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

Challenges and Opportunities in the Development of Organometallic Anticancer Drugs

Peptide-drug conjugates as effective prodrug strategies for targeted delivery.

Vanadium is special in at least two respects: on the one hand, the tetrahedral anion vanadate(V) is similar to the phosphate anion; vanadate can thus interact with various physiological substrates that are otherwise functionalized by phosphate. On the other hand, the transition metal vanadium can easily expand its sphere beyond tetrahedral coordination, and switch between the oxidation states +V, +IV and +III in a physiological environment. The similarity between vanadate and phosphate may account for the antidiabetic potential of vanadium compounds with carrier ligands such as maltolate and picolinate, and also for vanadium's mediation in cardiovascular and neuronal defects. Other potential medicinal applications of more complex vanadium coordination compounds, for example in the treatment of parasitic tropical diseases, may also be rooted in the specific properties of the ligand sphere. The ease of the change in the oxidation state of vanadium is employed by prokarya (bacteria and cyanobacteria) as well as by eukarya (algae and fungi) in respiratory and enzymatic functions. Macroalgae (seaweeds), fungi, lichens and Streptomyces bacteria have available haloperoxidases, and hence enzymes that enable the 2-electron oxidation of halide X− with peroxide, catalyzed by a Lewis-acidic VV center. The X+ species thus formed can be employed to oxidatively halogenate organic substrates, a fact with implications also for the chemical processes in the atmosphere. Vanadium-dependent nitrogenases in bacteria (Azotobacter) and cyanobacteria (Anabaena) convert N2 + H+ to NH4+ + H2, but are also receptive for alternative substrates such as CO and C2H2. Among the enigmas to be solved with respect to the utilization of vanadium in nature is the accumulation of VIII by some sea squirts and fan worms, as well as the purport of the nonoxido VIV compound amavadin in the fly agaric.

https://pubs.rsc.org/en/content/articlepdf/2015/mt/c4mt00304g

The role of vanadium in biology

Bioinorganic chemistry of titanium.

In vitro and in vivo evaluation of doxorubicin conjugates with the divalent peptide E-[c(RGDfK)2] that targets integrin alphavbeta3.

Analyses of Titanocenes in the spheroid-based cellular angiogenesis assay.

Antitumor activity of vanadocene Y and its selenocyanate derivative in xenografted caki-1 tumors in mice

Antitumor Activity of Oxali-Titanocene Y in Xenografted CAKI-1 Tumors in Mice

The 4-diethylaminomethylbenzyl-substituted titanocene dichloride (Titanocene Y*), which is completely water- soluble and showed nanomolar activity against the human renal cancer cells CAKI-1, was tested in vitro in an antiangiogenesis assay against human umbilical vein endothelial cells, HUVEC, delivering an IC50 value of 23 +/- 17 {Mu}M. Titanocene Y* was then given at 25, 50 and 75 mg/kg/d, on five consecutive days per week for up to three weeks to one cohort of six CAKI-1 tumor-bearing female NMRI:nu/nu mice, while a further cohort was treated with solvent only. At the two higher dosages Titanocene Y* showed high toxicity leading to mortality, while the titanocene-treated mouse cohort treated with the lowest dosage showed a moderate but statistically significant tumor growth reduction with respect to the solvent-treated control group, with an optimal T/C value of 76% at the end of the experiment. Immunohistological analysis revealed that the expression of the proliferation marker Ki-67 was reduced by 21%. Furthermore, anti-angiogenic activity was identified by CD31 staining; the number of micro vessels in a defined tumor area decreased by 23% due to Titanocene Y* treatment. The substance caused dose-dependent body weight loss but did not reduce the number of white blood cells at doses of 25 and 50 mg/kg/d.

Holger Weber

Papers

In vitro and in vivo evaluation of doxorubicin conjugates with the divalent peptide E-[c(RGDfK)2] that targets integrin alphavbeta3.

Analyses of Titanocenes in the spheroid-based cellular angiogenesis assay.

Antitumor activity of vanadocene Y and its selenocyanate derivative in xenografted caki-1 tumors in mice

Antitumor Activity of Oxali-Titanocene Y in Xenografted CAKI-1 Tumors in Mice

The Antiangiogenic and Antitumoral Activity of Titanocene Y* In Vivo