Editorial pubs.acs.org/IC
Editorial for the ACS Select Virtual Issue on Emerging Investigators in Bioinorganic Chemistry
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into cellular environments.7,8 Other NIR dyes such as the metalloporphyrinoids, as described here by Professor Jun-Long Zhang, are also tunable and of interest for bioimaging.9 Approximately half of all proteins are thought to contain metal ions that are critical to their function. The function of metalloproteins ranges from the storage and transport of metal ions, metabolites, and electrons to catalysis of chemical transformations. Many of the metal-ion cofactors for proteins are transition-metal ions that have spectroscopic properties that are useful for defining coordination sites as well as monitoring reactivity. Manganese-, iron-, and nickel-based proteins and zinc peptides are described here by three investigators (Professors Elizabeth Nolan, Hannah Shafaat, and Somdatta Dey), who expertly attack the research problem with an armada of spectroscopic techniques. The dominant theme in this research, other than understanding the metal-ion coordination environment, is the role of these metalloproteins and peptides in the etiology of disease, as well as its prevention. Finally, the synthesis of metal-ion complexes that model metalloenzyme reactivity is a time-honored tradition in bioinorganic chemistry, which is still producing fascinating results.10 These so-called biomimetic studies have contributed toward a better understanding of the chemistry of complicated active sites that are not easily studied in the enzyme itself. While spectroscopic mimics have long been useful, mimicking reactivity dominates in the studies described here. Topics include the study of cluster mimics of the oxygen-evolving system in photosystem II (PSII), iron clusters for modeling the mechanism of nitrogenase, and the role of hydrogen bonding in reactivity such as nitrite reduction or bond breaking. The publications by investigators in model chemistry contribute richly toward the development of both novel inorganic chemistry and enzymology. One group of investigators (Professors Valerie Pierre, Matthew Allen, Ankona Datta, and Goran Angelovski) published on lanthanide complexes and lanthanide(III)containing proteins. Ln ions have superb magnetic and spectroscopic properties that make them the premier choice as the metal ion for applications requiring luminescent probes or MRI contrast agents. Three of these emerging investigators (Professors Pierre, Allen, and Datta) report research on the development of new lanthanide-containing compounds for sensing metabolites. and a fourth by Professor Angelovski reports research on a responsive lanthanide MRI contrast agent. At the University of Minnesota, St. Paul, MN, Professor Valerie Pierre and her group explored a family of terbium(III) macrocyclic complexes as cellular probes.11 The macrocyclic complexes under study contain pendent groups that act as antennae for the sensitization of terbium(III) luminescence. An antenna based on 2-methylisophthalamide was the most promising choice because of its ease of synthesis and good
n this ACS Select Virtual Issue, we feature the research of 17 emerging investigators in the field of bioinorganic chemistry (who have received their Ph.D. since 2004) and have published their work in Inorganic Chemistry, Journal of the American Chemical Society, ACS Chemical Biology, or ACS Chemical Neuroscience, mostly in 2014 or 2015 (http://pubs.acs.org/ page/vi/bioinorganic-chemistry.html). The work of these investigators is representative of the truly broad nature of bioinorganic chemistry and is at the forefront of the development of new inorganic complexes for diagnostics and medicine and of tools for chemical biology and in the characterization of metalloproteins, enzymes, and their model complexes. Notably, their chemistry features both biologically essential elements (manganese, iron, copper, nickel, and zinc) and elements that are used for medicinal or diagnostic purposes (lanthanide, ruthenium, palladium, and platinum). Some of the featured areas of bioinorganic chemistry have a long history. The beginnings of inorganic medicinal chemistry can be traced back to Paul Erhlich’s work using arsenic-based compounds (arsphenamine)1 to treat syphilis more than 100 years ago. In more recent