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Hydrogen sulfide (H2S) is an endogenously produced gasotransmitter involved in many physiological processes that are integral to proper cellular functioning. Due to its profound anti-inflammatory and antioxidant properties, H2S plays important roles in preventing inflammatory skin disorders and improving wound healing. Transdermal H2S delivery is a therapeutically viable option for the management of such disorders. However, current small-molecule H2S donors are not optimally suited for transdermal delivery and typically generate electrophilic byproducts that may lead to undesired toxicity. Here, we demonstrate that H2S release from metal-organic frameworks (MOFs) bearing coordinatively unsaturated metal centers is a promising alternative for controlled transdermal delivery of H2S. Gas sorption measurements and powder X-ray diffraction (PXRD) studies of 11 MOFs support that the Mg-based framework Mg2(dobdc) (dobdc4- = 2,5-dioxidobenzene-1,4-dicarboxylate) is uniquely well-suited for transdermal H2S delivery due to its strong yet reversible binding of H2S, high capacity (14.7 mmol/g at 1 bar and 25 °C), and lack of toxicity. In addition, Rietveld refinement of synchrotron PXRD data from H2S-dosed Mg2(dobdc) supports that the high H2S capacity of this framework arises due to the presence of three distinct binding sites. Last, we demonstrate that transdermal delivery of H2S from Mg2(dobdc) is sustained over a 24 h period through porcine skin. Not only is this significantly longer than sodium sulfide but this represents the first example of controlled transdermal delivery of pure H2S gas. Overall, H2S-loaded Mg2(dobdc) is an easily accessible, solid-state source of H2S, enabling safe storage and transdermal delivery of this therapeutically relevant gas.
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Administração Cutânea , Sulfeto de Hidrogênio , Estruturas Metalorgânicas , Sulfeto de Hidrogênio/química , Sulfeto de Hidrogênio/administração & dosagem , Estruturas Metalorgânicas/química , Animais , Suínos , Pele/metabolismoRESUMO
Gases are essential for various applications relevant to human health, including in medicine, biomedical imaging, and pharmaceutical synthesis. However, gases are significantly more challenging to safely handle than liquids and solids. Herein, we review the use of porous materials, such as metal-organic frameworks (MOFs), zeolites, and silicas, to adsorb medicinally relevant gases and facilitate their handling as solids. Specific topics include the use of MOFs and zeolites to deliver H2S for therapeutic applications, 129Xe for magnetic resonance imaging, O2 for the treatment of cancer and hypoxia, and various gases for use in organic synthesis. This Perspective aims to bring together the organic, inorganic, medicinal, and materials chemistry communities to inspire the design of next-generation porous materials for the storage and delivery of medicinally relevant gases.
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The rare earth elements (REEs) are critical resources for many clean energy technologies, but are difficult to obtain in their elementally pure forms because of their nearly identical chemical properties. Here, an analogue of macropa, G-macropa, was synthesized and employed for an aqueous precipitation-based separation of Nd3+ and Dy3+. G-macropa maintains the same thermodynamic preference for the large REEs as macropa, but shows smaller thermodynamic stability constants. Molecular dynamics studies demonstrate that the binding affinity differences of these chelators for Nd3+ and Dy3+ is a consequence of the presence or absence of an inner-sphere water molecule, which alters the donor strength of the macrocyclic ethers. Leveraging the small REE affinity of G-macropa, we demonstrate that within aqueous solutions of Nd3+, Dy3+, and G-macropa, the addition of HCO3- selectively precipitates Dy2(CO3)3, leaving the Nd3+-G-macropa complex in solution. With this method, remarkably high separation factors of 841 and 741 are achieved for 50:50 and 75:25 mixtures. Further studies involving Nd3+:Dy3+ ratios of 95:5 in authentic magnet waste also afford an efficient separation as well. Lastly, G-macropa is recovered via crystallization with HCl and used for subsequent extractions, demonstrating its good recyclability.
