Elisa Tomat

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• Curtis, C. J., Astashkin, A. V., Conradie, J., Ghosh, A., & Tomat, E. (2021). Ligand-Centered Triplet Diradical Supported by a Binuclear Palladium(II) Dipyrrindione. Inorganic chemistry, 60(16), 12457-12466.
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  Oligopyrroles form a versatile class of redox-active ligands and electron reservoirs. Although the stabilization of radicals within oligopyrrolic π systems is more common for macrocyclic ligands, bidentate dipyrrindiones are emerging as compact platforms for one-electron redox chemistry in transition-metal complexes. We report the synthesis of a bis(aqua) palladium(II) dipyrrindione complex and its deprotonation-driven dimerization to form a hydroxo-bridged binuclear complex in the presence of water or triethylamine. Electrochemical, spectroelectrochemical, and computational analyses of the binuclear complex indicate the accessibility of two quasi-reversible ligand-centered reduction processes. The product of a two-electron chemical reduction by cobaltocene was isolated and characterized. In the solid state, this cobaltocenium salt features a folded dianionic complex that maintains the hydroxo bridges between the divalent palladium centers. X-band and Q-band EPR spectroscopic experiments and DFT computational analysis allow assignment of the dianionic species as a diradical with spin density almost entirely located on the two dipyrrindione ligands. As established from the EPR temperature dependence, the associated exchange coupling is weak and antiferromagnetic ( ≈ -2.5 K), which results in a predominantly triplet state at the temperatures at which the measurements have been performed.
• Gaur, K., Pérez Otero, S. C., Benjamín-Rivera, J. A., Rodríguez, I., Loza-Rosas, S. A., Vázquez Salgado, A. M., Akam, E. A., Hernández-Matias, L., Sharma, R. K., Alicea, N., Kowaleff, M., Washington, A. V., Astashkin, A. V., Tomat, E., & Tinoco, A. D. (2021). Iron Chelator Transmetalative Approach to Inhibit Human Ribonucleotide Reductase. JACS Au, 1(6), 865-878.
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  Efforts directed at curtailing the bioavailability of intracellular iron could lead to the development of broad-spectrum anticancer drugs given the metal's role in cancer proliferation and metastasis. Human ribonucleotide reductase (RNR), the key enzyme responsible for synthesizing the building blocks of DNA replication and repair, depends on Fe binding at its R2 subunit to activate the catalytic R1 subunit. This work explores an intracellular iron chelator transmetalative approach to inhibit RNR using the titanium(IV) chemical transferrin mimetic (cTfm) compounds Ti(HBED) and Ti(Deferasirox). Whole-cell EPR studies reveal that the compounds can effectively attenuate RNR activity though seemingly causing different changes to the labile iron pool that may account for differences in their potency against cells. Studies of Ti(IV) interactions with the adenosine nucleotide family at pH 7.4 reveal strong metal binding and extensive phosphate hydrolysis, which suggest the capacity of the metal to disturb the nucleotide substrate pool of the RNR enzyme. By decreasing intracellular Fe bioavailability and altering the nucleotide substrate pool, the Ti cTfm compounds could inhibit the activity of the R1 and R2 subunits of RNR. The compounds arrest the cell cycle in the S phase, indicating suppressed DNA replication, and induce apoptotic cell death. Cotreatment cell viability studies with cisplatin and Ti(Deferasirox) reveal a promising synergism between the compounds that is likely owed to their distinct but complementary effect on DNA replication.
• Sung, Y. S., Wu, W., Ewbank, M. A., Utterback, R. D., Marty, M. T., & Tomat, E. (2021). Albumin Conjugates of Thiosemicarbazone and Imidazole-2-thione Prochelators: Iron Coordination and Antiproliferative Activity. ChemMedChem, 16(18), 2764-2768.
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  The central role of iron in tumor progression and metastasis motivates the development of iron-binding approaches in cancer chemotherapy. Disulfide-based prochelators are reductively activated upon cellular uptake to liberate thiol chelators responsible for iron sequestration. Herein, a trimethyl thiosemicarbazone moiety and the imidazole-2-thione heterocycle are incorporated in this prochelator design. Iron binding of the corresponding tridentate chelators leads to the stabilization of a low-spin ferric center in 2 : 1 ligand-to-metal complexes. Native mass spectrometry experiments show that the prochelators form stable disulfide conjugates with bovine serum albumin, thus affording novel bioconjugate prochelator systems. Antiproliferative activities at sub-micromolar levels are recorded in a panel of breast, ovarian and colorectal cancer cells, along with significantly lower activity in normal fibroblasts.
• Tomat, E., & Curtis, C. J. (2021). Biopyrrin Pigments: From Heme Metabolites to Redox-Active Ligands and Luminescent Radicals. Accounts of chemical research, 54(24), 4584-4594.