times, the development of metallodrugs has been advanced by the discovery of cisplatinum complexes for the treatment of many common types of cancer.2 Modern medicinal inorganic chemistry is quite diverse and includes antimicrobial and antiparasitic drugs that contain silver, or the main-group elements, antimony, arsenic, or bismuth as well as second- and third-row transition-metalion complexes.3 In this vein, photoactivated cytotoxic ruthenium(II) complexes and photoactivated iron(II) releasing complexes are described by Professors Edith Glazer and Gilles Gasser, respectively, as highlighted in this virtual issue. More recently, there has been an emphasis on metal ions that accumulate in the brain, especially ones that may be implicated in neurological diseases.4 The addition of chelates to remove them is described by two of the investigators featured here (Professors Mi Hee Lim and Kayla Green). The use of metal ions for diagnostics is a newer area of research. For in vivo MRI studies, which began in the late 1970s, metal-ion contrast agents such as gadolinium(III) complexes were developed along with this new field.5 Studies of gadolinium(III) contrast agents have contributed to the more general understanding of the aqueous solution and coordination chemistry of lanthanide(III) complexes. Luminescence studies appeared earlier than those of magnetic resonance imaging (MRI), with experiments dating from the 1930s, and have been of increasing interest over the years with the development of confocal microscopy for imaging subcellar compartments.6,7 Lanthanide luminescence is extremely useful for cellular imaging, especially for emission in the near-infrared (NIR). The long lifetimes (up to milliseconds) associated with emission from certain lanthanide(III) ions has been very useful for time-resolved studies. Modulation of lanthanide(III) luminescence upon metabolite binding, or upon reaction with reactive oxygen species (ROS), has led to interesting insights © 2015 American Chemical Society
Published: December 7, 2015 11039
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properties but markedly different trends as photodynamic therapy agents (PDTs) in cell culture.21 The anionic complex shows higher light-mediated toxicity and lowered toxicity in the dark in comparison to the cationic complex. The two complexes demonstrate altered cellular localization, and even the mechanism of cell death, suggesting a simple approach to modulating PDT agents by changing the overall charge of the complex. A second study from this group involves strained ruthenium(II) complexes that contain 2,2′-phenanthroline ligands with methyl substituents adjacent to the coordinating nitrogen atoms.22 These strained complexes eject a ligand upon irradiation with light and demonstrate 19-fold more potent cancer cell killing than cis-platin. This demonstrates a beautifully simple way to tune the reactivity by changing a single ligand substituent. Next, studies by Dr. Gilles Gasser and his collaborators at the University of Zurich, Zurich, Switzerland, showed that lightactivated aminoferrocene complexes are cytotoxic.24 These ferrocene derivatives contain a photolabile protecting group as well as a peptide with a mitochondria localization signal. Photoinduced release of the protecting groups leads to free iron ions, which preferentially kill cancer cells, possibly through interaction with ROS. This approach to produce labile iron(II) targets the increased ROS generation in cancer cells. A hot topic in bioinorganic chemistry is the role of metal ions in neurological disease. Of special interest is the role of copper, zinc, and iron in Alzheimer’s disease (AD). It has been postulated that these metal ions promote aggregation of amyloid-B (AB) peptide fragments. Such aggregation may be linked to brain plaque formation, which is a hallmark of the disease.4,20 Also of concern is the overproduction of ROS by these metal ions when bound to the aggregated peptides. In the first article summarized here, Professor Lim and her collaborators at Ulsan National Institute of Science and Technology, Ulsan, South Korea, synthesized a new derivative that targets both metal-free and -bound AB peptides to suppress aggregation.25 Interestingly, this compound, 4(dimethylamino)-2-[[[2-(hydroxymethyl)quinolin-8-yl]amino]methyl]phenol, was designed based on