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Ischemia-reperfusion injury (IRI), which describes the cell damage and death that occurs after blood and oxygen are restored to ischemic or hypoxic tissue, is a significant factor within the mortality rates of heart disease and stroke patients. At the cellular level, the return of oxygen triggers an increase in reactive oxygen species (ROS) and mitochondrial calcium (mCa2+) overload, which both contribute to cell death. Despite the widespread occurrence of IRI in different pathological conditions, there are currently no clinically approved therapeutic agents for its management. In this Perspective, we will briefly discuss the current therapeutic options for IRI and then describe in great detail the potential role and arising applications of metal-containing coordination and organometallic complexes for treating this condition. This Perspective categorizes these metal compounds based on their mechanisms of action, which include their use as delivery agents for gasotransmitters, inhibitors of mCa2+ uptake, and catalysts for the decomposition of ROS. Lastly, the challenges and opportunities for inorganic chemistry approaches to manage IRI are discussed.
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Complexos de Coordenação , Traumatismo por Reperfusão , Humanos , Espécies Reativas de Oxigênio/metabolismo , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Morte Celular , Metais , OxigênioRESUMO
Nuclear medicine leverages radioisotopes of a wide range of elements, a significant portion of which are metals, for the diagnosis and treatment of disease. To optimally use radioisotopes of the metal ions, or radiometals, for these applications, a chelator that efficiently forms thermodynamically and kinetically stable complexes with them is required. The chelator also needs to attach to a biological targeting vector that locates pathological tissues. Numerous chelators suitable for small radiometals have been established to date, but chelators that work well for large radiometals are significantly less common. In this Account, we describe recent progress by us and others in the advancement of ligands for large radiometal chelation with emerging applications in nuclear medicine.First, we discuss and analyze the coordination chemistry of the chelator macropa, a macrocyclic ligand that contains the 18-crown-6 backbone and two picolinate pendent arms, with large metal ions in the context of nuclear medicine. This ligand is known for its unusual reverse size selectivity, the preference for binding large over small metal ions. The radiolabeling properties of macropa with large radiometals 225Ac3+, 132/135La3+, 131Ba2+, 223Ra2+, 213Bi3+, and related in vivo investigations are described. The development of macropa derivatives containing different pendent donors or rigidifying groups in the macrocyclic core is also briefly reviewed.Next, efforts to transform macropa into a radiopharmaceutical agent via covalent conjugation to biological targeting vectors are summarized. In this discussion, two types of bifunctional analogues of macropa reported in the literature, macropa-NCS and mcp-click, are presented. Their implementation in different radiopharmaceutical agents is discussed. Bioconjugates containing macropa attached to small-molecule targeting vectors or macromolecular antibodies are presented. The in vitro and in vivo evaluations of these constructs are also discussed.Lastly, chelators with dual size selectivity are described. This class of ligands exhibits good affinities for both large and small metal ions. This property is valuable for nuclear medicine applications that require the simultaneous chelation of both large and small radiometals with complementary therapeutic and diagnostic properties. Recently, we reported an 18-membered macrocyclic ligand called macrodipa that attains this selectivity pattern. This chelator, its second-generation analogue py-macrodipa, and their applications for chelating the medicinally relevant large 135La3+, 225Ac3+, 213Bi3+, and small 44Sc3+ ions are also presented. Studies with these radiometals show that py-macrodipa can effectively radiolabel and stably retain both large and small radiometals. Overall, this Account makes the case for innovative ligand design approaches for novel emerging radiometal ions with unusual coordination chemistry properties.