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  Redox-active ligands in coordination chemistry not only modulate the reactivity of the bound metal center but also serve as electron reservoirs to store redox equivalents. Among many applications in contemporary chemistry, the scope of redox-active ligands in biology is exemplified by the porphyrin radicals in the catalytic cycles of multiple heme enzymes (e.g., cytochrome P450, catalase) and the chlorophyll radicals in photosynthetic systems. This Account reviews the discovery of two redox-active ligands inspired by oligopyrrolic fragments found in biological settings as products of heme metabolism.Linear oligopyrroles, in which pyrrole heterocycles are linked by methylene or methine bridges, are ubiquitous in nature as part of the complex, multistep biosynthesis and degradation of hemes and chlorophylls. Bile pigments, such as biliverdin and bilirubin, are common and well-studied tetrapyrroles with characteristic pyrrolin-2-one rings at both terminal positions. The coordination chemistry of these open-chain pigments is less developed than that of porphyrins and other macrocyclic oligopyrroles; nevertheless, complexes of biliverdin and its synthetic analogs have been reported, along with fluorescent zinc complexes of phytobilins employed as bioanalytical tools. Notably, linear conjugated tetrapyrroles inherit from porphyrins the ability to stabilize unpaired electrons within their π system. The isolated complexes, however, present helical structures and generally limited stability.Smaller , which feature three or two pyrrole rings and the characteristic oxidized termini, have been known for several decades following their initial isolation as urinary pigments and heme metabolites. Although their coordination chemistry has remained largely unexplored, these compounds are structurally similar to the well-established tripyrrin and dipyrrin ligands employed in a broad variety of metal complexes. In this context, our study of the coordination chemistry of and was motivated by the potential to retain on these compact, versatile platforms the reversible ligand-based redox chemistry of larger tetrapyrrolic systems.The tripyrrindione ligand coordinates several divalent transition metals (i.e., Pd(II), Ni(II) Cu(II), Zn(II)) to form neutral complexes in which an unpaired electron is delocalized over the conjugated π system. These compounds, which are stable at room temperature and exposed to air, undergo reversible one-electron processes to access different redox states of the ligand system without affecting the oxidation state and coordination geometry of the metal center. We also characterized ligand-based radicals on the dipyrrindione platform in both homoleptic and heteroleptic complexes. In addition, this study documented noncovalent interactions (e.g., interligand hydrogen bonds with the pyrrolinone carbonyls, π-stacking of ligand-centered radicals) as important aspects of this coordination chemistry. Furthermore, the fluorescence of the zinc-bound tripyrrindione radical and the redox-switchable emission of a dipyrrindione BODIPY-type fluorophore showcased the potential interplay of redox chemistry and luminescence in these compounds. Supported by computational analyses, the portfolio of properties revealed by this investigation takes the tripyrrindione and dipyrrindione motifs of heme metabolites to the field of redox-active ligands, where they are positioned to offer new opportunities for catalysis, sensing, supramolecular systems, and functional materials.
• Astashkin, A. V., Utterback, R. D., Sung, Y. S., & Tomat, E. (2020). Iron Complexes of an Antiproliferative Aroyl Hydrazone: Characterization of Three Protonation States by Electron Paramagnetic Resonance Methods. Inorganic chemistry, 59(16), 11377-11384.
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  Tridentate aroyl hydrazones are effective metal chelators in biological settings, and their activity has been investigated extensively for medicinal applications in metal overload, cancer, and neurodegenerative diseases. The aroyl hydrazone motif is found in the recently reported prochelator (AH1-S), which has shown antiproliferative proapoptotic activity in mammalian cancer cell lines. Intracellular reduction of this disulfide prochelator leads to the formation of mercaptobenzaldehyde benzoylhydrazone chelator AH1 and to iron sequestration, which in turn impacts cell growth. Herein, we investigate the iron coordination chemistry of AH1 to determine the structural and spectroscopic properties of the iron complexes in the solid state and in solution. A neutral iron(III) complex of 2:1 ligand-to-metal stoichiometry was isolated and characterized fully to reveal two different binding modes for the tridentate AH1 ligand. Specifically, one ligand binds in the monoanionic keto form, whereas the other ligand coordinates as a dianionic enolate. Continuous-wave electron paramagnetic resonance experiments in frozen solutions indicated that this neutral complex is one of three low-spin iron(III) complexes observed depending on the pH of the solution. Electron spin echo envelope modulation (ESEEM) experiments allowed assignment of the three species to different protonation states of the coordinated ligands. Our ESEEM analysis provides a method to distinguish the coordination of aroyl hydrazones in the keto and enolate forms, which influences both the ligand field and overall charge of the complex. As such, this type of analysis could provide valuable information in a variety of studies of iron complexes of aroyl hydrazones, ranging from the investigation of spin-crossover behavior to tracking of their distribution in biological samples.
• Schnetz, M., Meier, J. K., Rehwald, C., Mertens, C., Urbschat, A., Tomat, E., Akam, E. A., Baer, P., Roos, F. C., Brüne, B., & Jung, M. (2020). The Disturbed Iron Phenotype of Tumor Cells and Macrophages in Renal Cell Carcinoma Influences Tumor Growth. Cancers, 12(3).
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  Accumulating evidence suggests that iron homeostasis is disturbed in tumors. We aimed at clarifying the distribution of iron in renal cell carcinoma (RCC). Considering the pivotal role of macrophages for iron homeostasis and their association with poor clinical outcome, we investigated the role of macrophage-secreted iron for tumor progression by applying a novel chelation approach. We applied flow cytometry and multiplex-immunohistochemistry to detect iron-dependent markers and analyzed iron distribution with atomic absorption spectrometry in patients diagnosed with RCC. We further analyzed the functional significance of iron by applying a novel extracellular chelator using RCC cell lines as well as patient-derived primary cells. The expression of iron-regulated genes was significantly elevated in tumors compared to adjacent healthy tissue. Iron retention was detected in tumor cells, whereas tumor-associated macrophages showed an iron-release phenotype accompanied by enhanced expression of ferroportin. We found increased iron amounts in extracellular fluids, which in turn stimulated tumor cell proliferation and migration. In vitro, macrophage-derived iron showed pro-tumor functions, whereas application of an extracellular chelator blocked these effects. Our study provides new insights in iron distribution and iron-handling in RCC. Chelators that specifically scavenge iron in the extracellular space confirmed the importance of macrophage-secreted iron in promoting tumor growth.