the structure of a known organic AB imaging agent, which was adapted to bind metal ions such as copper(II). The new compound binds copper(II) and inhibits ROS production, which may be important in alleviating the oxidative stress associated with AD. The initial data suggested that this compound crossed the blood brain barrier in mice, which is a promising result for further development of the compounds as therapeutic agents. The second featured author reporting on this topic, Professor Kayla Green, and her collaborators at Texas Christian University, Fort Worth, TX, and the University of North Texas Health Science Center, Denton, TX, showed that a macrocyclic ligand can be used to disrupt and prevent copper(II)-induced AB aggregation.26 Interestingly, the pyridine group in the macrocyclic ring confers an antioxidant capacity to the ligand, as shown in cell culture assays and developed further by changing substituents on the pyridine ring.27 The next set of investigators study metalloenzymes and chelating peptides. Professor Elizabeth Nolan at Massachusetts Institute of Technology, Cambridge, MA, and her collaborators study metalloenzymes that are involved as antimicrobials.23 In the first submission featured here, human calprotectin (CP) was examined as a rare example of a manganese(II)sequestering protein.28 Structural studies including X-ray
quantum yield but led to terbium(III) complexes that are not taken up by cells. Capitalizing on this result, Pierre and her coworkers suggest that complexes with 2-methylisophthalamide pendents are best used as probes for extracellular analytes. Modification of the carboxyamide pendents of the macrocyclic ligands with a series of hydrophilic and hydrophobic groups produces a family of terbium(III) complexes, most of which do not affect the cell viability. Another investigator in this area of research, Professor Ankona Datta at the Tata Institute of Fundamental Research, Mumbai, India, showed that lanthanide ions bound in place of calcium(II) to the peripheral membrane protein annexin V (Anx V) interact with phospholipids.12 Binding of the phospholipid to TbIII-Anx V produces luminescence changes that are specific over other types of simple phosphate derivatives. This result is a significant advance toward the creation of new luminescent sensors for phospholipids, which are important in biological signaling. Finally, Professor Matthew Allen and his group at Wayne State University, Detroit, MI, showed that europium(II) cryptate complexes produce strong luminescence even in water.13 Divalent europium(II) is not very stable in aerated aqueous solution, and complexes typically oxidize to the more common trivalent europium(III) species. Initial data suggest that the europium(II) complex has no bound water molecules but contains a bound chloride ion instead. Interestingly, these data may have ramifications for work on europium(II) MRI contrast agents under development in the Allen laboratory.14 Europium(II) is an unusual choice for an MRI contrast agent because of its instability in aqueous solution. The isoelectronic ion, gadolinium(III), is the more common choice for a T1 MRI contrast agent.5,15 Dr. Goran Angelovski and his group at the Max Planck Institute for Biological Cybernetics, Tübingen, Germany, explored gadolinium(III) complexes as calcium(II)responsive probes and for sensing neurotransmitters.16−18 While calcium(II)-responsive MRI probes themselves are not new, these studies focus on the calcium(II)-induced changes in T1 relaxivity in a 3D cell culture of primary glial cells as well as in vivo studies in rats. Metrics toward using these probes for brain imaging are given. Professor Jun-Long Zhang and his group at Peking University in Beijing, China, also work in the field of molecular engineering of new metal complexes for imaging applications, but they use noble metals.9 This group reported on the development of new phosphorescent metalloporphyrinoids for NIR bioimaging. Higher-stability luminophores are produced by varying the structure of these platinum(II)- or palladium(II)-coordinated porphodilactones. Tunable NIR luminescence and high up-conversion capacity for sensitizing triplet acceptors are also features of these porphyrinoids. Another set of investigators (Professors Edith Glazer, Gilles Gasser, Mi Hee Lim, and Kayla Green) focus on metallodrugs and