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.
Journal ArticleDOI
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.
Journal ArticleDOI
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.
Journal ArticleDOI
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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Journal ArticleDOI
Oxali-titanocene Y: a potent anticancer drug.
TL;DR: The in vitro and ex vivo experiments showed that renal cell cancer is the prime target for this novel class of titanocenes, but there is significant activity against ovarian, prostate, cervical, lung, colon, and breast cancers as well.
Journal ArticleDOI
Modifying the structure of dinuclear ruthenium complexes with antitumor activity
Maria G. Mendoza-Ferri,Christian G. Hartinger,Alexey A. Nazarov,Wolfgang Kandioller,Kay Severin,Bernhard K. Keppler +5 more
TL;DR: In this paper, a series of dinuclear ruthenium(II) complexes with longer spacers was synthesized, and the pyridinone ring was modified by replacing the methyl group by an ethyl group.
Journal ArticleDOI
Antiproliferative activity of Titanocene Y against tumor colony-forming units
Olaf Oberschmidt,Axel R. Hanauske,Clara Pampillón,Nigel J. Sweeney,Katja Strohfeldt,Matthias Tacke +5 more
TL;DR: It is shown that the surprisingly good response of nonsmall cell lung cancer and colon cancer against Titanocene Y at its lowest concentration was well comparable or better with respect to cisplatin, given at a concentration of 1.0 μmol/l.
Journal ArticleDOI
Transition-metal-mediated synthesis of novel carbocyclic nucleoside analogues with antitumoral activity
TL;DR: By measuring DNA fragmentation, it could be shown that the activity results from induction of apoptosis, and some of the compounds possess pronounced antitumoral properties.
Journal ArticleDOI
Organometallic analogues of tamoxifen: Effect of the amino side-chain replacement by a carbonyl ferrocenyl moiety in hydroxytamoxifen
Anh Nguyen,Siden Top,Anne Vessières,Pascal Pigeon,Michel Huché,Elizabeth A. Hillard,Gérard Jaouen +6 more
TL;DR: A lipophilic and stable organometallic entity, –OCH2CO-[(g 5 -C5H4)FeCp], has replaced this key functional side chain, while keeping a good affinity for the estrogen receptor and an antiproliferative activity on cancer cells.