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Introduction to the Organometallics in Biology and Medicine Issue
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transition-metal cyclopentadienyl, arene, and related structures,6 examples of which have also found uses as tools in nontherapeutic studies. Moving away from therapeutics to other areas of biology and chemical biology, organometallics have found applications both as sensors for proteins and in monitoring protein−protein interactions.7 Organometallic complexes comprising a variety of radioisotopes8 are emerging as promising candidates for radioimaging and therapy, taking advantage of the organometallic chemistry of the radioisotopes of rhenium and technetium in PET and SPECT imaging and Auger electron therapy.9 The imaging field also exploits the spectral isolation of metal carbonyl stretching bands in IR microscopy and related techniques.10 Optical imaging, in particular fluorescence microscopy, has been a particular growth area for organometallics in biology in the past few years, exploiting the luminescence associated with second- and third-row transitionmetal complexes, in which triplet states give long-lived emission and large Stokes shifts, ideal properties for such imaging agents.4 In particular, rhenium and technetium polypyridine factricarbonyl complexes and iridium cyclometalates are at the forefront of this emerging field of organometallic chemistry. This special issue contains a mixture of review articles and original research papers highlighting the diversity and strength of organometallics in biology and medicine. Overviews have been specially commissioned from international leaders in the relevant areas and composed in such a way as to introduce these fields to organometallic chemists who are less familiar with biology and medicine. They include descriptions of COreleasing molecules in therapy, organometallic anticancer and antimalarial agents, fluorescence cell imaging agents, and organometallics in radioimaging and therapy. The original invited research articles cover a wide range of topics: antitumor and antiparasitic compounds and imaging, sensing, and diagnostic applications of main-group and transition-metal organometallics. The contents of this special issue demonstrate that biological and medicinal applications of organometallics can include main-group-metal and earlytransition-metal complexes, as well as the better known latertransition-metal examples, and demonstrate the wide range of applications and structural types alluded to above. Contributions include articles covering therapeutic applications of the platinum-group organometallics such as ruthenium-based antitumor agents and the biological properties of organopalladium and platinum species. Organoiron complexes are important in the areas of CO-releasing molecules and in antimalarial and anticancer applications. Main-group organometallics are represented by a contribution on organosilicon analogues of the artificial sweetener aspartame, and early transition metals in anticancer work are included in a report on titanocene dichlorides. The multiple functions of rhenium
he application of organometallic compounds in biology and medicine is nothing newindeed, nature has been using organometallic systems to sustain life for a rather long time. The organometallic chemistry of cobalamine, better known as vitamin B12, and derivatives has been investigated for decades, along with that of a variety of enzymes and cofactors containing metal−carbon bonds. The structure of vitamin B12 was determined by Dorothy Hodgkin, for which she was awarded the Nobel Prize in Chemistry in 1964. In the past, however, synthetic organometallics have tended to be designed for applications in industrial fields such as catalysis rather than in the biological domain. This focus has largely resulted from the sensitivity of certain organometallics to water and oxygen and from concerns over the toxicity of many metals, in particular the heavier transition metals which have such a rich organometallic chemistry. However, many organometallic compounds are entirely stable to water and air, and while many do show some toxicity to certain organisms, this property may be desirable for certain therapeutic applications. Therefore, it is not surprising that with no fundamental obstacles to their application under physiological conditions and the vast range of geometries, reactivities, and tunable physicochemical features such as polarity, charge, and lipophilicity available to the imaginative organometallic chemist, there are now numerous applications of organometallic complexes in biology and medicine. Moreover, there is perhaps no greater challenge than delineating the mechanism by which an organometallic compound exerts a particular effect, medicinal or otherwise, in an environment as complicated as a cell or more complex organisms, including rodents and even humans. As a field of research, bioorganometallic chemistry, which encompasses organometallics in biology and medicine, seems rather new compared to the more established field of bioinorganic chemistry. Gérard Jouen coined the expression “bioorganometallic” in 1985 as he rightly felt that “...a critical mass of separate but novel results had been reached that required a unifying term to identify this type of research...”