on the design of compounds that might interact with metals in the body. The evolution of new types of metallodrugs is currently based on a better understanding of their mechanism of action. Two groups here reported on metallodrugs, one featuring ruthenium(II) or rhenium19 complexes and one using iron(II) complexes, which have widely different mechanisms of action. In a report on “old complexes, new tricks”, Professor Glazer and her group at the University of Kentucky, Lexington, KY, showed that two well-known ruthenium(II) polypyridyl complexes differing only by their ancillary functional groups (to give an overall 4− or 2+ charge) show similar photophysical 11040
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coordinated to the ligand, an interstitial μ4-oxide, and a fourth distinct iron accessible for binding substrates such as NO.33 Interestingly, the complex shows three distinct and reversible redox events that lead to changes in the oxidation state in the iron core. The authors show that the apical iron binds NO and that the activation of NO is dependent on the redox state of the cluster. In Professor Leslie Murray’s group at the University of Florida, Gainesville, FL, a cyclophane, which contains βdiketiminate donor groups, was shown to bind to three metal ions.34,35 This ligand was used to produce copper clusters that may have biomimetic values, including a structurally characterized trinuclear copper(I) cluster that contains a μ3-chloride bridge.34 Treatment of the cluster with elemental sulfur gives a bridging μ3-sulfide and a mixed-valence copper(I)/copper(II) cluster. These systems are of interest because the cyclophane ligand enforces a coordinatively unsaturated geometry on the copper centers, which may be of interest for further examination of the reactivity. In a second report, Murray et al. studied a trinuclear iron(II) cluster and its reactivity relevant to dinitrogen reduction in work inspired by research on nitrogenase.35 Azide reacts with the cluster and is incorporated as a bridging ligand. Heating of the azido cluster produces a new mononitride cluster. The mononitride cluster surprisingly does not demonstrate redox processes, suggesting that it is not likely to be an intermediate along a path toward the reduction of dinitrogen. Both Professors Fout and Harrop reported models for nitrite reduction on nonheme iron complexes. In Professor Fout’s laboratory at the University of Illinois at Urbana−Champaign, Champaign, IL, a tripodal ligand is used to form an iron(II) complex to address the mechanism of nitrite reduction.36 In particular, it is questioned whether a ligand that is capable of forming a hydrogen bond to bound substrates might facilitate the reduction of nitrite. The authors showed that an iron(II) complex reacts with nitrite to produce iron(III) oxo and NO gas, which suggests that protonation of a bound nitrite by a ligand amino group promotes reductive NO bond cleavage. The second investigator reporting on this topic is Professor Todd Harrop at the University of Georgia, Athens, GA. His group reported on a iron(II) complex of a neutral planar ligand with two imines and two imidazoles, leaving two axial sites for binding nitrite.37 The isolated dinitrite complex is reduced by chlorobenzenethiol to give an iron nitrosyl complex. Given that acid is required, proton-coupled redox is proposed. The iron(II) complex featured here demonstrates catalytic NO2− reduction to NO with demonstrated turnover properties. In a final example of the importance of hydrogen bonding in inorganic complexes that may have biomimetic value, Professor Nathaniel Szymczak and his group at the University of Michigan, Ann Arbor, MI, reported on a tripodal ligand based on hydroxypyridine that shows intermolecular hydrogenbonding interactions with bound chloride in both copper(I) and copper(II) complexes.38 Stronger hydrogen-bonding interactions in the copper(I) complex compared to the copper(II) complex were inferred from both the structural data and a comparison to ligands lacking hydrogen-bonding capability. These studies support modulation of the Cu−Cl bond stability through hydrogen-bonding interactions. Please join me in celebrating the accomplishments of these emerging investigators! Their stimulating work is driving the field of bioinorganic chemistry forward in new and exciting directions.
