Ruthenium anticancer compounds: myths and realities of the emerging metal-based drugs

Ruthenium anticancer drugs have attracted an increasing interest in the last 20 years and two of them have entered clinical trials. Compared to platinum drugs, the complexes based on ruthenium are often identified as less toxic and capable of overcoming the resistance induced by platinum drugs in cancer cells. These activities were attributed to the transportation to tumour cells by transferrin and to the selective activation to more reactive species by the reducing environment of solid tumours as compared to healthy tissues. Ruthenium anticancer drugs have been almost always designed to mimic platinum drugs, particularly for targeting DNA. Indeed, none of the above properties has never been clearly demonstrated even for the ruthenium drugs that entered clinical trials. The suggestion for the future is to change the perspective when designing new chemical entities, abandoning the philosophy that guided the actual panel of ruthenium drugs and to look further into the fine mechanism by which the most relevant ruthenium complexes available kill the target tumour cells, then focusing on targets selective of tumour cells and responsible for cell growth and malignancy.     

Metal-based antitumour drugs in the post-genomic era: what comes next?

In our Dalton Transactions Perspective article entitled, 'Metal-based antitumour drugs in the post genomic era', (Dalton Trans., 2006, 1929-1933) we discussed metal-based drugs in light of past decades of research. We concluded that the post-genomic era would dictate a change in the direction of the field with knowledge of the genome increasingly allowing protein targets to be identified and not simply assuming that DNA is the only relevant target of metal-based drugs. Since our article was published new insights into the mode of action of metal-based drugs have emerged making some older findings increasingly relevant to current drug design. In this article we discuss these developments in terms of what we believe should be the future direction for the field.     

Spin vortices in the Abelian–Higgs model with cholesteric vacuum structure

We continue the study of U(1)$U\left(1\right)$ vortices with cholesteric vacuum structure. A new class of solutions is found which represent global vortices of the internal spin field. These spin vortices are characterized by a non-vanishing angular dependence at spatial infinity, or winding. We show that despite the topological Z₂${\mathbb{Z}}_2$ behavior of SO(3)$SO\left(3\right)$ windings, the topological charge of the spin vortices is of the Z$\mathbb{Z}$ type in the cholesteric. We find these solutions numerically and discuss the properties derived from their low energy effective field theory in 1+1$1+1$ dimensions.     

Organometallic ruthenium-based antitumor compounds with novel modes of action

Both metal complexes and organic molecules are widely used for the treatment of various diseases including cancer - in addition to surgery and radiotherapy. Recent years have witnessed a surge of interest in the application of organometallic compounds to treat cancer and other diseases. Indeed, the unique properties of organometallic compounds, intermediate between those of classical inorganic and organic materials provide new opportunities in medicinal chemistry. In this review, based on the award lecture at ICBOMC’10, we describe a class of ruthenium(II)-arene complexes that are weakly cytotoxic in vitro, but show selective antimetastatic activity in vivo. These compounds, [Ru(η⁶-p-arene)Cl₂(pta)] termed RAPTA, interact strongly with proteins, with the ability to discriminate binding to different proteins, but show a relatively low propensity to bind DNA, which is considered to be the main target of many metal-based drugs. The basic RAPTA structure is quite stable in physiological environments, and studies have shown that aquation of the chloride bonds occurs, it may not be an essential step for anticancer drug activity - direct substitution with biomolecular targets is also possible. Based on the favorable physicochemical properties of RAPTA compounds, combined with their highly promising pharmacological properties, the structure represents an ideal scaffold for rational drug design. Thus far, strategies to overcome drug resistance, by interference with critical enzymes responsible for drug deactivation, and tumor targeting, by tethering to human serum albumin via hydrolyzable linkers, have been demonstrated. However, many more approaches can be envisaged. In any case, the net result are a type of hybrid compounds, that occupy a niche somewhere between classical cisplatin-type anticancer agents that are widely applied to many tumor types and targeted therapies based on organic structures used to inhibit specific enzymes. As such, should these compounds prove themselves in the clinic it is not inconceivable that they could be rapidly refined to form personalized chemotherapies.     

Effects of MgCl2 Crystallographic Structure on Active Centre Formation in Immobilized Single‐Centre and Ziegler–Natta Catalysts for Ethylene Polymerization

The ability of a MgCl₂ support to activate a transition metal catalyst has been found to depend both on the crystallographic structure of the support and on the nature of the catalyst. A high degree of crystallographic disorder can be very effective for the immobilization and activation of titanium and vanadium complexes, but is not necessarily effective for zirconocene activation. A highly disordered support prepared by the reaction of MgBu₂ with HCl gave high activity with TiCl₄ but low activity with (n‐PrCp)₂ZrCl₂. High polymerization activities with the zirconocene were only obtained with supports of type MgCl₂/AlR_n(OEt)_3−n prepared from the reaction of AlR₃ with MgCl₂ · 1.1EtOH. These supports are characterized by additional peaks in the X‐ray diffraction pattern, indicating the presence of a crystalline structure which is absent in the other supports and contains highly Lewis acidic sites able to generate the active metallocenium species.