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Medicina Nuclear , Quelantes/química , Íons/química , Ligantes , Radioisótopos/químicaRESUMO
Burkitt lymphoma (BL) is an extremely aggressive but curable subtype of non-Hodgkin lymphoma. While younger patients have excellent outcomes in response to aggressive chemoimmunotherapy, the rarity of this disease in older patients and limitations caused by age, comorbidities, and performance status may negate survival advantages. This analysis assessed outcomes of older adults with BL through data provided by the Texas Cancer Registry (TCR). Patients ≥65 years with BL were assessed. Patients were dichotomized into 1997-2007 and 2008-2018. Median overall survival (OS) and disease-specific survival (DSS) were assessed using Kaplan-Meier methodology, and covariates including age, race, sex, stage, primary site, and poverty index were analyzed using Pearson Chi-squared analysis. Odds ratio (OR) with 95% confidence intervals (CI) was used to assess factors contributing to patients not offered systemic therapy. P value <0.05 was considered statistically significant. Non-BL mortality events were also categorized. There were 325 adults, 167 in 1997-2007 and 158 in 2008-2018; 106 (63.5%) and 121 (76.6%) received systemic therapy, a trend that increased with time (p = 0.010). Median OS for 1997-2007 and 2008-2018 was 5 months (95% CI 2.469, 7.531) and 9 months (95% CI 0.000, 19.154) (p = 0.013), and DSS was 72 months (95% CI 56.397, 87.603) (p = 0.604) and not reached, respectively. For patients that received systemic therapy, median OS was 8 months (95% CI 1.278, 14.722) and 26 months (95% CI 5.824, 46.176) (p = 0.072), respectively, and DSS was 79 months (95% CI: 56.416, 101.584) and not reached, respectively (p = 0.607). Age ≥75 years (HR 1.39 [95% CI 1.078, 1.791], p = 0.011) and non-Hispanic whites (HR 1.407 [95% CI 1.024, 1.935], p = 0.035) had poorer outcomes, and patients at the 20-100% poverty index (OR 0.387 [95% CI 0.163, 0.921], p = 0.032) and increasing age at diagnosis (OR 0.947 [95% CI 0.913, 0.983], p = 0.004) were less likely to receive systemic therapy. Of 259 (79.7%) deaths, 62 (23.9%) were non-BL deaths, and 6 (9.6%) of these were from a second cancer. This two-decade analysis of older Texas patients with BL indicates a significant improvement in OS over time. Although patients were more likely to receive systemic therapy over time, treatment disparities existed in patients residing in poverty-stricken regions of Texas and in advancing age. These statewide findings reflect an unmet national need to find a systemic therapeutic strategy that can be tolerated by and augment outcomes in the growing elderly population.
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Linfoma de Burkitt , Humanos , Idoso , Linfoma de Burkitt/tratamento farmacológico , Linfoma de Burkitt/epidemiologia , Texas/epidemiologia , Sistema de RegistrosRESUMO
The mitochondrial calcium uniporter (MCU) mediates uptake of calcium ions (Ca2+) into the mitochondria, a process that is vital for maintaining normal cellular function. Inhibitors of the MCU, the most promising of which are dinuclear ruthenium coordination compounds, have found use as both therapeutic agents and tools for studying the importance of this ion channel. In this study, six Co3+ cage compounds with sarcophagine-like ligands were assessed for their abilities to inhibit MCU-mediated mitochondrial Ca2+ uptake. These complexes were synthesized and characterized according to literature procedures and then investigated in cellular systems for their MCU-inhibitory activities. Among these six compounds, [Co(sen)]3+ (3, sen = 5-(4-amino-2-azabutyl)-5-methyl-3,7-diaza-1,9-nonanediamine) was identified to be a potent MCU inhibitor, with IC50 values of inhibition of 160 and 180 nM in permeabilized HeLa and HEK293T cells, respectively. Furthermore, the cellular uptake of compound 3 was determined, revealing moderate accumulation in cells. Most notably, 3 was demonstrated to operate in intact cells as an MCU inhibitor. Collectively, this work presents the viability of using cobalt coordination complexes as MCU inhibitors, providing a new direction for researchers to investigate in future studies.
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To harness radiometals in clinical settings, a chelator forming a stable complex with the metal of interest and targets the desired pathological site is needed. Toward this goal, we previously reported a unique set of chelators that can stably bind to both large and small metal ions, via a conformational switch. Within this chelator class, py-macrodipa is particularly promising based on its ability to stably bind several medicinally valuable radiometals including large 132/135La3+, 213Bi3+, and small 44Sc3+. Here, we report a 10-step organic synthesis of its bifunctional analogue py-macrodipa-NCS, which contains an amine-reactive -NCS group that is amenable for bioconjugation reactions to targeting vectors. The hydrolytic stability of py-macordipa-NCS was assessed, revealing a half-life of 6.0 d in pH 9.0 aqueous buffer. This bifunctional chelator was then conjugated to a prostate-specific membrane antigen (PSMA)-binding moiety, yielding the bioconjugate py-macrodipa-PSMA, which was subsequently radiolabeled with large 132/135La3+ and small 47Sc3+, revealing efficient and quantitative complex formation. The resulting radiocomplexes were injected into mice bearing both PSMA-expressing and PSMA-non-expressing tumor xenografts to determine their biodistribution patterns, revealing delivery of both 132/135La3+ and 47Sc3+ to PSMA+ tumor sites. However, partial radiometal dissociation was observed, suggesting that py-macrodipa-PSMA needs further structural optimization.