crystallography and electron paramagnetic resonance (EPR) spectroscopy are presented in this publication, which is coauthored with Professors Catherine Drennan and David Britt. One manganese(II), two calcium(II), and two sodium(I) ions are found per CP dimer, and, interestingly, the manganese(II) affinity of the protein depends on calcium(II). Essentially, calcium(II) promotes the formation of a highaffinity manganese(II) site, which has six histidine ligands, all of which are spectroscopically equivalent, as shown by EPR and ENDOR spectroscopy. In a second publication, Nolan and her group studied a host defense peptide, human defensin 5 (HD5), from small intestinal Paneth cells and show that HD5 binds zinc(II) ions with dissociation constants in the picomolar range.29 Given that it is the reduced form of this cysteine-rich peptide that binds metal ions, there is a link between the cellular redox state and metal-ion binding. Interestingly, the zinc(II)-bound form is resistant to proteolysis, suggesting that zinc(II) enables these peptides to survive in vivo. Professor Hannah Shafaat’s group at The Ohio State University, Columbus, OH, reported on characterization of the electron-transfer protein Azurin.30 In this study, the native copper ion has been substituted by nickel. An overall goal is to study the electron-rich nickel(I) oxidation state in a versatile protein platform for the development of structural and functional models of nickel metalloenzymes. The electrontransfer rates are high, especially considering the expected large geometric rearrangement to give the reduced species. Density functional theory calculations are in good agreement with EPR and UV−vis characterization of the nickel(I) center. Finally, Professor Somdatta Ghosh Dey and her group at the Indian Association for the Cultivation of Science, Kolkata, India, showed that iron(II) heme binds to human islet amyloid polypeptide (hIAPP).31 hIAPP may be linked to type 2 diabetes mellitus (T2Dm) because it deposits within the B cells of pancreatic islets of Langerhans. The spectroscopic data are consistent with histidine 18 ligating to the heme to give a highspin iron(II) complex, with the trans-axial site occupied by a water ligand. These heme-bound peptides produce reduced oxygen species, which may possibly play a role in creating B-cell dysfunction in T2Dm. Efforts to synthesize metal complexes as models of metalloenzymes are proceeding at a rapid pace, and research is moving toward more and more complicated metal-ion complexes, such as multinuclear clusters. In this vein, Professor Theodore Agapie and his group at California Institute of Technology, Pasadena, CA, published a report detailing the synthesis and characterization of nine new clusters, each of which contains three manganese(IV) and a single lanthanide(III) ion, as models of the oxygen-evolving complex of PSII.32 The clusters have the formula [(LLnIIIMnIV3O4(OAc)3(DMF)n]+, where n = 2 and 3 and L is a trianionic ligand that binds in a tridentate fashion to all three of the manganese(IV) ions in the cubane. An attraction of inserting lanthanide(III) ions into the cluster is the opportunity to use the monotonic change in the Lewis acidity across the series to study the effect on the reduction potential of the cluster. In fact, the reduction potential correlates to the pKa of the metal aquo ligand for lanthanide(III) as well as for alkaline-earth elements calcium(II) and strontium(II). This result may contribute to understanding the redox properties of the cluster, which are important in the biological water oxidation reaction catalyzed by PSII. In a further study utilizing the same ligand, the Agapie group prepared tetranuclear iron clusters with three iron ions 11041
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(32) Lin, P. H.; Takase, M. K.; Agapie, T. Inorg. Chem. 2015, 54, 59− 64. (33) de Ruiter, G.; Thompson, N. B.; Lionetti, D.; Agapie, T. J. Am. Chem. Soc. 2015, 137, 14094−14106, DOI: 10.1021/jacs.5b07397. (34) Di Francesco, G. N.; Gaillard, A.; Ghiviriga, I.; Abboud, K. A.; Murray, L. J. Inorg. Chem. 2014, 53, 4647−4654. (35) Ermert, D. M.; Gordon, J. B.; Abboud, K. A.; Murray, L. J. Inorg. Chem. 2015, 54, 9282−9289. (36) Matson, E. M.; Park, Y. J.; Fout, A. R. J. Am. Chem. Soc. 2014, 136, 17398−17401. (37) Sanders, B. C.; Hassan, S. M.; Harrop, T. C. J. Am. Chem. Soc. 2014, 136, 10230−10233. (38) Moore, C. M.; Quist, D. A.; Kampf, J. W.; Szymczak, N. K. Inorg. Chem. 2014, 53, 3278−3280.
Janet R. Morrow, Associate Editor AUTHOR INFORMATION
Notes
Views expressed in this editorial are those of the author and not necessarily the views of the ACS.
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REFERENCES
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