Editorial: Translating Bioinorganic Chemistry (2014)

The subdiscipline of bioinorganic chemistry known as ‘metals in medicine’ or ‘medicinal inorganic chemistry’ has matured into a rich and diverse area of research. The modern era of medicinal inorganic chemistry started as a relatively boutique community investigating a handful of subjects, largely focused on the use of metal ion complexes as therapeutics (‘metallopharmaceuticals’) or diagnostics (‘metallodiagnostics’). The compound cisplatin (cis-diaaminedichloroplatinum(II), Platinol®), a simple inorganic coordination compound containing no carbon atoms, is one of the world’s most widely prescribed anticancer agents and has long been touted as a great triumph of medicinal inorganic chemistry. Similarly, the widespread use of imaging agents based on gadolinium(III) for magnetic resonance imaging (MRI) and technetium-99m for nuclear medicine imaging are considered some of the more visible successes of ‘metals in medicine’. Today, medicinal inorganic chemistry is a much broader discipline that still includes the traditional topics of metallopharmaceuticals and metallodiagnostics, but also encompasses subjects such as understanding metal ion metabolism and trafficking in living systems, elucidating the role of metal ions in neurodegenerative disease, investigating metal-dependent proteins as therapeutic targets, and using metal-based molecular probes for studying biological systems. In addition, ongoing efforts to develop ever more creative and clever metal-derived compounds as therapeutic or diagnostic agents continue to thrive. In this Special Issue of ChemMedChem dedicated to medicinal inorganic chemistry, 28 articles are compiled that nicely illustrate both the diversity and state-of-the-science. Many of these articles cover the breadth of this rapidly growing discipline, including some of the more traditional areas such as platinum anticancer agents (e.g., contributions from Hey-Hawkins (DOI: 10.1002/cmdc.201402074), Margiotta (DOI: 10.1002/cmdc.201402028), Osella (DOI: 10.1002/cmdc.201400061), Rezaee (DOI: 10.1002/cmdc.201300462), and Sadler (DOI: 10.1002/cmdc.201402066)), identification of other metal-based therapeutics (e.g., articles from McGowan (DOI: 10.1002/cmdc.201402019), Metzler-Nolte (DOI: 10.1002/cmdc.201402001), Ott (DOI: 10.1002/cmdc.201400056), Schobert (DOI: 10.1002/cmdc.201400049), and Tshuva (DOI: 10.1002/cmdc.201400038)), and ‘smart’ MRI imaging agents driven by hypoxia (see the Minireview from Sherry et al.). Other studies in this themed issue explore more contemporary avenues of investigation, such as molecular sensors for metal trafficking, bioinorganic carriers of imaging agents, and combined ‘theranostic’ agents utilizing metal complexes (see Full Papers from Lippard (DOI: 10.1002/cmdc.201400014), Lapi (DOI: 10.1002/cmdc.201400048), and Alessio (DOI: 10.1002/cmdc.201300501), respectively). Even beyond these topics, many new frontiers and challenges remain. Some of the contributions to this themed issue give exciting perspectives on the future of metals in medicine. These include photoactive compounds that inactivate enzymes (i.e., contribution from Kodanko and co-workers; 10.1002/cmdc.201400081) or that release therapeutic small molecules such as carbon monoxide (i.e., Full Paper from Mascharak et al.; DOI: 10.1002/cmdc.201402007). Perhaps an even more bold statement on the future is the idea of catalytic drugs (Full Paper from Cowan et al.; 10.1002/cmdc.201400070). Can we rationally design metal complexes that catalytically inactivate a target in the complex biological milieu? Presumably, such compounds would break the paradigm that a drug be used in a ‘stoichiometric’ fashion, allowing for extremely low dosing requirements thereby providing both economic benefits as well as mitigating side effects. Historically there has been a divide between inorganic and medicinal chemistry that has often stymied attempts to move ideas in bioinorganic chemistry to technologies that could have a positive outcome on human health. However, more recently, this divide is being bridged thanks to government support (e.g., the Metals in Medicine funding opportunity from the US National Institutes of Health) and burgeoning entrepreneurism. Among the ranks of biotech startups, more companies are appearing that have a foundation (or partial foundation) in the discoveries from medicinal inorganic chemistry. Among the earlier biotech startups in this space was Prana (www.pranabio.com), which is focused on addressing neurodegerative diseases by using ‘metal protein attenuating compounds (MPACs). A more recent addition to this group is Viamet Pharmaceuticals (www.viamet.com). Primarily focused on metalloprotein inhibitors for fungal infections, Viamet has at least one compound in clinical trials. Another biotech startup with bioinorganic roots is Blend Therapeutics (www.blendtx.com; contributing author Stephen J. Lippard is a co-founder), which seeks to develop new platinum therapeutics, including combining platinum compounds with nanoparticle carriers for improved efficacy. Galera Therapeutics (www.galeratx.com) is focused on the development of superoxide dismutase (SOD) mimetics, an area long studied by the bioinorganic community, for a variety of disease indications. Another example is the oncology biotech startup Cleave Biosciences (www.cleavebio.com) that is focused on novel inhibitors of protein homeostasis pathways, some of which target metalloproteins (Guest Editor Seth Cohen is a co-founder). Collectively, these startups represent more than $ 100M in venture and pharmaceutical industry investment, a good sign of the increasingly translational nature of medicinal inorganic chemistry. Advances in bioinorganic chemistry have attracted sufficient attention from biotech-minded investors to begin modest, but real investment in medicinal inorganic chemistry. These investments will put the findings of this community to the test, perform important optimization and translational studies, and determine whether our faith in the d- and f-block of the Periodic Table to help solve important medical problems is justified. Solidifying the pipeline between inorganic chemistry and the clinic will not be an easy process. Although the field continues to push new scientific boundaries and is now attracting investor attention, the community will still need to undo conventional wisdom (e.g., demonstrate that not all ‘heavy metal complexes’ are toxic), combat stigmas (e.g., show that inorganic compounds are amenable to rational structure–activity relationship (SAR) optimization), and communicate even more effectively with those in other scientific disciplines (e.g., present our findings at medicinal chemistry symposia and conferences) to convince and ultimately prove that medicinal inorganic chemistry has the capacity to find innovative solutions to problems in human health. I for one am optimistic. The quality of new discoveries, the introduction of new technologies and tools to answer challenging biochemical questions, and the increasing cohesion and tenacity of the ‘metals in medicine’ community are all positive signs. Indeed, this summer, the community will gather for the 7th semi-annual Gordon Research Conference (GRC) on Metals in Medicine. Started in 2002, this GRC has helped to bring together the community in order to advance the latest ideas and promote the field. The continued growth and vibrancy of this conference since its inception is a further indication of the increasing impact of medicinal inorganic chemistry. The origin of metals in medicine has a deep and rich history that is rooted in the heart of medicinal chemistry. The concepts of selective chemotherapy and SAR elucidation date back to studies by Paul Ehrlich (1908 Nobel Prize in Medicine) that led to the development of the first drug effective against syphilis, an arsenic-containing compound called arsphenamine (salvarsan). It is again time for the inorganic and medicinal chemists to ally themselves in order to foster new discoveries in medicine. In the title of this Editorial, ‘Translating Bioinorganic Chemistry’, the word translating takes on a double-meaning: both translating research findings and discoveries in inorganic chemistry for use in the clinic and also, in a more rudimentary sense, simply translating the languages of inorganic and medicinal chemistry to their respective audiences, so that each group of scientists has a better understanding and appreciation for the work going on in each field. I hope this themed issue of ChemMedChem facilitates this process. In this regard, although dedicated issues on medical inorganic chemistry have appeared in inorganic journals or general topic journals, to the best of our knowledge, this is the first medicinal chemistry journal to dedicate an issue to the role of inorganic chemistry in human health. For this, I thank ChemMedChem and the publishing team at Wiley-VCH for their foresight and interest in this important topic, and for acting as translators between the medicinal and inorganic chemistry research communities. 1 1 Seth M. Cohen, Ph.D. Special Issue Guest Editor International Advisory Board Member ChemMedChem