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Inhibitors of the mitochondrial calcium uniporter (MCU) are valuable tools for studying the role of mitochondrial Ca2+ in various pathophysiological conditions. In this study, a new fluorogenic MCU inhibitor, RuOCou, is presented. This compound is an analogue of the known MCU inhibitor Ru265 that contains fluorescent axial coumarin carboxylate ligands. Upon aquation of RuOCou and release of the axial coumarin ligands, a simultaneous increase in its MCU-inhibitory activity and fluorescence intensity is observed. The fluorescence response of this compound enabled its aquation to be monitored in both HeLa cell lysates and live HeLa cells. This fluorogenic prodrug represents a potential theranostic MCU inhibitor that can be leveraged for the treatment of human diseases related to MCU activity.
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Canais de Cálcio , Mitocôndrias , Humanos , Células HeLa , Ligantes , Mitocôndrias/metabolismo , Cálcio/metabolismoRESUMO
Actinium-225 (225Ac) is one of the most promising radionuclides for targeted alpha therapy (TAT). With a half-life of 9.92 days and a decay chain that emits four high-energy α particles, 225Ac is well-suited for TAT when conjugated to macromolecular targeting vectors that exhibit extended in vivo circulation times. The implementation of 225Ac in these targeted constructs, however, requires a suitable chelator that can bind and retain this radionuclide in vivo. Previous work has demonstrated the suitability of a diaza-18-crown-6 macrocyclic chelator H2macropa for this application. Building upon these prior efforts, in this study, two rigid variants of H2macropa, which contain either one (H2BZmacropa) or two (H2BZ2macropa) benzene rings within the macrocyclic core, were synthesized and investigated for their potential use for 225Ac TAT. The coordination chemistry of these ligands with La3+, used as a nonradioactive model for Ac3+, was carried out. Both NMR spectroscopic and X-ray crystallographic studies of the La3+ complexes of these ligands revealed similar structural features to those found for the related complex of H2macropa. Thermodynamic stability constants of the La3+ complexes, however, were found to be 1 and 2 orders of magnitude lower than those of H2macropa for H2BZmacropa and H2BZ2macropa, respectively. The decrease in thermodynamic stability was rationalized via the use of density functional theory calculations. 225Ac radiolabeling and serum stability studies with H2BZmacropa showed that this chelator compares favorably with H2macropa. Based on these promising results, a bifunctional version of this chelator, H2BZmacropa-NCS, was synthesized and conjugated to the antibody codrituzumab (GC33), which targets the liver cancer biomarker glypican-3 (GPC3). The resulting GC33-BZmacropa conjugate and an analogous GC33-macropa conjugate were evaluated for their 225Ac radiolabeling efficiencies, antigen-binding affinities, and in vivo biodistribution in HepG2 liver cancer tumor-bearing mice. Although both conjugates were comparably effective in their radiolabeling efficiencies, [225Ac]Ac-GC33-BZmacropa showed slightly poorer serum stability and biodistribution than [225Ac]Ac-GC33-macropa. Together, these results establish H2BZmacropa-NCS as a new bifunctional chelator for the preparation of 225Ac radiopharmaceuticals.
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Actínio , Quelantes , Actínio/química , Actínio/uso terapêutico , Animais , Quelantes/química , Ligantes , Camundongos , Radioisótopos/química , Compostos Radiofarmacêuticos/química , Distribuição TecidualRESUMO
Radioisotopes of metallic elements, or radiometals, are widely employed in both therapeutic and diagnostic nuclear medicine. For this application, chelators that efficiently bind the radiometal of interest and form a stable metal-ligand complex with it are required. Toward the development of new chelators for nuclear medicine, we recently reported a novel class of 18-membered macrocyclic chelators that is characterized by their ability to form stable complexes with both large and small rare-earth metals (Ln3+), a property referred to as dual size selectivity. A specific chelator in this class called py-macrodipa, which contains one pyridyl group within its macrocyclic core, was established as a promising candidate for 135La3+, 213Bi3+, and 44Sc3+ chelation. Building upon this prior work, here we report the synthesis and characterization of a new chelator called py2-macrodipa with two pyridyl units fused into the macrocyclic backbone. Its coordination chemistry with the Ln3+ series was investigated by NMR spectroscopy, X-ray crystallography, density functional theory (DFT) calculations, analytical titrations, and transchelation assays. These studies reveal that py2-macrodipa retains the expected dual size selectivity and possesses an enhanced thermodynamic affinity for all Ln3+ compared to py-macrodipa. By contrast, the kinetic stability of Ln3+ complexes with py2-macrodipa is only improved for the light, large Ln3+ ions. Based upon these observations, we further assessed the suitability of py2-macrodipa for use with 225Ac3+, a large radiometal with valuable properties for targeted α therapy. Radiolabeling and stability studies revealed py2-macrodipa to efficiently incorporate 225Ac3+ and to form a complex that is inert in human serum over 3 weeks. Although py2-macrodipa does not surpass the state-of-the-art chelator macropa for 225Ac3+ chelation, it does provide another effective 225Ac3+ chelator. These studies shed light on the fundamental coordination chemistry of the Ln3+ series and may inspire future chelator design efforts.
