Editorial Cite This: Chem. Rev. 2019, 119, 727−729
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Introduction: Metals in Medicine
Chem. Rev. 2019.119:727-729. Downloaded from pubs.acs.org by 37.9.41.73 on 01/25/19. For personal use only.
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cubism, or orphism),5 metallocentric drug development also breaks with paradigms of conventional pharmaceutical discovery and transgresses beyond traditional disciplinary boundaries. In different biological contexts and coordination environments, one and the same metal ion can have a very different influence on biological processes, similar to the different effect one particular color may have on the observer depending on the environment. The work of Sonia Delaunay provides the inspiration for the cover art, which plays with color in depicting abstract renderings of concepts from the review articles in this Thematic Issue of Metals in Medicine. With a similar sensibility for context, we take a moment to reflect back to the first Thematic Issue of Chemical Reviews that appeared on Medicinal Inorganic Chemistry, guest-edited by Michael Abrams and Chris Orvig, back in 1999.6 Highlighting changes of the field and identifying advancements and completely new aspects that were unheard of then provides a useful magnifying glass for visualizing the state of the field today. In the process, it will become apparent how advances in other fieldsbe it new compound classes or materials, bioanalytical instrumentation, biomedical sciences, or even seemingly remote fields such as photophysics or immunologyhave in return fostered progress in Metals in Medicine and made advances possible that were not even conceivable 20 years ago. A look at the 1999 Table of Contents is particularly revealing with respect to the metals that are covered. Not surprising, cisplatin and Pt-based drugs are heavily featured, as are Gd and Tc, with individual articles treating Au, V, Bi, and Li separately. The intervening years have witnessed a continued expansion of the periodic table of medicinal elements, with more work now devoted to Ru and other noble metals such as Os, Ir, and Re, while Au remains a focus metal for future therapeutic drug candidates. Cancer continues to predominate the application space, while needed innovation against infectious diseases invites creative approaches that include finding active agents across the periodic table, as reviewed by Gasser in the context of neglected tropical diseases. Moreover, in the last 20 years areas of interest have moved into focus where unique properties of metal complexes are particularly prone to excel. One example is photochemotherapy, or more specifically photodynamic therapy (PDT), which was an emerging concept in 1999, and where now McFarland and co-workers describe a compound that is in clinical trials. This project arose from a tumor-centered approach, as part of a complete PDT package that included a tailor-made compound together with the light component and protocol for treating invasive bladder cancer. Soldevila Barreda and Metzler-Nolte describe “catalytic metallodrugs” as an exciting class of compounds that brings the rich knowledge of transition-metal catalysis to medicinal contexts. In contrast to 1999, when the only reference to medicinal
n 1969, Barnett Rosenberg, Loretta Van Camp, and Thomas Krigas published a seminal paper that described the antiproliferative activity of a very simple inorganic compound, today known as cisplatin.1 That discovery arguably marks the modern emergence of Metals in Medicine, the topic of this particular Thematic Issue, as a distinct field of investigation. A number of aspects in this cisplatin story are noteworthy.2,3 For one, this is a classic example of fortuity in science and careful experimentation with proper control experiments, as Rosenberg’s team was actually studying completely unrelated phenomena and was not intentionally investigating platinum compounds. Second, the first biological experiments (after morphological changes in bacteria were observed) were directly on mice, and clinical trials on humans started as early as 1971, with approval granted by the FDA in 1978record speed by today’s standards.4 Finally, the success of this seemingly simple inorganic compound sparked investigations that required strongly interlinking biology and inorganic chemistry in order to elucidate the mechanism of action of Pt-containing drugs and synthesize new, potentially more potent compounds. More broadly, the discovery that an inorganic complex caused the dramatic biological effect that Loretta saw through her microscope’s lens has inspired a whole field to bring a metallocentric view to the process of drug discovery. The use of metals for health and healing is in fact an ancient practice stretching back thousands of years. The concept of using modern medicinal chemistry approaches to intentionally investigate the structure and properties of inorganic complexes for medicinal function has matured immensely in the 50 years since the Rosenberg paper. Today, Metals in Medicine comprehensively describes medicinal inorganic chemistry approaches to discover and develop pharmaceutical agents that involve metal-dependent processes. Such agents encompass metallodrugs in which a metal complex is itself the active agent, as well as agents that themselves do not contain a metal but that act on native biometals or metal-containing biomolecules or that influence metal trafficking pathways in ways that affect cellular processes. Leveraging the power of all of these categories for therapeutic or diagnostic benefit requires thinking about the properties of metal complexation in a biological context. Appreciating the relationship between metals and biomolecules provides infinitely diverse opportunities to influence the properties, speciation, reactivity, and ultimately biological effect of metals in the given medicinal context. This relationship brings to mind the theory of colors that so influenced the artist Sonia Delaunay, whose principles of simultaneous design made her an important figure in the history of modern art.5 In her words: “One who knows how to appreciate color relationships, the influence of one color on another, their contrasts and dissonances, is promised an infinitely diverse imagery.” Much like Delaunay’s work broke from convention to open our eyes through the use of color and shape rather than figural representation (in so-called orphic © 2019 American Chemical Society
Special Issue: Metals in Medicine Published: January 23, 2019 727
DOI: 10.1021/acs.chemrev.8b00685 Chem. Rev. 2019, 119, 727−729
Chemical Reviews
Editorial