• Gautam, R., Petritis, S. J., & Tomat, E. (2019). Redox-Switchable Cyan Fluorescence of a BODIPY Analog Inspired by Propentdyopent Pigments. EUROPEAN JOURNAL OF INORGANIC CHEMISTRY, 68-72.
• Jung, M., Mertens, C., Tomat, E., & Brüne, B. (2019). Iron as a Central Player and Promising Target in Cancer Progression. International journal of molecular sciences, 20(2).
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  Iron is an essential element for virtually all organisms. On the one hand, it facilitates cell proliferation and growth. On the other hand, iron may be detrimental due to its redox abilities, thereby contributing to free radical formation, which in turn may provoke oxidative stress and DNA damage. Iron also plays a crucial role in tumor progression and metastasis due to its major function in tumor cell survival and reprogramming of the tumor microenvironment. Therefore, pathways of iron acquisition, export, and storage are often perturbed in cancers, suggesting that targeting iron metabolic pathways might represent opportunities towards innovative approaches in cancer treatment. Recent evidence points to a crucial role of tumor-associated macrophages (TAMs) as a source of iron within the tumor microenvironment, implying that specifically targeting the TAM iron pool might add to the efficacy of tumor therapy. Here, we provide a brief summary of tumor cell iron metabolism and updated molecular mechanisms that regulate cellular and systemic iron homeostasis with regard to the development of cancer. Since iron adds to shaping major hallmarks of cancer, we emphasize innovative therapeutic strategies to address the iron pool of tumor cells or cells of the tumor microenvironment for the treatment of cancer.
• Swain, A., Cho, B., Gautam, R., Curtis, C. J., Tomat, E., & Huxter, V. (2019). Ultrafast Dynamics of Tripyrrindiones in Solution Mediated by Hydrogen-Bonding Interactions. The journal of physical chemistry. B, 123(26), 5524-5535.
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  The optical properties and ultrafast dynamics of hexaethyl tripyrrin-1,14-dione (HTD1) are tuned by hydrogen-bonding interactions between the solute and the solvent. In solvents with low hydrogen-bonding affinity, HTD1 preferentially forms hydrogen-bonded dimers, whereas in solvents that can either donate or accept hydrogen bonds HTD1 is present as a monomer. The distinction between dimer and monomer determines the dynamics of the system, with faster internal conversion observed in the dimer form. The ultrafast dynamics were characterized using time-correlated single photon counting, fluorescence upconversion, and transient absorption measurements. The time-resolved dynamics of both the monomer and dimer in solution were modeled using a Pauli master equation treatment for a three level system. The solvent-dependent optical properties were measured using steady-state absorption and fluorescence. This data was then used to calculate the quantum yield and extinction coefficients.
• Gautam, R., Petritis, S. J., Astashkin, A. V., & Tomat, E. (2018). Paramagnetism and Fluorescence of Zinc(II) Tripyrrindione: A Luminescent Radical Based on a Redox-Active Biopyrrin. Inorganic chemistry, 57(24), 15240-15246.
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  The ability of bilins and other biopyrrins to form fluorescent zinc complexes has been known for more than a century; however, the exact identity of the emissive species remains uncertain in many cases. Herein, we characterize the hitherto elusive zinc complex of tripyrrin-1,14-dione, an analogue of several orange urinary pigments. As previously observed for its Pd(II), Cu(II), and Ni(II) complexes, tripyrrindione binds Zn(II) as a dianionic radical and forms a paramagnetic complex carrying an unpaired electron on the ligand π-system. This species is stable at room temperature and undergoes quasi-reversible ligand-based redox chemistry. Although the complex is isolated as a coordination dimer in the solid state, optical absorption and electron paramagnetic resonance spectroscopic studies indicate that the monomer is prevalent in a tetrahydrofuran solution. The paramagnetic Zn(II) tripyrrindione complex is brightly fluorescent (λ = 599 nm, λ = 644 nm, Φ = 0.23 in THF), and its study provides a molecular basis for the observation, made over several decades since the 1930s, of fluorescent behavior of tripyrrindione pigments in the presence of zinc salts. The zinc-bound tripyrrindione radical is thus a new addition to the limited number of stable radicals that are fluorescent at room temperature.
• Tomat, E., Akam, E. A., Utterback, R. D., Marcero, J. R., & Dailey, H. R. (2018). Disulfide-masked iron prochelators: Effects on cell death, proliferation, and hemoglobin production. Journal of Biological Inorganic Chemistry.
• Gautam, R., Astashkin, A. V., Chang, T. M., Shearer, J., & Tomat, E. (2017). Interactions of Metal-Based and Ligand-Based Electronic Spins in Neutral Tripyrrindione π Dimers. Inorganic chemistry, 56(11), 6755-6762.
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  The ability of tetrapyrrolic macrocycles to stabilize unpaired electrons and engage in π-π interactions is essential for many electron-transfer processes in biology and materials engineering. Herein, we demonstrate that the formation of π dimers is recapitulated in complexes of a linear tripyrrolic analogue of naturally occurring pigments derived from heme decomposition. Hexaethyltripyrrindione (HTD1) coordinates divalent transition metals (i.e., Pd, Cu, Ni) as a stable dianionic radical and was recently described as a robust redox-active ligand. The resulting planar complexes, which feature a delocalized ligand-based electronic spin, are stable at room temperature in air and support ligand-based one-electron processes. We detail the dimerization of neutral tripyrrindione complexes in solution through electron paramagnetic resonance (EPR) and visible absorption spectroscopic methods. Variable-temperature measurements using both EPR and absorption techniques allowed determination of the thermodynamic parameters of π dimerization, which resemble those previously reported for porphyrin radical cations. The inferred electronic structure, featuring coupling of ligand-based electronic spins in the π dimers, is supported by density functional theory (DFT) calculations.
