Application of inorganic chemistry for non-cancer therapeutics

Electrons come and go, ligands come on and off, structures can be fixed or malleable, the choice of element can span the periodic table, and all of these aspects can be combined to elicit a (hopefully) targeted biological response. Welcome to the themed issue “Application of inorganic chemistry for non-cancer therapeutics”, in which we seek to showcase the many ways in which principles of inorganic chemistry can be applied to tackle challenges in human health and disease. Recent themed issues of Dalton Transactions have explicitly covered metal anticancer compounds (2009) and radiopharmaceuticals (2011), so our intent here is to emphasize other arenas where the creativity of inorganic chemists can contribute to the development of novel therapeutic agents.

In some ways, the field of medicinal inorganic chemistry originated with the Ancients, who turned to the mystical appeal of gold and copper for healing powers. In the modern era, the world's first blockbuster drug was the arsenic-containing anti-syphilis agent salvarsan. And the poster child of inorganic medicines, cisplatin, continues to be a widely used anticancer agent. Today's inorganic chemists have much more sophisticated synthetic control and mechanistic understanding, but can we translate that knowledge into targeted drugs that are selective for a disease state while sparing healthy cells and tissues?

Targeted agents are a theme that reverberates throughout this themed issue. An example is found in the excellent Perspective article by Pascale Delangle and Elizabeth Mintz (DOI: 10.1039/C2DT12188C) that provides an overview of copper chelation therapy in Wilson's disease and suggests a strategy for targeted copper chelators that take inspiration from cellular copper transport proteins. Continuing in the area of metal chelation is another excellent Perspective article, this one by Robert Hider (DOI: 10.1039/C2DT12159J) who discusses the many factors required in the design of clinically useful iron chelators for the treatment of β-thalassemia, sickle cell anemia, and potentially for neurodegenerative disorders and microbial infection. One of these factors is pK_a, a property that Hider and coworkers explore in a separate contribution (DOI: 10.1039/C2DT12396G) dealing with computational methods for predicting pK_a's of pyridinone iron chelators. Des Richardson, Paul Bernhardt and the rest of their team (DOI: 10.1039/C2DT12387H) also incorporate these design factors in the synthesis of new iron chelators, some of which may be useful as protective agents for iron overload, while the toxicity of others makes them potential antiproliferative agents. The contribution by Seth Cohen and coworkers (DOI: 10.1039/C2DT12373H) also looks at chelation of endogenous metal ions, but in the context of metalloproteinase inhibitors, while Mi Hee Lim and coworkers (DOI: 10.1039/C2DT12207C) investigate several flavonoid compounds as part of a targeted chelation approach that would use bifunctional small molecules to modulate metal–amyloid aggregates found in Alzheimer's disease. An alternative approach to targeting amyloid aggregates is provided by Christelle Hureau and coworkers (DOI: 10.1039/C2DT12177H), who examine the ability of cyclometalated platinum compounds to bind amyloid-beta species and disturb their copper-bound form. Yet other papers look at metals in the context of neurodegeneration and/or oxidative stress: Julia Brumaghim et al. (DOI: 10.1039/C2DT30060E) quantify the ability of various neurotransmitters, neurological drugs and supplements to prevent iron- and copper-mediated DNA damage, while Christian Amatore, Clotilde Policar and coworkers (DOI: 10.1039/C2DT12479C) evaluate anti-oxidant properties of manganese superoxide dismutase mimics.

Another common theme in this issue is “anti”, as in antibacterial, antiviral, and antiparasitic. Two Perspective articles tackle this theme, one by Malay Patra, Gilles Gasser and Nils Metzler-Nolte (DOI: 10.1039/C2DT12460B) that reviews organometallic compounds as antibacterial agents, and the other by Christophe Biot, Maribel Navarro and coworkers (DOI: 10.1039/C2DT12247B) that focuses specifically on antimalarial agents. Both reviews promote the idea that derivatizing drug molecules with organometallic units may impart added pharmacological properties or overcome resistance. Chris Orvig, Michael Adam and coworkers (DOI: 10.1039/C2DT12050J) introduce a multifunctional addition to this theme by combining antimalarial chloroquine derivatives with both ferrocene and carbohydrates as targeting vectors, while Ulrich Schatzschneider, Ebbe Nordlander and coworkers (DOI: 10.1039/C2DT30077J) make chloroquine derivatives with cyclopentadienyl manganese (and rhenium) tricarbonyl units and test their activities against malaria, leishmania and trypanosomia parasites.

While organometallic derivatization holds promise, there currently are no design rules that guarantee an added benefit of each individual unit, as Elizabeth Hillard and coworkers (DOI: 10.1039/C2DT12180H) found for ferrocene-modified compounds that did not give the desired selectivity for bacterial toxicity over human cell toxicity. The popular ferrocene also appears in the communication by Ines Neundorf et al. (DOI: 10.1039/C2DT12211A), who attached it to a cell-penetrating peptide. Silver has long been known to have antimicrobial properties, and two contributions in this issue, one by Vickie McKee et al. (DOI: 10.1039/C2DT12166B) and one by Wiley Youngs et al. (DOI: 10.1039/C2DT00055E) introduce new silver(I) complexes with antimicrobial activity.

Organometallics are not the only agents in the “anti” category. Richard Keene and coworkers look at using inert dinuclear polypyridylruthenium(II) compounds to bind DNA and inhibit microbial protein–DNA interactions, whereas J. A. Cowan and coworkers (DOI: 10.1039/C2DT00026A), describe artificial nucleases that fuse a DNA-reactive metal chelate with a viral-specific targeting domain. Dinorah Gambino, Lucía Otero and coworkers (DOI: 10.1039/C2DT12179D) describe metal complexation to bisphosphonates as a strategy to improve the pharmacological properties of agents active against neglected tropical diseases, while F. Javier de la Mata et al. (DOI: 10.1039/C2DT11793B) use a similar concept to look at antiviral properties of polyanionic metal-binding ligands and, because zinc complexation enhances the anti-HIV activity of cyclam macrocycles, Peter Sadler and coworkers (DOI: 10.1039/C2DT30140G) examine the many configurations possible in zinc–cyclam complexes.

Antidiabetic is another anti to add to the list. In this area, vanadium compounds have a long history, and two contributions here deal with their biotransformation, particularly their binding to serum albumin as examined by Tamás Kiss et al. (DOI: 10.1039/C2DT12193J), and their interactions with cellular membranes, as examined by Debbie Crans and coworkers (DOI: 10.1039/C2DT30521F).

Finally, while most of the compounds mentioned above deal with d-block metals, the Frontier article by Edward Tiekink (DOI: 10.1039/C2DT12225A) reminds us that main group elements have a range of biological profiles. Notably, he points out that toxic elements like arsenic and platinum have made their way into clinical use, and that compounds of selenium and tellurium are deserving of more attention.

I'd like to take this opportunity to personally thank all the authors who contributed to this issue. I hope that you, the readers, will find some inspiration in the stories that follow.

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