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)

http://pubs.acs.org/doi/pdf/10.1021/jm100020w

Organometallic Anticancer Compounds

New trends for metal complexes with anticancer activity.

http://pubs.acs.org/doi/pdf/10.1021/cr400460s

Metallodrugs in Medicinal Inorganic Chemistry

In undergraduate level organometallic chemistry courses students are usually taught that organometallic compounds are toxic and unstable in air and water. While this is true of many complexes, some are also non-toxic and stable in air and water. Indeed, bioorganometallic chemistry, the study of biomolecules or biologically active molecules that contain at least one carbon directly bound to a metal, is a thriving subject, and air and water stability is a general pre-requisite. This interdisciplinary field is located at the borderline between chemistry, biochemistry, biology and medicine. In this tutorial review, various aspects of bioorganometallic chemistry are introduced, with the main emphasis on medicinal organometallic compounds. Organometallic therapeutics for cancer, HIV and malaria and other medicinal applications are described. It is also shown how rational ligand design has led to new improved therapies much in the same way that an organometallic chemist working in catalysis will design new ligands for improved activities.

Bioorganometallic chemistry—from teaching paradigms to medicinal applications

Cancer is rapidly becoming the top killer in the world. Most of the FDA approved anticancer drugs are organic molecules, while metallodrugs are very scarce. The advent of the first metal based therapeutic agent, cisplatin, launched a new era in the application of transition metal complexes for therapeutic design. Due to their unique and versatile biochemical properties, ruthenium-based compounds have emerged as promising anti-cancer agents that serve as alternatives to cisplatin and its derivertives. Ruthenium(iii) complexes have successfully been used in clinical research and their mechanisms of anticancer action have been reported in large volumes over the past few decades. Ruthenium(ii) complexes have also attracted significant attention as anticancer candidates; however, only a few of them have been reported comprehensively. In this review, we discuss the development of ruthenium(ii) complexes as anticancer candidates and biocatalysts, including arene ruthenium complexes, polypyridyl ruthenium complexes, and ruthenium nanomaterial complexes. This review focuses on the likely mechanisms of action of ruthenium(ii)-based anticancer drugs and the relationship between their chemical structures and biological properties. This review also highlights the catalytic activity and the photoinduced activation of ruthenium(ii) complexes, their targeted delivery, and their activity in nanomaterial systems.

/pdf/the-development-of-anticancer-ruthenium-ii-complexes-from-35e09q82ra.pdf

The development of anticancer ruthenium(II) complexes: from single molecule compounds to nanomaterials

The cover picture shows the X-ray structures of some new half-sandwich (or piano-stool) RuII-[9]aneS3 complexes ([9]aneS3 = 1,3,7-trithiacyclononane) against a background of cells in culture. The complexes of the type [RuCl2(L)([9]aneS3)], [RuCl(L)2([9]aneS3)][CF3SO3], and [Ru(dmsoS)(L)2([9]aneS3)][CF3SO3]2 (L = 1,3,5-triaza-7-phosphaadamantane, PTA; (L)2 = 2 PTA or chelating N-ligand) were prepared from Ru-[9]aneS3-dmso precursors and structurally characterized, both in solution and in the solid state. Some of them are analogues of known cytotoxic half-sandwich RuII(η6-arene) organometallic compounds of the type [RuCl(en)(η6-arene)][PF6] and [RuCl2(PTA)(η6-arene)], in which the aromatic fragment is replaced by the sulfur macrocycle [9]aneS3 while the rest of the coordination sphere is left unchanged. Preliminary in vitro tests performed on some complexes against the mouse adenocarcinoma cancer cell line (TS/A) and the human mammary normal cell line (HBL-100) showed that, in general, the Ru-[9]aneS3 compounds have a cytotoxicity comparable to that of the corresponding organometallic analogues. These results suggest that the aromatic fragment of the piano-stool RuII compounds is not an essential feature for the in vitro anticancer activity, and it might be effectively replaced by another face-capping ligand with a low steric demand, such as [9]aneS3. Details are discussed in the article by E. Alessio et al. on p. 3423 ff. This work was performed within the framework of COST Action D20, a collaboration between WG 0001 and WG 0005.

Is the Aromatic Fragment of Piano-Stool Ruthenium Compounds an Essential Feature for Anticancer Activity? The Development of New RuII-[9]aneS3 Analogues (Eur. J. Inorg. Chem. 17/2005)

Claudine Scolaro

Papers

Is the Aromatic Fragment of Piano-Stool Ruthenium Compounds an Essential Feature for Anticancer Activity? The Development of New RuII-[9]aneS3 Analogues (Eur. J. Inorg. Chem. 17/2005)