• Rooker, D. R., Klyubka, Y., Gautam, R., Tomat, E., & Buccella, D. (2017). Peptide-Based Fluorescent Probes for Deacetylase and Decrotonylase Activity: Toward a General Platform for Real-Time Detection of Lysine Deacylation. ChemBioChem.
• Akam, E. A., & Tomat, E. (2016). Targeting Iron in Colon Cancer via Glycoconjugation of Thiosemicarbazone Prochelators. BIOCONJUGATE CHEMISTRY, 27(8), 1807-1812.
• Gautam, R., Chang, T. M., Astashkin, A. V., Lincoln, K. M., & Tomat, E. (2016). Propentdyopent: The scaffold of a heme metabolite as an electron reservoir in transition metal complexes. CHEMICAL COMMUNICATIONS.
• Mertens, C., Akam, E. A., Rehwald, C., Bruene, B., Tomat, E., & Jung, M. (2016). Intracellular Iron Chelation Modulates the Macrophage Iron Phenotype with Consequences on Tumor Progression. PLOS ONE, 11(11).
• Mertens, C., Akam, E. A., Rehwald, C., Brüne, B., Tomat, E., & Jung, M. (2016). Intracellular Iron Chelation Modulates the Macrophage Iron Phenotype with Consequences on Tumor Progression. PloS one, 11(11), e0166164.
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  A growing body of evidence suggests that macrophage polarization dictates the expression of iron-regulated genes. Polarization towards iron sequestration depletes the microenvironment, whereby extracellular pathogen growth is limited and inflammation is fostered. In contrast, iron release contributes to cell proliferation, which is important for tissue regeneration. Moreover, macrophages constitute a major component of the infiltrates in most solid tumors. Considering the pivotal role of macrophages for iron homeostasis and their presence in association with poor clinical prognosis in tumors, we approached the possibility to target macrophages with intracellular iron chelators. Analyzing the expression of iron-regulated genes at mRNA and protein level in primary human macrophages, we found that the iron-release phenotype is a characteristic of polarized macrophages that, in turn, stimulate tumor cell growth and progression. The application of the intracellular iron chelator (TC3-S)2 shifted the macrophage phenotype from iron release towards sequestration, as determined by the iron-gene profile and atomic absorption spectroscopy (AAS). Moreover, whereas the addition of macrophage supernatants to tumor cells induced tumor growth and metastatic behavior, the supernatant of chelator-treated macrophages reversed this effect. Iron chelators demonstrated potent anti-neoplastic properties in a number of cancers, both in cell culture and in clinical trials. Our results suggest that iron chelation could affect not only cancer cells but also the tumor microenvironment by altering the iron-release phenotype of tumor-associated macrophages (TAMs). The study of iron chelators in conjunction with the effect of TAMs on tumor growth could lead to an improved understanding of the role of iron in cancer biology and to novel therapeutic avenues for iron chelation approaches.
• Tomat, E. (2016). Coordination Chemistry of Linear Tripyrroles: Promises and Perils. COMMENTS ON INORGANIC CHEMISTRY, 36(6), 327-342.
• Akam, E. A., Gautam, R., & Tomat, E. (2015). Metal binding effects of sirtuin inhibitor sirtinol. Supramolecular Chemistry, 28(1-2), 108-116.
• Gautam, R., Loughrey, J. J., Astashkin, A. V., Shearer, J., & Tomat, E. (2015). Tripyrrindione as a Redox-Active Ligand: Palladium(II) Coordination in Three Redox States. Angewandte Chemie - International Edition, 54(49), 14894-14897.
• Tomat, E., Gautam, R., Akam, E. A., Astashkin, A. V., & Loughrey, J. J. (2015). Sirtuin inhibitor sirtinol is an intracellular iron chelator. Chemical Communications, 51, 5104–5107.
• Akam, E. A., Chang, T. M., Astashkin, A. V., & Tomat, E. (2014). Intracellular reduction/activation of a disulfide switch in thiosemicarbazone iron chelators. Metallomics, 6(10), 1905-1912.
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  Iron scavengers (chelators) offer therapeutic opportunities in anticancer drug design by targeting the increased demand for iron in cancer cells as compared to normal cells. Prochelation approaches are expected to avoid systemic iron depletion as chelators are liberated under specific intracellular conditions. In the strategy described herein, a disulfide linkage is employed as a redox-directed switch within the binding unit of an antiproliferative thiosemicarbazone prochelator, which is activated for iron coordination following reduction to the thiolate chelator. In glutathione redox buffer, this reduction event occurs at physiological concentrations and half-cell potentials. Consistent with concurrent reduction and activation, higher intracellular thiol concentrations increase cell susceptibility to prochelator toxicity in cultured cancer cells. The reduction of the disulfide switch and intracellular iron chelation are confirmed in cell-based assays using calcein as a fluorescent probe for paramagnetic ions. The resulting low-spin Fe(iii) complex is identified in intact Jurkat cells by EPR spectroscopy measurements, which also document a decreased concentration of active ribonucleotide reductase following exposure to the prochelator. Cell viability and fluorescence-based assays show that the iron complex presents low cytotoxicity and does not participate in intracellular redox chemistry, indicating that this antiproliferative chelation strategy does not rely on the generation of reactive oxygen species.
• Chang, T. M., Sinharay, S., Astashkin, A. V., & Tomat, E. (2014). Prodigiosin Analogue Designed for Metal Coordination: Stable Zinc and Copper Pyrrolyldipyrrins. Inorganic Chemistry, 53(14), 7518-7526.