Assuntos
Complexos de Coordenação , Elementos da Série dos Lantanídeos , Metais Terras Raras , Quelantes/química , Complexos de Coordenação/química , Humanos , Elementos da Série dos Lantanídeos/química , Ligantes , Radioisótopos/químicaRESUMO
The mitochondrial calcium uniporter (MCU) is a transmembrane protein that resides on the inner membrane of the mitochondria and mediates calcium uptake into this organelle. Given the critical role of mitochondrial calcium trafficking in cellular function, inhibitors of this channel have arisen as tools for studying the biological relevance of this process and as potential therapeutic agents. In this study, four new analogues of the previously reported Ru-based MCU inhibitor [ClRu(NH3)4(µ-N)Ru(NH3)4Cl]Cl3 (Ru265) are reported. These compounds, which bear axial carboxylate ligands, are of the general formula [(RCO2)Ru(NH3)4(µ-N)Ru(NH3)4(O2CR)]X3, where X = NO3- or CF3SO3- and R = H (1), CH3 (2), CH2CH3 (3), and (CH2)2CH3 (4). These complexes were fully characterized by IR spectroscopy, NMR spectroscopy, and elemental analysis. X-ray crystal structures of 1 and 3 were obtained, revealing the expected presence of both the linear Ru(µ-N)Ru core and axial formate and propionate ligands. The axial carboxylate ligands of complexes 1-4 are displaced by water in buffered aqueous solution to give the aquated compound Ru265'. The kinetics of these processes were measured by 1H NMR spectroscopy, revealing half-lives that span 5.9-9.9 h at 37 °C. Complex 1 with axial formate ligands underwent aquation approximately twice as fast as the other compounds. In vitro cytotoxicity and mitochondrial membrane potential measurements carried out in HeLa and HEK293T cells demonstrated that none of these four complexes negatively affects cell viability or mitochondrial function. The abilities of 1-4 to inhibit mitochondrial calcium uptake in permeabilized HEK293T cells were assessed and compared to that of Ru265. Fresh solutions of 1-4 are approximately 2-fold less potent than Ru265 with IC50 values in the range of 14.7-19.1 nM. Preincubating 1-4 in aqueous buffers for longer time periods to allow for the aquation reactions to proceed increases their potency of mitochondrial uptake inhibition to match that of Ru265. This result indicates that 1-4 are aquation-activated prodrugs of Ru265'. Finally, 1-4 were shown to inhibit mitochondrial calcium uptake in intact, nonpermeabilized cells, revealing their value as tools and potential therapeutic agents for mitochondrial calcium-related disorders.
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Cálcio , Pró-Fármacos , Humanos , Cálcio/metabolismo , Formiatos , Células HEK293 , LigantesRESUMO
The radionuclides 225Ac3+ and 213Bi3+ possess favorable physical properties for targeted alpha therapy (TAT), a therapeutic approach that leverages α radiation to treat cancers. A chelator that effectively binds and retains these radionuclides is required for this application. The development of ligands for this purpose, however, is challenging because the large ionic radii and charge-diffuse nature of these metal ions give rise to weaker metal-ligand interactions. In this study, we evaluated two 18-membered macrocyclic chelators, macrodipa and py-macrodipa, for their ability to complex 225Ac3+ and 213Bi3+. Their coordination chemistry with Ac3+ was probed computationally and with Bi3+ experimentally via NMR spectroscopy and X-ray crystallography. Furthermore, radiolabeling studies were conducted, revealing the efficient incorporation of both 225Ac3+ and 213Bi3+ by py-macrodipa that matches or surpasses the well-known chelators macropa and DOTA. Incubation in human serum at 37 °C showed that â¼90% of the 225Ac3+-py-macrodipa complex dissociates after 1 d. The Bi3+-py-macrodipa complex possesses remarkable kinetic inertness reflected by an EDTA transchelation challenge study, surpassing that of Bi3+-macropa. This work establishes py-macrodipa as a valuable candidate for 213Bi3+ TAT, providing further motivation for its implementation within new radiopharmaceutical agents.
