reduce undesired side effects.
In this context, organometallic compounds, which are defined as metal complexes containing at least one direct, covalent metal−carbon bond, have recently been found to be promising anticancer drug candidates. Organometallics have a great structural variety (ranging from linear to octahedral and even beyond), have far more diverse stereochemistry than organic compounds (for an octahedral complex with six different ligands, 30 stereoisomers exist!), and by rational ligand design, provide control over key kinetic properties (such as hydrolysis rate of ligands). Furthermore, they are kinetically stable, usually uncharged, and relatively lipophilic and their metal atom is in a low oxidation state. Because of these fundamental differences compared to “classical coordination metal complexes”, organometallics offer ample opportunities in the design of novel classes of medicinal compounds, potentially with new metal-specific modes of action. Interestingly, all the typical classes of organometallics such as metallocenes, half-sandwich, carbene-, CO-, or π-ligands, which have been widely used for catalysis or biosensing purposes, have now also found application in medicinal chemistry (see Figure Figure11 for an overview of these typical classes of organometallics).
Figure 1
Summary of the typical classes of organometallic compounds used in medicinal chemistry.
In this Perspective, we report on the recent advances in the discovery of organometallics with proven antiproliferative activity. We are emphasizing those compounds where efforts have been made to identify their molecular target and mode of action by biochemical or cell biology studies. This Perspective covers more classes of compounds and in more detail than a recent tutorial review by Hartinger and Dyson.(5) Furthermore, whereas recent reviews and book contributions attest to the rapid development of bioorganometallic chemistry in general,6,7 this Perspective focuses on their potential application as anticancer chemotherapeutics. Another very recent review article categorizes inorganic anticancer drug candidates by their modes of action.(8) It should be mentioned that a full description of all currently investigated types of compounds is hardly possible anymore in a concise review. For example, a particularly promising class of organometallic anticancer compounds, namely, radiolabeled organometallics, has been omitted for space limitations. Recent developments of such compounds have been reviewed in detail by Alberto.(9)read more
Citations
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Metallodrugs in Medicinal Inorganic Chemistry
Katja Dralle Mjos,Chris Orvig +1 more
Antitumour metal compounds: more than theme and variations
Michael A. Jakupec,Markus Galanski,Vladimir B. Arion,Christian G. Hartinger,Bernhard K. Keppler +4 more
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.
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Metal N-heterocyclic carbene complexes as potential antitumor metallodrugs
TL;DR: This review describes the advances that have been achieved in using transition metal complexes containing NHC ligands as antitumor agents and clearly demonstrate the great potential of metal-NHC complexes as antitUMor agents.
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Exploration of the medical periodic table: towards new targets
TL;DR: Progress in identifying and defining target sites has been accelerated recently by advances in proteomics, genomics and metal speciation analysis, and examples of metal compounds and chelating agents (enzyme inhibitors) currently in clinical use, clinical trials or preclinical development are highlighted.
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Noble metals in medicine: Latest advances
Serenella Medici,Massimiliano Francesco Peana,Valeria Marina Nurchi,Joanna Izabela Lachowicz,Guido Crisponi,Maria Antonietta Zoroddu +5 more
TL;DR: A detailed account of the latest results of metal-based drugs and their potential uses in the cure of severe diseases is provided and the number of published studies in this field is huge.
References
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Tuning the hydrophobicity of ruthenium(II)–arene (RAPTA) drugs to modify uptake, biomolecular interactions and efficacy
Claudine Scolaro,Adrian B. Chaplin,Christian G. Hartinger,Alberta Bergamo,Moreno Cocchietto,Bernhard K. Keppler,Gianni Sava,Paul J. Dyson +7 more
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Highly Antiproliferative Ruthenium(II) and Osmium(II) Arene Complexes with Paullone-Derived Ligands
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Exploring Chemical Space with Organometallics: Ruthenium Complexes as Protein Kinase Inhibitors
Eric Meggers,G. Ekin Atilla-Gokcumen,Howard Bregman,Jasna Maksimoska,Seann P. Mulcahy,Nicholas Pagano,Douglas S. Williams +6 more
TL;DR: In this paper, the authors describe a ruthenium-based inhibitor for protein kinases GSK-3 and Pim-1 by using the class of indolocarbazole alkaloids as a lead structure.
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Tuning the Hydrolytic Aqueous Chemistry of Osmium Arene Complexes with N,O-Chelating Ligands to Achieve Cancer Cell Cytotoxicity
TL;DR: This work shows how the rational control of chemical reactivity (hydrolysis, acidity, formation of hydroxo-bridged dinuclear species) can allow the design of cytotoxic anticancer OsII arene complexes.
Journal ArticleDOI
Ferrocenoyl pyridine arene ruthenium complexes with anticancer properties: synthesis, structure, electrochemistry, and cytotoxicity.
TL;DR: Cyclic voltammetry revealed a good correlation of the RuII/RuIII redox potentials of 1-4 and the number of alkyl substituents in the arene ligand.