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  The pyrrolyldipyrrin motif is found in several naturally occurring prodigiosin pigments. The potential roles of the interactions of prodigiosins with transition metals and the properties of metal-bound pyrrolyldipyrrins, however, have been difficult to assess because of the very limited number of well-characterized stable complexes. Here, we show that the introduction of a meso-aryl substituent and an ethyl ester group during the sequential assembly of the three heterocycles affords a pyrrolyldipyrrin of enhanced coordinating abilities when compared to that of natural prodigiosins. UV-visible absorption studies indicate that this ligand promptly binds Zn(II) ions with 2:1 ligand-to-metal stoichiometry and Cu(II) ions with 1:1 stoichiometry. Notably, no addition of base is required for the formation of the resulting stable complexes. The crystal structures reveal that whereas the tetrahedral zinc center engages two nitrogen donors on each ligand, the pseudosquare planar copper complex features coordination of all three pyrrolic nitrogen atoms and employs the ester group as a neutral ligand. This first example of coordination of a redox-active transition metal within a fully conjugated pyrrolyldipyrrin framework was investigated spectroscopically by electron paramagnetic resonance to show that the 1:1 metal-to-ligand ratio found in the crystal structure is also maintained in solution.
• Blakemore, L. J., Tomat, E., Lippard, S. J., & Trombley, P. Q. (2013). Zinc released from olfactory bulb glomeruli by patterned electrical stimulation of the olfactory nerve. METALLOMICS, 5(3), 208-213.
• Blakemore, L. J., Tomat, E., Lippard, S. J., & Trombley, P. Q. (2013). Zinc released from olfactory bulb glomeruli by patterned electrical stimulation of the olfactory nerve. Metallomics, 5(3), 208-213.
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  PMID: 23392381;PMCID: PMC3587726;Abstract: Zinc is a trace element with a multitude of roles in biological systems including structural and cofactor functions for proteins. Although most zinc in the central nervous system (CNS) is protein bound, the CNS contains a pool of mobile zinc housed in synaptic vesicles within a subset of neurons. Such mobile zinc occurs in many brain regions, such as the hippocampus, hypothalamus, and cortex, but the olfactory bulb (OB) contains one of the highest such concentrations in the CNS. Zinc is distributed throughout the OB, with the glomerular and granule cell layers containing the highest levels. Here, we visualize vesicular zinc in the OB using zinc-responsive fluorescent probes developed by one of us. Moreover, we provide the first demonstration that vesicular pools of zinc can be released from olfactory nerve terminals within individual glomeruli by patterned electrical stimulation of the olfactory nerve designed to mimic the breathing cycle in rats. We also provide electrophysiological evidence that elevated extracellular zinc potentiates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated synaptic events. AMPA receptors are required for the synchronous activation of neurons within individual OB glomeruli, and zinc-mediated potentiation leads to enhanced synaptic summation. © 2013 The Royal Society of Chemistry.
• Chang, T. M., & Tomat, E. (2013). Disulfide/thiol switches in thiosemicarbazone ligands for redox-directed iron chelation. DALTON TRANSACTIONS, 42(22), 7846-7849.
• Chang, T. M., & Tomat, E. (2013). Disulfide/thiol switches in thiosemicarbazone ligands for redox-directed iron chelation. Dalton Transactions, 42(22), 7846-7849.
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  PMID: 23591852;Abstract: A disulfide bond is incorporated in the scaffold of thiosemicarbazone iron chelators as a reduction/activation switch. Following reduction, thiol-containing ligands stabilize iron ions in their trivalent oxidation state. The antiproliferative activity of the new chelating systems is assessed in human cancer cell lines and in normal tissue. © 2013 The Royal Society of Chemistry.
• Pluth, M. D., Tomat, E., & Lippard, S. J. (2011). Biochemistry of mobile zinc and nitric oxide revealed by fluorescent sensors. Annual Review of Biochemistry, 80, 333-355.
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  PMID: 21675918;PMCID: PMC3117437;Abstract: Biological mobile zinc and nitric oxide (NO) are two prominent examples of inorganic compounds involved in numerous signaling pathways in living systems. In the past decade, a synergy of regulation, signaling, and translocation of these two species has emerged in several areas of human physiology, providing additional incentive for developing adequate detection systems for Zn(II) ions and NO in biological specimens. Fluorescent probes for both of these bioinorganic analytes provide excellent tools for their detection, with high spatial and temporal resolution. We review the most widely used fluorescent sensors for biological zinc and nitric oxide, together with promising new developments and unmet needs of contemporary Zn(II) and NO biological imaging. The interplay between zinc and nitric oxide in the nervous, cardiovascular, and immune systems is highlighted to illustrate the contributions of selective fluorescent probes to the study of these two important bioinorganic analytes. © 2011 by Annual Reviews. All rights reserved.
• Tomat, E., & Lippard, S. J. (2010). Imaging mobile zinc in biology. Current Opinion in Chemical Biology, 14(2), 225-230.
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  PMID: 20097117;PMCID: PMC2847655;Abstract: Trafficking and regulation of mobile zinc pools influence cellular functions and pathological conditions in multiple organs, including brain, pancreas, and prostate. The quest for a dynamic description of zinc distribution and mobilization in live cells fuels the development of increasingly sophisticated probes. Detection systems that respond to zinc binding with changes of their fluorescence emission properties have provided sensitive tools for mobile zinc imaging, and fluorescence microscopy experiments have afforded depictions of zinc distribution within live cells and tissues. Both small-molecule and protein-based fluorescent probes can address complex imaging challenges, such as analyte quantification, site-specific sensor localization, and real-time detection. © 2009 Elsevier Ltd. All rights reserved.
• Tomat, E., & Lippard, S. J. (2010). Ratiometric and intensity-based zinc sensors built on rhodol and rhodamine platforms. Inorganic Chemistry, 49(20), 9113-9115.