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QuelantesRESUMO
Uranium-230 is an α-emitting radionuclide with favorable properties for use in targeted α-therapy (TAT), a type of nuclear medicine that harnesses α particles to eradicate cancer cells. To successfully implement this radionuclide for TAT, a bifunctional chelator that can stably bind uranium in vivo is required. To address this need, we investigated the acyclic ligands H2dedpa, H2CHXdedpa, H2hox, and H2CHXhox as uranium chelators. The stability constants of these ligands with UO22+ were measured via spectrophotometric titrations, revealing log ßML values that are greater than 18 and 26 for the "pa" and "hox" chelators, respectively, signifying that the resulting complexes are exceedingly stable. In addition, the UO22+ complexes were structurally characterized by NMR spectroscopy and X-ray crystallography. Crystallographic studies reveal that all six donor atoms of the four ligands span the equatorial plane of the UO22+ ion, giving rise to coordinatively saturated complexes that exclude solvent molecules. To further understand the enhanced thermodynamic stabilities of the "hox" chelators over the "pa" chelators, density functional theory (DFT) calculations were employed. The use of the quantum theory of atoms in molecules revealed that the extent of covalency between all four ligands and UO22+ was similar. Analysis of the DFT-computed ligand strain energy suggested that this factor was the major driving force for the higher thermodynamic stability of the "hox" ligands. To assess the suitability of these ligands for use with 230U TAT in vivo, their kinetic stabilities were probed by challenging the UO22+ complexes with the bone model hydroxyapatite (HAP) and human plasma. All four complexes were >95% stable in human plasma for 14 days, whereas in the presence of HAP, only the complexes of H2CHXdedpa and H2hox remained >80% intact over the same period. As a final validation of the suitability of these ligands for radiotherapy applications, the in vivo biodistribution of their UO22+ complexes was determined in mice in comparison to unchelated [UO2(NO3)2]. In contrast to [UO2(NO3)2], which displays significant bone uptake, all four ligand complexes do not accumulate in the skeletal system, indicating that they remain stable in vivo. Collectively, these studies suggest that the equatorial-spanning ligands H2dedpa, H2CHXdedpa, H2hox, and H2CHXhox are highly promising candidates for use in 230U TAT.
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QuelantesRESUMO
As an element-equivalent theranostic pair, lead-203 (203Pb, 100% EC, half-life = 51.92 h) and lead-212 (212Pb, 100% ß-, half-life = 10.64 h), through the emission of γ rays and an α particle in its decay chain, respectively, can aid in the development of personalized targeted radionuclide treatment for advanced and currently untreatable cancers. With these isotopes currently being used in clinical trials, an understanding of the relationship between the chelator structure, ability to incorporate the radiometal, and metal-complex stability is needed to help design appropriate chelators for clinical use. Herein, we report an investigation into the effect of ring size in macrocyclic chelators where pyridine, an intermediate Lewis base, acts as an electron donor toward lead. Crown-4Py (4,7,13,16-tetrakis(pyridin-2-ylmethyl)-1,10-dioxa-4,7,13,16-tetraazacyclooctadecane), cyclen-4Py (1,4,7,10-tetrakis(pyridin-2-ylmethyl)-1,4,7,10-tetraazacyclododecane), and NOON-2Py (7,16-bis(pyridin-2-ylmethyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane) were synthesized and analyzed for their ability to coordinate Pb2+. Metal complex stability was investigated via [203Pb]Pb2+ radiolabeling studies, 1H NMR spectroscopy, X-ray crystallography, and potentiometry. With the smallest macrocyclic backbone, cyclen-4Py had the highest radiochemical yield, while, in descending order, crown-4Py and NOON-2Py had the lowest. Thermodynamic stability constants (log KML) of 19.95(3), 13.29(5), and 11.67 for [Pb(Cyclen-4Py)]2+, [Pb(Crown-4Py)]2+, and [Pb(NOON-2Py)]2+, respectively, correlated with their radiochemical yields. The X-ray crystal structure of the least stable complexes [Pb(NOON-2Py)]2+ revealed a hemidirected Pb2+ center, as reflected by a void within the coordination sphere, and [Pb(Crown-4Py)]2+ showed an average Pb-N pyridine interatomic distance of >3 Å. By contrast, the crystal structure of [Pb(Cyclen-4Py)]2+ showed shorter Pb-N pyridine interactions, and in solution, only one highly symmetric isomer existed for this complex, whereas conformational flexibility was observed for both [Pb(Crown-4Py)]2+ and [Pb(NOON-2Py)]2+ at the NMR timescale. This study illustrates the importance of the macrocyclic backbone size when incorporating bulky electron-donor groups into the design of a macrocyclic chelator as it affects the accessibility of lead to the donor arms. Our results show that cyclen-4Py is a promising chelator for future studies with this theranostic pair.