.1 In the ensuing years the medicinal applications of organometallics have come to the fore, and a variety of biological and medicinal applications using the structural diversity and chemical tunability of organometallic chemistry have emerged. In addition to the simplest organometallic therapeutic agents with a metal−carbon single bond, such as organoarsenes,2 structures as diverse as metal compounds with π-coordinated arenes and cyclopentadienyl ligands, metal carbonyl complexes, and cyclometalates have been evaluated in applications such as chemotherapy,1 radioimaging,3 fluorescent cell imaging, and biological materials.4 In the medicinal field, an amazing structural range of organometallics has been evaluated as antitumor and antibacterial agents and in the emerging area of CO-releasing molecules, which utilize the slow release of carbon monoxide from various transition-metal carbonyls to deliver controlled doses of CO for therapeutic effect. CO signaling pathways are just as vital as those of NO.5 A wide range of antitumor species has been developed, many based on © 2012 American Chemical Society
Special Issue: Organometallics in Biology and Medicine Received: August 2, 2012 Published: August 27, 2012 5671
dx.doi.org/10.1021/om300737y | Organometallics 2012, 31, 5671−5672
Organometallics
Editor's Page
carbonyls as fluorescence imaging agents in their own right, as mimics for technetium species and CO release, are reflected in the number of papers covering rhenium and technetium chemistry, from imaging with amino acid derived rhenium species, rhenium and technetium metallocarboranes and metallopeptides, fluorescent imaging of rhenium−PNA conjugates, and rhenium bioconjugation from zinc species to fluorescence imaging with fluorous rhenium polypyridyls. A contribution concerning rhenium−lanthanide hybrid agents for biological imaging extends the coverage of the periodic table into the f block. Finally, the growing interest in the biological applications of organogold species is represented with contributions concerning the cytotoxicity of gold N-heterocyclic carbene complexes and a report of combined cytotoxicity and fluorescence imaging studies of gold alkynyls. These reviews and articles show the exciting organometallic chemistry that is being discovered at the interface of biology and medicine. It is evident from many of the papers that collaborations are essential to drive this multidisciplinary field forward. Not surprisingly, many synthetic organometallic chemists are collaborating with biologists and clinicians in order to find new innovative tools to illuminate biological processes, to identify and diagnose diseases, and ultimately to cure diseases such as cancers. We hope that this collection of reviews and articles is not merely a welcome source of information but one that stimulates the field further, motivating other organometallic chemists to use their skills and knowhow to solve problems in biology and medicine.
(9) Alberto, R. Medicinal Organometallic Chemistry. Top. Organomet. Chem. 2010, 32, 219. (10) Policar, C.; Waern, J. B.; Plamont, M.-A.; Clède, S.; Mayet, C.; Prazeres, R.; Ortega, J.-M.; Vessières, A.; Dazzi, A. Angew. Chem., Int. Ed. 2011, 50, 860.
Michael P. Coogan, Guest Editor* Department of Chemistry, Cardiff University, Cardiff CF10 3AT, U.K.
Paul J. Dyson, Guest Editor* Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
Manfred Bochmann, Associate Editor
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School of Chemistry, University of East Anglia, Norwich NR4 7TJ, U.K.
AUTHOR INFORMATION
Corresponding Author
*E-mail: CooganMP@cardiff.ac.uk (M.P.C.); paul.dyson@epfl. ch (P.J.D.). Notes
The authors declare no competing financial interest.
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REFERENCES
(1) Jouen, G.; Beck, W.; McGlinchey, M. J. In Bioorganometallics; Jouen, G., Ed.; Wiley-VCH: Weinheim, Germany, 2005. (2) Lloyd, N. C.; Morgan, H. W.; Nicholson, B. K.; Ronimus., R. S. Angew. Chem., Int. Ed. 2005, 44, 41. (3) Taillefer, R.; DePuey, E. G.; Udelson, J. E.; Beller, G. A.; Latour, Y.; Reeves, F. J. Am. Coll. Cardiol. 1997, 29, 69. (4) Balasingham, R. G.; Coogan, M. P.; Thorp-Greenwood, F. L. Dalton Trans. 2011, 40, 11663. (5) Motterlini, R.; Otterbein, L. E. Nat. Rev. Drug Discovery 2010, 9, 728. (6) Bruijnincx, P. C. A.; Sadler, P. J. Curr. Opin. Chem. Biol. 2008, 12, 197. (7) Scheck, R. A.; Schepartz, A. Acc. Chem. Res. 2011, 44, 654. (8) Bartholomä, M.; Valliant, J.; Maresca, K. P.; Babich, J.; Zubieta, J. Chem. Commun. 2009, 493. 5672
dx.doi.org/10.1021/om300737y | Organometallics 2012, 31, 5671−5672
