RESUMEN
Hydroxyl radical (·OH) scavenging capacity (HOSC) estimation is essential for evaluating antioxidants, natural extracts, or drugs against clinical diseases. While nanozymes offer advantages in related applications, they still face limitations in activity and selectivity. In response, this work showcases the fabrication of laminarin-modulated osmium (laminarin-Os) nanoclusters (1.45 ± 0.05 nm), functioning as peroxidase-like nanozymes within a colorimetric assay tailored for rational HOSC estimation. This study validates both the characterization and remarkable stability of laminarin-Os. By leveraging the abundant surface negative charges of laminarin-Os and the surface hydroxyls of laminarin, oxidation reactions are facilitated, augmenting laminarin-Os's affinity for 3,3',5,5'-tetramethylbenzidine (TMB) (KM = 0.04 mM). This enables the laminarin-Os-based colorimetric assay to respond to ·OH more effectively than citrate-, albumin-, or other polysaccharides-based Os. In addition, experimental results also validate the selective peroxidase-like behavior of laminarin-Os under acidic conditions. Antioxidants like ascorbic acid, glutathione, tannic acid, and cysteine inhibit absorbance at 652 nm in the colorimetric platform using laminarin-Os's peroxidase-like activity. Compared with commercial kits, this assay demonstrates superior sensitivity (e.g., responds to ascorbic acid 0.01-0.075 mM, glutathione 1-15 µg/mL, tannic acid 0.5-5 µM, and monoammonium glycyrrhizinate cysteine 1.06-10.63 µM) and HOSC testing for glutathione, tannic acid, and monoammonium glycyrrhizinate cysteine. Overall, this study introduces a novel Os nanozyme with exceptional TMB affinity and ·OH selectivity, paving the way for HOSC estimation in biomedical research, pharmaceutical analysis, drug quality control, and beyond.
Asunto(s)
Bencidinas , Depuradores de Radicales Libres , Glucanos , Radical Hidroxilo , Osmio , Bencidinas/química , Colorimetría/métodos , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/farmacología , Glucanos/química , Radical Hidroxilo/química , Radical Hidroxilo/análisis , Osmio/química , Oxidación-Reducción , Peroxidasa/química , Peroxidasa/metabolismoRESUMEN
Anticancer agents that exhibit catalytic mechanisms of action offer a unique multi-targeting strategy to overcome drug resistance. Nonetheless, many in-cell catalysts in development are hindered by deactivation by endogenous nucleophiles. We have synthesised a highly potent, stable Os-based 16-electron half-sandwich ('piano stool') catalyst by introducing a permanent covalent tether between the arene and chelated diamine ligand. This catalyst exhibits antiproliferative activity comparable to the clinical drug cisplatin towards triple-negative breast cancer cells and can overcome tamoxifen resistance. Speciation experiments revealed Os to be almost exclusively albumin-bound in the extracellular medium, while cellular accumulation studies identified an energy-dependent, protein-mediated Os accumulation pathway, consistent with albumin-mediated uptake. Importantly, the tethered Os complex was active for in-cell transfer hydrogenation catalysis, initiated by co-administration of a non-toxic dose of sodium formate as a source of hydride, indicating that the Os catalyst is delivered to the cytosol of cancer cells intact. The mechanism of action involves the generation of reactive oxygen species (ROS), thus exploiting the inherent redox vulnerability of cancer cells, accompanied by selectivity for cancerous cells over non-tumorigenic cells.