the range of enzyme targets as well as ligands with which to target them, as reviewed by Cohen, who provides a broad overview of drug discovery efforts that focus on metal-binding pharmacophores intentionally designed against metalloenzyme targets. Another conceptually new development that is reflected for example in the article of Wright is chemistry “beyond the molecule”, that is the use of nanomaterials in diagnosis and therapy. While this is a new area, and its particular advantages, as well as associated risks, are still being explored, there is clearly a lot of space for nanoscience applications in medicine. Lastly, we note an exciting new development in anticancer therapeutics that is quickly moving into focus, namely the interplay of metallodrugs and the immune system. Remarkably, Rosenberg presciently noted that platinum-treated mice were resistant to a new induction of tumor growth, which he correctly (but without being able to prove this at the time) attributed to an “immunologic memory” of anticancer treatment. In this Thematic Issue, Berger and colleagues summarize the scattered but steadily growing knowledge of the intimate interplay of a patient’s immune system and the treatment with metal-based drugs. In some cases, metal-based anticancer agents seem to illicit strong immune responses; understanding how these responses influence therapy will certainly require unconventional approaches beyond the classic search arena for modes-of-action and target identification. Moreover, the combination therapy of metallodrugs and immune modulators (e.g., checkpoint inhibitors) is just emerging, and given the strong immune response to some metallodrugs, this combination holds incredible promise for future therapeutic intervention. As one sign of a maturing field, a Gordon Research Conference on “Metals in Medicine” was inaugurated in 2002, just three years after the first Thematic Issue on the topic appeared in Chemical Reviews. This conference series has now grown to an intellectual nucleus for development of the field. Our own journey into this second Thematic Issue on the topic is closely linked to the eighth edition of that “GRC MiM” in 2016, that the two of us cochaired. We were subsequently invited to guest-edit this Issue, and for us, it has been a wonderful opportunity to continue the series of trans-Atlantic Skype calls to hash out themes, exchange ideas, and sharpen our insights not only into the field of science as such but also into all the joys and adversities associated with publishing such a Thematic issue. It has been a rewarding experience for us, working with the authors, with the editorial team of Chemical Reviews (in particular Ruma Banerjee and Lou Larsen), and toward the end very intensely with Mary O’Reilly, who designed the cover art that we hope communicates many of the aspects of our common passion, that is Medicinal Bioinorganic Chemistry. As Editors we are well aware that there is an element of fortune and coincidence in the selection of articles that ultimately appear in the printed version of such a Thematic Issue. There are some topics that we would have loved to see included but that had already received deep coverage in Chemical Review in recent years7,8 and others that we would have loved to see published but quite simply did not make it to the production deadlinebut we hope they will be linked to the Thematic Issue later in the sense of a Virtual Issue. We would like to thank all of those who contributed and hope that you enjoy reading the articles, finding inspiration for your own research or teaching about Metals in Medicine in this Thematic Issue.
applications of catalytic metal complexes was to mimic the enzyme superoxide dismutase, today a broad variety of “unnatural” molecular transformations can be effected inside living cells, with many more on the horizon. As in 1999, the development of nuclear medicine, radiodiagnostics, and contrast agents for magnetic resonance imaging continues to drive innovation in medical diagnostics and therapy. As detailed in separate articles in this Thematic Issue by Packard, Orvig, and Caravan, new developments in these areas derive from improved availability for some isotopes in hospital settings, new ligands with improved properties for targeted imaging and special purposes, and dramatic improvements in instrument technology. All these taken together greatly contribute to patient benefit, making diagnostics and radiotherapy faster, more reliable, safer, and often more convenient for patients. Beyond “new” elements and the innovative use of established and new ligands, we observe major new developments in bioanalytical techniques, some of which explicitly rely on the presence of non-natural elements. Bioanalytical techniques such as atomic absorption spectroscopy (AAS) and plasma-coupled analytical techniques such as ICP-OES and ICP-MS for elemental analysis, but also synchroton-based techniques such as X-ray fluorescence, X-ray absorption, and even their related microscopy versions are having an impact on our understanding of the speciation and localization of elements in biological tissues and even individual cells. These advances are providing insight into metal ion trafficking with unprecedented precision and resolution. One outcome of this improved understanding is the possibility to target metal complexes to stressed cells or diseased tissues while leaving neighboring, benign cells untouched. Separate articles by Marmion and Guo provide elegant examples of metal complexes designed with specific targeting or responsiveness to various cellular stimuli in mind. Importantly, much of our understanding of molecular differences at the cellular level is being enabled by genomic and proteomic techniques that were not even on the agenda 20 years ago. Moving forward, these advances provide a vast tapestry for creative design of metalbased drugs. In addition to a broader use of elements across the periodic table and advances in bioanalytical techniques, our muchimproved understanding of metallobiology in general has opened unprecedented opportunities for intervention. For example, our insights into metal ion homeostasis have grown exponentially, and where we had a mostly systemic understanding of metal ion intoxication and homeostasis in 1999, we now have a much more detailed molecular picture of many of the enzymes, transporters, and metallochaperones involved, including numerous biomolecular interactions and their regulation. This knowledge, in turn, provides a spotlight to bring new therapeutic prospects into focus. As exemplified in the specific case of M. tuberculosis described by Goulding in this Issue, opportunities to interfere with metal trafficking pathways are opening new possibilities to fight microbial infections. Emerging knowledge of metallobiology in the context of neurodegenerative processes has also burgeoned in the last two decades. While many questions remain, approaches that bring principles of inorganic chemistry to bear on these systems are providing new insights, as highlighted in the article by Lim. Metalloenzymes were recognized as targets for inhibitor design on a few selected targets only in 1999, but the intervening 20 years have opened 728
DOI: 10.1021/acs.chemrev.8b00685 Chem. Rev. 2019, 119, 727−729
Chemical Reviews
Editorial
Katherine J. Franz* Alexander F. Hehmeyer Professor, Duke University
Nils Metzler-Nolte*
Ruhr University Bochum
AUTHOR INFORMATION ORCID
Katherine J. Franz: 0000-0002-9015-0998 Nils Metzler-Nolte: 0000-0001-8111-9959 Notes
Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.