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  PMID: 20860360;PMCID: PMC2956166;Abstract: A xanthene-forming condensation reaction yields rhodol and rhodamine dyes carrying a zinc-binding ligand that includes the aniline-type nitrogen donor of the fluorophores. Upon zinc coordination in neutral aqueous solution, rhodol RF3 behaves as a ratiometric sensor, and rhodamine RA1 acts as a turn-off intensitybased indicator. Both fluorescent compounds bind the divalent zinc cation with micromolar affinity. © 2010 American Chemical Society.
• You, Y., Tomat, E., Hwang, K., Atanasijevic, T., Nam, W., Jasanoff, A. P., & Lippard, S. J. (2010). Manganese displacement from Zinpyr-1 allows zinc detection by fluorescence microscopy and magnetic resonance imaging. Chemical Communications, 46(23), 4139-4141.
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  PMID: 20454746;PMCID: PMC2880654;Abstract: A paramagnetic manganese complex of a fluorescein-based probe affords a dual-modality zinc sensor featuring an improved fluorescence dynamic range and an MRI readout. © 2010 The Royal Society of Chemistry.
• Cuesta, L., Tomat, E., Lynch, V. M., & Sessler, J. L. (2008). Binuclear organometallic ruthenium complexes of a Schiff base expanded porphyrin. Chemical Communications, 3744-3746.
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  PMID: 18685763;Abstract: The synthesis of binuclear organometallic ruthenium complexes of an expanded porphyrin-type macrocycle is reported; pyrrolic hydrogen bonding donors were found to interact with ancillary ligands in the primary coordination sphere and to stabilize coordinated dioxygen in an η2-fashion. © The Royal Society of Chemistry.
• Tomat, E., Nolan, E. M., Jaworski, J., & Lippard, S. J. (2008). Organelle-specific zinc detection using zinpyr-labeled fusion proteins in live cells. Journal of the American Chemical Society, 130(47), 15776-15777.
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  PMID: 18973293;PMCID: PMC2645946;Abstract: A protein labeling approach is employed for the localization of a zinc-responsive fluorescent probe in the mitochondria and in the Golgi apparatus of living cells. ZP1, a zinc sensor of the Zinpyr family, was functionalized with a benzylguanine moiety and thus converted into a substrate (ZP1BG) for the human DNA repair enzyme alkylguaninetransferase (AGT or SNAP-Tag). The labeling reaction of purified glutathione S-transferase tagged AGT with ZP1BG and the zinc response of the resulting protein-bound sensor were confirmed in vitro. The new detection system, which combines a protein labeling methodology with a zinc fluorescent sensor, was tested in live HeLa cells expressing AGT in specific locations. The enzyme was genetically fused to site-directing proteins that anchor the probe onto targeted organelles. Localization of the zinc sensors in the Golgi apparatus and in the mitochondria was demonstrated by fluorescence microscopy. The protein-bound fluroescence detection system is zinc-responsive in living cells. Copyright © 2008 American Chemical Society.
• Sessler, J. L., & Tomat, E. (2007). Transition-metal complexes of expanded porphyrins. Accounts of Chemical Research, 40(5), 371-379.
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  PMID: 17397134;PMCID: PMC2522265;Abstract: Over the last 2 decades, the rapid development of new synthetic routes for the preparation of expanded porphyrin macrocycles has allowed for the exploration of a new frontier consisting of "porphyrin-like" coordination chemistry. In this Account, we summarize our exploratory forays into the still relatively poorly explored area of oligopyrrolic macrocycle metalation chemistry. Specifically, we describe our successful formation of both mono- and binuclear complexes and, in doing so, highlight the diversity of coordination modes available to expanded porphyrin-type ligands. The nature of the inserted cation, the emerging role of tautomeric equilibria, and the importance of hydrogen-bonding interactions in regulating this chemistry are also discussed. © 2007 American Chemical Society.
• Sessler, J. L., Melfi, P. J., Tomat, E., & Lynch, V. M. (2007). Copper(II) and oxovanadium(V) complexes of hexaphyrin(1.0.1.0.0.0). Dalton Transactions, 629-632.
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  Abstract: A binuclear in-plane copper (II) complex and an oxovanadium (v) derivative were prepared and characterized for the expanded porphyrin hexapyrin (1.01.0.0.0) that coordinates both early and late transition metals. Copper acetate was added to the free base form of isoamethyrin leading to an immediate color change from dark yellow to red. Crystals suitable for x ray analysis were grown from a CH2Cl2/cyclohexane mixture after purification through column chromatography over neutral alumina. The macrocycle needs to distort slightly to fit the two copper atoms. The complexes contain very different metal centers and serve to show that isoamethyrin is able to stabilize two different transition metal coordination modes.
• Tomat, E., Cuesta, L., Lynch, V. M., & Sessler, J. L. (2007). Binuclear fluoro-bridged zinc and cadmium complexes of a Schiff base expanded porphyrin: Fluoride abstraction from the tetrafluoroborate anion. Inorganic Chemistry, 46(16), 6224-6226.
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  PMID: 17630733;Abstract: Reactions of the Schiff base oligopyrrolic octaazamacrocycle 1 with BF 4- salts of divalent zinc and cadmium result in fluoride anion abstraction and the formation of difluoride-bridged metal complexes. X-ray diffraction analyses provide support for the notion that hydrogen-bonding interactions, involving the N-H groups of the macrocycle and the coordinated fluoride ions, play an important role in stabilizing these new complexes. © 2007 American Chemical Society.