Asunto(s)
Antineoplásicos , Proliferación Celular , Complejos de Coordinación , Osmio , Humanos , Catálisis , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Osmio/química , Osmio/farmacología , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/síntesis química , Femenino , Línea Celular Tumoral , Especies Reactivas de Oxígeno/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Estructura MolecularRESUMEN
Diabetic wounds are susceptible to bacterial infections, largely linked to high blood glucose levels (hyperglycemia). To treat such wounds, enzymes like glucose oxidase (GOx) can be combined with nanozymes (nanomaterials mimic enzymes) to use glucose effectively for purposes. However, there is still room for improvement in these systems, particularly in terms of process simplification, enzyme activity regulation, and treatment effects. Herein, the approach utilizes GOx to directly facilitate the biomineralized growth of osmium (Os) nanozyme (GOx-OsNCs), leading to dual-active centers and remarkable triple enzyme activities. Initially, GOx-OsNCs use vicinal dual-active centers, enabling a self-cascaded mechanism that significantly enhances glucose sensing performance compared to step-by-step reactions, surpassing the capabilities of other metal sources such as gold and platinum. In addition, GOx-OsNCs are integrated into a glucose-sensing gel, enabling instantaneous visual feedback. In the treatment of infected diabetic wounds, GOx-OsNCs exhibit multifaceted benefits by lowering blood glucose levels and exhibiting antibacterial properties through the generation of hydroxyl free radicals, thereby expediting healing by fostering a favorable microenvironment. Furthermore, the catalase-like activity of GOx-OsNCs aids in reducing oxidative stress, inflammation, and hypoxia, culminating in improved healing outcomes. Overall, this synergistic enzyme-nanozyme blend is user-friendly and holds considerable promise for diverse applications.
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Glucosa Oxidasa , Osmio , Glucosa Oxidasa/química , Glucosa Oxidasa/metabolismo , Animales , Osmio/química , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/uso terapéutico , Cicatrización de Heridas/efectos de los fármacos , Ratones , Glucemia/metabolismo , Diabetes Mellitus Experimental , Humanos , Glucosa/metabolismo , Infección de Heridas/tratamiento farmacológico , Infección de Heridas/metabolismoRESUMEN
The study of the localization of secondary metabolites in both plants and the cell cultures on the intravital sections is hampered by the difficulty of obtaining thin, correctly oriented sections. Techniques for fixing tissues in resins allow these difficulties to be overcome. Properly selected tissue fixation techniques allow using different dyes to identify the compound of interest. In addition, some components of tissue fixation can act as fixatives and as a dye for identifying secondary metabolites. For example, osmium tetroxide, which fixes lipids in tissues, stains phenolic compounds black. This paper describes methods for the detection of phenolic compounds in morphogenic callus culture of buckwheat using osmium tetroxide, Toluidine Blue O dye, and ferric chloride as dyes in epoxy resin-embedded cell culture with double fixation of the material and when material fixed in Karnovsky's fixative.
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Colorantes , Fagopyrum , Compuestos Férricos , Tetróxido de Osmio , Cloruros , Cloruro de Tolonio , Fijadores , Fijación del Tejido , Técnicas de Cultivo de Célula , Hierro , OsmioRESUMEN
A series of new chelating bidentate (SS) alkylimidazole-2-thione-Ru(II)/Os(II) complexes (3ai, 3aii, 3aiii, 3bii/4aiii, 4bi, 4bii), and the tridentate (SNS) pyridine-2,6-diylimidazole-2-thione-Ru(II)/Os(II) complexes (5bi, 5civ/6bi, 6ci, 6civ) in the forms [MII(cym)(L)Cl]PF6 and [MII(cym)(L)]PF6 (M = Ru or Os, cym = η6-p-cymene, and L = heterocyclic derivatives of thiourea) respectively, were successfully synthesized. Spectroscopic and analytical methods were used to characterize the complexes and their ligands. Solid-state single-crystal X-ray diffraction analyses revealed a "piano-stool" geometry around the Ru(II) or Os(II) centers in the respective complexes. The complexes were investigated for in vitro chemotherapeutic activities against human cervical carcinoma (HeLa) and the non-cancerous cell line (Hek293) using the MTT assay. The compounds 3aii, 5civ, 5bi, 4aiii, 6ci, 6civ, and the reference drug, 5-fluorouracil were found to be selective toward the tumor cells; the compounds 3ai, 3aiii, 3bii, 4bi, 4bii, and 6bi, which were found not to be selective between normal and tumor cell lines. The IC50 value of the tridentate half-sandwich complex 5bi (86 ± 9 µM) showed comparable anti-proliferative activity with the referenced commercial anti-cancer drug, 5-fluorouracil (87 ± 15 µM). The pincer (SNS) osmium complexes 6ci (36 ± 10 µM) and 6civ (40 ± 4 µM) were twice as effective as the reference drug 5-fluorouracil at the respective dose concentrations. However, the analogous pincer (SNS) ruthenium complex 5civ was ineffective and did not show anti-proliferative activity, even at a higher concentration of 147 ± 1 µM. These findings imply that the higher stability of the chelating (SS) and the pincer (SNS) ligand architectures in the complexes improves the biological (anti-proliferative) activity of the complexes by reducing the chance of ligand dissociation under physiological conditions. In general, the pincer (SNS) osmium complexes were found to be more cytotoxic than their ruthenium analogues, suggesting that the anti-proliferative activity of the imidazole-2-thione-Ru/Os complexes depends on the ligand's spatial coordination, the nature of the metal center, and the charge of the metal complex ions.