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Complexos de Coordenação , Ciclamos , Quelantes , Complexos de Coordenação/química , Cristalografia por Raios X , Chumbo , Ligantes , Piridinas/químicaRESUMO
Target identification remains a critical challenge in inorganic drug discovery to deconvolute potential polypharmacology. Herein, we describe an improved approach to prioritize candidate protein targets based on a combination of dose-dependent chemoproteomics and treatment effects in living cancer cells for the rhenium tricarbonyl compound TRIP. Chemoproteomics revealed 89 distinct dose-dependent targets with concentrations of competitive saturation between 0.1 and 32â µM despite the broad proteotoxic effects of TRIP. Target-response networks revealed two highly probable targets of which the Fe-S cluster biogenesis factor NUBP2 was competitively saturated by free TRIP at nanomolar concentrations. Importantly, TRIP treatment led to a down-regulation of Fe-S cluster containing proteins and upregulated ferritin. Fe-S cluster depletion was further verified by assessing mitochondrial bioenergetics. Consequently, TRIP emerges as a first-in-class modulator of the scaffold protein NUBP2, which disturbs Fe-S cluster biogenesis at sub-cytotoxic concentrations in ovarian cancer cells.
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Proteínas Ferro-Enxofre , Neoplasias Ovarianas , Rênio , Humanos , Feminino , Proteínas Ferro-Enxofre/metabolismo , Mitocôndrias/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Ferritinas/metabolismoRESUMO
Nuclear medicine leverages different types of radiometals for disease diagnosis and treatment, but these applications usually require them to be stably chelated. Given the often-disparate chemical properties of these radionuclides, it is challenging to find a single chelator that binds all of them effectively. Toward addressing this problem, we recently reported a macrocyclic chelator macrodipa with an unprecedented "dual-size-selectivity" pattern for lanthanide (Ln3+) ions, characterized by its high affinity for both the large and the small Ln3+ ( J. Am. Chem. Soc, 2020, 142, 13500). Here, we describe a second-generation "macrodipa-type" ligand, py-macrodipa. Its coordination chemistry with Ln3+ was thoroughly investigated experimentally and computationally. These studies reveal that the Ln3+-py-macrodipa complexes exhibit enhanced thermodynamic and kinetic stabilities compared to Ln3+-macrodipa, while retaining the unusual dual-size selectivity. Nuclear medicine applications of py-macrodipa for chelating radiometals with disparate chemical properties were assessed using the therapeutic 135La3+ and diagnostic 44Sc3+ radiometals representing the two size extremes within the rare-earth series. Radiolabeling and stability studies demonstrate that the rapidly formed complexes of these radionuclides with py-macrodipa are highly stable in human serum. Thus, in contrast to gold standard chelators like DOTA and macropa, py-macrodipa can be harnessed for the simultaneous, efficient binding of radiometals with disparate ionic radii like La3+ and Sc3+, signifying a substantial achievement in nuclear medicine. This concept could enable the facile incorporation of a breadth of medicinally relevant radiometals into chemically identical radiopharmaceutical agents. The fundamental coordination chemistry learned from py-macrodipa provides valuable insight for future chelator development.