• Sessler, J. L., Melfi, P. J., Tomat, E., Callaway, W., Huggins, M. T., Gordon, P. L., Keogh, D. W., Date, R. W., Bruce, D. W., & Donnio, B. (2006). Schiff base oligopyrrolic macrocycles as ligands for lanthanides and actinides. Journal of Alloys and Compounds, 418(1-2), 171-177.
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  Abstract: The coordination of f-block cations with Schiff base oligopyrrolic macrocycles is discussed. Analysis of the mesophase of a uranyl 2,5-diformylpyrrole-derived expanded porphyrin complex through temperature-dependent X-ray diffraction (XRD) methods has provided evidence for liquid-crystalline properties, and for molecular stacking into columns, arranged in a 2D hexagonal lattice. In separate studies, UV-vis spectral analysis has indicated the formation of three new f-block oligopyrrolic complexes. Addition of neptunyl ([NpO2]2+) or plutonyl ([PuO2]2+) chloride salts to the free base of a dipyrromethane-derived Schiff base macrocycle induces an immediate spectral change, namely the growth of a Q-like band at 630 nm. Such changes in the absorption spectra cause a dramatic color change from pale yellow to blue. It is postulated that oxidation of this macrocycle, stimulated by reduction of the metal center, leads to the observed spectral changes. An immediate visible and spectral change is also observed with the reaction of lutetium silylamide (Lu[N(Si(CH3)3)2]3), with a different, tetrapyrrole-containing Schiff base macrocycle. In this case, the formation of a complex with 1:1 metal-to-ligand binding stoichiometry is further supported by MALDI-TOF mass spectrometry. © 2005 Elsevier B.V. All rights reserved.
• Sessler, J. L., Tomat, E., & Lynch, V. M. (2006). Coordination of oxovanadium(v) in an expanded porphyrin macrocycle. Chemical Communications, 4486-4488.
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  PMID: 17283793;Abstract: The formation of a dioxovanadium(v) complex of an expanded porphyrin-type Schiff base macrocycle is reported; the tetrapyrrolic ligand undergoes a tautomeric shift which permits a bimodal recognition of the nonspherical cationic guest. © The Royal Society of Chemistry 2006.
• Sessler, J. L., Tomat, E., & Lynch, V. M. (2006). Positive homotropic allosteric binding of silver(I) cations in a Schiff base oligopyrrolic macrocycle. Journal of the American Chemical Society, 128(13), 4184-4185.
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  PMID: 16568966;Abstract: The binuclear silver(I) complex of a Schiff base oligopyrrolic macrocycle was prepared in high yield and fully characterized. UV-visible absorption and 1H NMR spectroscopic analyses reveal that coordination of Ag(I) cations is subject to a strong positive homotropic allosteric effect. Copyright © 2006 American Chemical Society.
• Sessler, J. L., Tomat, E., Mody, T. D., Lynch, V. M., Veauthier, J. M., Mirsaidov, U., & Markert, J. T. (2005). A Schiff base expanded porphyrin macrocycle that acts as a versatile binucleating ligand for late first-row transition metals. Inorganic Chemistry, 44(7), 2125-2127.
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  PMID: 15792442;Abstract: The coordination chemistry of the Schiff base polypyrrolic octaaza macrocycle 1 toward late first-row transition metals was investigated. Binuclear complexes with the divalent cations Ni(II), Cu(II), and Zn(II) and with the monovalent cation Cu(I) were prepared and characterized. Air oxidation of the Cu(I) ions in the latter complex to their divalent oxidation state resulted in a change in the coordination mode relative to the macrocycle. © 2005 American Chemical Society.
• Veauthier, J. M., Tomat, E., Lynch, V. M., Sessler, J. L., Mirsaidov, U., & Markert, J. T. (2005). Calix[4]pyrrole Schiff base macrocycles: Novel binucleating ligands for Cu(I) and Cu(II). Inorganic Chemistry, 44(19), 6736-6743.
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  PMID: 16156632;Abstract: New bimetallic copper(I) and copper(II) complexes of dipyrromethane-derived Schiff base macrocycles are reported. Two different structural motifs were identified, providing support for the notion that ligands of this type can support a variety of coordination modes. In the case of the Cu(I) complexes, the metal centers were found to have a distorted tetrahedral geometry and be coordinated to two imine nitrogens on each side of the ligand, with the exact structure depending on the choice of Schiff base macrocycle. In contrast to what is seen for Cu(I), with Cu(II) as the coordinated cation the Cu(II) metal centers assumed distorted square planar geometries, and both pyrrole N-Cu and imine N-Cu interactions were confirmed by single-crystal X-ray diffraction analysis. This structural analysis revealed a copper-copper distance of 3.47 Å, while SQUID magnetic susceptibility data provided evidence for antiferromagnetic coupling between the two metal centers. © 2005 American Chemical Society.
• Vlaic, G., Fornasiero, P., Martra, G., Fonda, E., Kaspar, J., Marchese, L., Tomat, E., Coluccia, S., & Graziani, M. (2000). Morphology of rhodium particles in ex-chloride Rh/Ce0.5Zr0.5O2 catalyst. Journal of Catalysis, 190(1), 182-190.
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  The morphology of rhodium particles in a 5 wt% Rh/Ce0.5Zr0.5O2 catalyst subjected to different treatments is investigated by EXAFS, HREM, and H-2 chemisorption. Despite the high Rh loading highly dispersed metal particles are observed in the sample. In the presence of NO and CO, the Rh particles are easily oxidized to give small Rh oxide clusters, and the high rhodium dispersion is retained even after a further reduction at 773 K. Comparison with an Rh/Al2O3 prepared under identical conditions clearly suggests that the presence of the Ce0.5Zr0.5O2 support favors high dispersion of rhodium particles. Despite the fact that RhCl3. nH(2)O has been employed as precursor, no chloride could be detected in the Rh nearest-neighbor shell, suggesting its migration over the support. (C) 2000 Academic Press.