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Antineoplásicos , Complejos de Coordinación , Cimenos , Rutenio , Humanos , Rutenio/química , Osmio , Ligandos , Células HEK293 , Tionas , Quelantes/química , Antineoplásicos/química , Complejos de Coordinación/química , Línea Celular Tumoral , FluorouraciloRESUMEN
Acute kidney injury (AKI) is a common adverse event in chemotherapy patients. AKI is accompanied by the generation of reactive oxygen species (ROS) and inflammation. Therefore, the management of ROS and inflammation is a potential strategy for AKI mitigation. Herein, polyethylene glycol-coated osmium nanozyme-based antidotes (Os) are developed for imaging-guided photothermal therapy (PTT) in combination with cisplatin (Pt); while, avoiding AKI induced by high-dose Pt. Os nanoantidotes can enhance the efficiency of tumor treatment during combined PTT and chemotherapy and inhibit tumor metastasis by improving the hypoxic and inflammatory tumor microenvironment. Os nanoantidotes preferentially accumulate in the kidney because of their 2-nm size distribution; and then, regulate inflammation by scavenging ROS and generating oxygen to alleviate Pt-induced AKI. Os nanoantidotes can be cleared from the kidneys by urine excretion but can be degraded under hydrogen peroxide stimulation, reducing the bio-retention of these compounds. By integrating PTT with inflammatory regulation, Os nanoantidotes have the potential to reduce the side effects of chemotherapy, offering an alternative route for the clinical management of cancer patients with chemotherapy-induced AKI.
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Lesión Renal Aguda , Antineoplásicos , Neoplasias , Humanos , Osmio/efectos adversos , Especies Reactivas de Oxígeno/metabolismo , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/patología , Neoplasias/patología , Inflamación , Línea Celular Tumoral , Microambiente TumoralRESUMEN
The activation of inert CâH bonds by transition metals is of considerable industrial and academic interest, but important gaps remain in our understanding of this reaction. We report the first experimental determination of the structure of the simplest hydrocarbon, methane, when bound as a ligand to a homogenous transition metal species. We find that methane binds to the metal center in this system through a single M···H-C bridge; changes in the 1JCH coupling constants indicate clearly that the structure of the methane ligand is significantly perturbed relative to the free molecule. These results are relevant to the development of better CâH functionalization catalysts.
Asunto(s)
Metano , Osmio , Ligandos , MetalesRESUMEN
Biological nanoparticles, such as bacterial outer membrane vesicles (OMVs), are routinely characterized through transmission electron microscopy (TEM). In this study, we report a novel method to prepare OMVs for TEM imaging. To preserve vesicular shape and structure, we developed a dual fixation protocol involving osmium tetroxide incubation prior to negative staining with uranyl acetate. Combining osmium tetroxide with uranyl acetate resulted in preservation of sub-50 nm vesicles and improved morphological stability, enhancing characterization of lipid-based nanoparticles by TEM.