REFERENCES
Biography
(1) Rosenberg, B.; VanCamp, L.; Trosko, J. E.; Mansour, V. H. Platinum Compounds: A New Class of Potent Antitumor Agents. Nature 1969, 222, 385−386. (2) Hoeschele, J. D. Dr Barnett Rosenberg − A Personal Perspective. Dalton Trans. 2016, 45, 12966−12969. (3) Rosenberg, B. In Cisplatin; Lippert, B., Ed.; Verlag Helvetica Chimica Acta: Zürich, 1999; Chapter 1, 3−27. (4) Lippert, B. Cisplatin; Verlag Helvetica Chimica Acta: Zürich, 1999. (5) Á rbol, M. R.; Godefroy, G.; de Monti, M. Sonia Delaunay: Art, Design and Fashion; Museo Thyssen-Bornemisza. 2017, 9788417173012. (6) Orvig, C.; Abrams, M. J. Medicinal Inorganic Chemistry: Introduction. Chem. Rev. 1999, 99, 2201−2203. (7) Wilson, J. J.; Lippard, S. J. Synthetic Methods for the Preparation of Platinum Anticancer Complexes. Chem. Rev. 2014, 114, 4470− 4495. (8) Johnstone, T. C.; Suntharalingam, K.; Lippard, S. J. The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs. Chem. Rev. 2016, 116, 3436−3486.
Katherine J. Franz is the Alexander F. Hehmeyer Professor and Chair of Chemistry at Duke University in Durham, North Carolina, USA. After formative undergraduate research experiences with Prof. James Loehlin at Wellesley College and Dr. Richard Fish at the Lawrence Berkeley National Laboratory, she earned a Ph.D. in inorganic chemistry with Prof. Stephen J. Lippard at MIT and an NIH postdoctoral fellowship with Prof. Barbara Imperiali, also at MIT. Kathy was a Council Member of the Society of Biological Inorganic Chemistry until recently and serves on the Editorial Advisory Boards of several journals. Since 2003, Kathy and her research group at Duke have used the principles of inorganic chemistry to develop new chemical tools and bioactive compounds to manipulate the location, speciation, and reactivity of metal ions in biological systems for potentially therapeutic benefit. Chairing the 2016 Metals in Medicine Gordon Conference with Nils Metzler-Nolte was another formative experience and led directly to this thematic issue. Nils Metzler-Nolte has been full professor of Inorganic Chemistry at Ruhr University Bochum since 2006. After his Ph.D. in Munich and a postdoc in Oxford, his first independent positions were in Muelheim / Germany and in Heidelberg as Professor for Pharmaceutical and Medicinal Inorganic Chemistry (2000−2006). He served as Dean of the University-wide graduate school from 2009 to 2012 and was Vice President for Early Career Researchers and International Affairs of his University between 2010 and 2012. Nils was Speaker of the DFGfunded Research Unit “Biological Function of Organometallic Compounds” and Council Member of the Society of Biological Inorganic Chemistry. His work was recognized by several fellowships and awards, the most recent being the Julius von Haast award of the Royal Society of New Zealand. Nils serves on the international advisory board of several journals and is an Associate Editor for Dalton Transactions. With research interests in medicinal organometallic chemistry and functional metal bioconjugates, the group is running a full program from inorganic synthesis to cell biology. Together with Kathy Franz he was Chair of the Metals in Medicine Gordon Conference in 2016, a formative experience which led directly to this Thematic Issue. 729
DOI: 10.1021/acs.chemrev.8b00685 Chem. Rev. 2019, 119, 727−729