Presentations

• Tomat, E. (2017, April). Invited presentation. Los Alamos National Laboratory.
• Tomat, E. (2017, January). Contributed presentation. Gordon Research Conference, Metals in Biology, Ventura, CA.
• Tomat, E. (2017, May). Contributed presentation. University of Arizona Cancer Center Scientific Retreat, Tucson, AZ.
• Tomat, E. (2017, May). Invited presentation. 2017 Georgian Bay International Conference on Bioinorganic Chemistry (CanBIC), Parry Sound, Ontario (Canada).
• Tomat, E. (2017, September). Invited presentation. University of Connecticut.
• Tomat, E. (2016, April). Invited presentation. Baylor University, Department of Chemistry and Biochemistry.
• Tomat, E. (2016, April). Invited presentation. California Institute of Technology, Department of Chemistry, Pasadena, CA.
• Tomat, E. (2016, April). Invited presentation. Georgia Institute of Technology, Department of Chemistry, Atlanta, GA.
• Tomat, E. (2016, April). Invited presentation. University of California San Diego, Department of Chemistry and Biochemistry, La Jolla, CA.
• Tomat, E. (2016, April). Invited presentation. University of Georgia, Department of Chemistry, Athens, GA.
• Tomat, E. (2016, December). Invited presentation. Auburn University, Department of Chemistry and Biochemistry, Auburn, AL.
• Tomat, E. (2016, February). Invited presentation. University of Oregon, Department of Chemistry, Eugene, OR.
• Tomat, E. (2016, January). Invited presentation. Freie Universität Berlin, Institut für Chemie und Biochemie, Berlin (Germany).
• Tomat, E. (2016, July). Invited presentation. Gordon Research Conference, Chemistry and Biology of Tetrapyrroles, Newport, RI.
• Tomat, E. (2016, June). Invited presentation. Gordon Research Conference, Metals in Medicine, Andover, NH.
• Tomat, E. (2016, March). Invited presentation. American Chemical Society National Meeting, San Diego, CA.
• Tomat, E. (2016, March). Invited presentation. New York University, Department of Chemistry, New York City, NY.
• Tomat, E. (2016, March). Invited presentation. University of California Berkeley, Department of Chemistry, Berkeley, CA.
• Tomat, E. (2016, November). Invited presentation. University of Texas at Austin, Department of Chemistry, Austin, TX.
• Tomat, E. (2015, August). Contributed presentation. American Chemical Society National Meeting, Boston, MA.
• Tomat, E. (2015, December). Contributed presentation. Pacifichem 2015, Symposium on “Accessing the Full Potential of Redox-Active Ligands: Reactivity and Applications”, Honolulu, HI.
• Tomat, E. (2015, December). Contributed presentation. Pacifichem 2015, Symposium on “New Frontiers in Bioinorganic Chemistry”, Honolulu, HI.
• Tomat, E. (2015, February). Invited presentation. Texas Christian University, Department of Chemistry, Fort Worth, TX.
• Tomat, E. (2015, January). Invited presentation. Breast Cancer Multidisciplinary Translational Research Retreat, Arizona Cancer Center.
• Tomat, E. (2015, November). Invited presentation. Texas A&M University, Department of Chemistry, College Station, TX.
• Tomat, E. (2015, November). Invited presentation. University of North Texas, Department of Chemistry, Arlington, TX.
• Tomat, E. (2015, October). Invited presentation. Tulane University, Department of Chemistry, New Orleans, LA.
• Tomat, E. (2015, September). Invited presentation. International meeting on Metals in Medicine − Novel Approaches and Insights, Jerusalem, Israel.
• Tomat, E. (2014, August). Invited presentation. American Chemical Society National Meeting, San Francisco, CA.
• Tomat, E. (2014, December). Invited presentation. Goethe University Frankfurt, Institute of Biochemistry, College of Medicine, Frankfurt, Germany.
• Tomat, E. (2014, June). Contributed presentation. Gordon Research Conference, Metals in Medicine, Andover, NH.
• Tomat, E. (2014, March). Contributed presentation. American Chemical Society National Meeting, Dallas, TX.
• Tomat, E. (2014, October). Invited presentation. Arizona State University, Department of Chemistry and Biochemistry, Tempe, AZ.
• Tomat, E. (2013, April). Contributed presentation. American Chemical Society National Meeting, New Orleans, LA.
• Tomat, E. (2013, April). Invited presentation. Drug Discovery and Developmental Therapeutics Seminar Series, College of Pharmacy, University of Arizona.
• Tomat, E. (2013, December). Invited presentation. Cancer Biology Seminar Series, Arizona Cancer Center, University of Arizona Medical Center.
• Tomat, E. (2013, January). Contributed presentation. Gordon Research Conference, Metals in Biology, Ventura, CA.
• Tomat, E. (2013, July). Invited presentation. Medicinal Redox Inorganic Chemistry Conference, Erlangen-Nürnberg, Germany.
• Tomat, E. (2013, November). Invited presentation. American Chemical Society Southwest Regional Meeting, Waco, TX.
• Tomat, E. (2012, January). Contributed presentation. Gordon Research Conference, Metals in Biology, Ventura, CA.
• Tomat, E. (2012, November). Contributed presentation. American Chemical Society Southwest Regional Meeting, Baton Rouge, LA.
• Tomat, E. (2011, May). Contributed presentation. NIH Mentoring Workshop for Junior Faculty, Dallas, TX.
• Tomat, E. (2010, September). Invited presentation. Biological Chemistry Program Journal Club, University of Arizona.