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Quelantes/química , Elementos da Série dos Lantanídeos/química , Compostos Macrocíclicos/química , Piridinas/química , Sistemas de Liberação de Medicamentos , Desenho de Fármacos , Ligação de Hidrogênio , Modelos Moleculares , Estrutura MolecularRESUMO
Resistance to currently available antifungal drugs has quietly been on the rise but overshadowed by the alarming spread of antibacterial resistance. There is a striking lack of attention to the threat of drug-resistant fungal infections, with only a handful of new drugs currently in development. Given that metal complexes have proven to be useful new chemotypes in the fight against diseases such as cancer, malaria, and bacterial infections, it is reasonable to explore their possible utility in treating fungal infections. Herein we report a series of cobalt(III) Schiff base complexes with broad-spectrum antifungal activity. Some of these complexes show minimum inhibitory concentrations (MIC) in the low micro- to nanomolar range against a series of Candida and Cryptococcus yeasts. Additionally, we demonstrate that these compounds show no cytotoxicity against both bacterial and human cells. Finally, we report the first inâ vivo toxicity data on these compounds in Galleria mellonella, showing that doses as high as 266â mg kg-1 are tolerated without adverse effects, paving the way for further inâ vivo studies of these complexes.
Assuntos
Antifúngicos/farmacologia , Antibacterianos/farmacologia , Candida , Cobalto , Complexos de Coordenação/toxicidade , Humanos , Testes de Sensibilidade Microbiana , Bases de SchiffRESUMO
The radionuclide 213Bi can be applied for targeted α therapy (TAT): a type of nuclear medicine that harnesses α particles to eradicate cancer cells. To use this radionuclide for this application, a bifunctional chelator (BFC) is needed to attach it to a biological targeting vector that can deliver it selectively to cancer cells. Here, we investigated six macrocyclic ligands as potential BFCs, fully characterizing the Bi3+ complexes by NMR spectroscopy, mass spectrometry, and elemental analysis. Solid-state structures of three complexes revealed distorted coordination geometries about the Bi3+ center arising from the stereochemically active 6s2 lone pair. The kinetic properties of the Bi3+ complexes were assessed by challenging them with a 1000-fold excess of the chelating agent diethylenetriaminepentaacetic acid (DTPA). The most kinetically inert complexes contained the most basic pendent donors. Density functional theory (DFT) and quantum theory of atoms in molecules (QTAIM) calculations were employed to investigate this trend, suggesting that the kinetic inertness is not correlated with the extent of the 6s2 lone pair stereochemical activity, but with the extent of covalency between pendent donors. Lastly, radiolabeling studies of 213Bi (30-210 kBq) with three of the most promising ligands showed rapid formation of the radiolabeled complexes at room temperature within 8 min for ligand concentrations as low as 10-7 M, corresponding to radiochemical yields of >80%, thereby demonstrating the promise of this ligand class for use in 213Bi TAT.
Assuntos
Bismuto/uso terapêutico , Quelantes/uso terapêutico , Complexos de Coordenação/uso terapêutico , Éteres de Coroa/uso terapêutico , Neoplasias/tratamento farmacológico , Compostos Radiofarmacêuticos/uso terapêutico , Bismuto/química , Quelantes/síntese química , Quelantes/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Éteres de Coroa/química , Teoria da Densidade Funcional , Humanos , Cinética , Ligantes , Estrutura Molecular , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/químicaRESUMO
The endoplasmic reticulum (ER) has recently emerged as a promising target for anticancer agents. Cytotoxic compounds that target the ER often exhibit selectivity for cancer cells over non-cancer cells. Furthermore, the induction of ER stress often leads to immunogenic cell death, providing another factor that contributes to the clinical efficacy of drugs that target this organelle. Among potential ER stress-inducing agents, metal complexes, which possess redox activity and modular structures, have arisen as promising candidates. In the last two decades, dozens of metal complexes have been reported that kill cancer cells via ER stress induction, and many of these complexes exhibit nanomolar activity in vitro as well as powerful tumor inhibition in vivo. In this review, we summarize the current state of investigations on the ER stress-inducing properties of metal complexes. This review starts with a description of the ER, its function, and its role in cancer progression and treatment. Following this discussion, a guide to experimental methods that can be used by researchers to detect ER stress is provided. The majority of this review summarizes previous studies on metal-based anticancer agents that cause ER stress. Finally, a discussion on the perspectives and significance of using metal complexes as ER stress-inducing agents for the treatment of cancer is provided, along with a summary of structural trends that contribute to this type of biological activity.