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Colorantes , Tetróxido de Osmio , Microscopía Electrónica , Membrana Externa Bacteriana , Microscopía Electrónica de Transmisión , Coloración y Etiquetado , OsmioRESUMEN
We present the synthesis and characterization of six new heteroleptic osmium(II) complexes of the type [Os(C^N)(N^N)2]OTf (N^N = 2,2'-bipyridine and dipyrido[3,2-d:2',3'-f]quinoxaline; C^N = deprotonated methyl 1-butyl-2aryl-benzimidazolecarboxylate) with varying substituents in the R3 position of the phenyl ring of the cyclometalating C^N ligand. The new compounds are highly kinetically inert and absorb a full-wavelength range of visible light. An investigation of the antiproliferative activity of the new compounds has been performed using a panel of human cancer and noncancerous 2D cell monolayer cultures under dark conditions and green light irradiation. The results demonstrate that the new Os(II) complexes are markedly more potent than conventional cisplatin. The promising antiproliferative activity of selected Os(II) complexes was also confirmed using 3D multicellular tumor spheroids, which have the characteristics of solid tumors and can mimic the tumor tissue microenvironment. The mechanism of antiproliferative action of complexes has also been investigated and revealed that the investigated Os(II) complexes activate the endoplasmic reticulum stress pathway in cancer cells and disrupt calcium homeostasis.
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Antineoplásicos , Complejos de Coordinación , Neoplasias , Humanos , Relación Estructura-Actividad , Osmio/farmacología , Calcio , Línea Celular Tumoral , Bencimidazoles/farmacología , Homeostasis , Antineoplásicos/farmacología , Complejos de Coordinación/farmacologíaRESUMEN
Five osmium(II) polypyridyl complexes of the general formula [Os(4,7-diphenyl-1,10-phenanthroline)2 L]2+ were synthesized as photosensitizers for photodynamic therapy by varying the nature of the ligand L. Thanks to the pronounced π-extended structure of the ligands and the heavy atom effect provided by the osmium center, these complexes exhibit a high absorption in the near-infrared (NIR) region (up to 740â nm), unlike related ruthenium complexes. This led to a promising phototoxicity in vitro against cancer cells cultured as 2D cell layers but also in multicellular tumor spheroids upon irradiation at 740â nm. The complex [Os(4,7-diphenyl-1,10-phenanthroline)2 (2,2'-bipyridine)]2+ was found to be the most efficient against various cancer cell lines, with high phototoxicity indexes. Experiments on CT26 tumor-bearing BALB/c mice also indicate that the OsII complexes could significantly reduce tumor growth following 740â nm laser irradiation. The high phototoxicity in the biological window of this structurally simple complex makes it a promising photosensitizer for cancer treatment.
Asunto(s)
Complejos de Coordinación , Neoplasias , Fotoquimioterapia , Rutenio , Animales , Ratones , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Fármacos Fotosensibilizantes/química , Osmio/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/uso terapéutico , Complejos de Coordinación/química , Neoplasias/tratamiento farmacológico , Rutenio/farmacología , Rutenio/químicaRESUMEN
Humans exploit heavy metals for various industrial and economic reasons. Although some heavy metals are essential for normal physiology, others such as Tellurium (Te), Thallium (TI), antimony (Sb), and Osmium (Os) are highly toxic and can lead to Polycystic Ovarian Syndrome (PCOS), a common female factor of infertility. The current study was undertaken to determine levels of the heavy metals TI, Te, Sb and Os in serum of PCOS females (n = 50) compared to healthy non-PCOS controls (n = 56), and to relate such levels with Total Antioxidant Capacity (TAC), activity of key antioxidant enzymes, oxidative stress marker levels and redox status. PCOS serum samples demonstrated significantly higher levels of TI, Te, Sb and Os and diminished TAC compared to control (p < 0.001). Furthermore, there was significant inhibition of SOD, CAT and several glutathione-related enzyme activities in sera of PCOS patients with concurrent elevations in superoxide anions, hydrogen and lipid peroxides, and protein carbonyls, along with disrupted glutathione homeostasis compared to those of controls (p < 0.001 for all parameters). Additionally, a significant negative correlation was found between the elevated levels of heavy metals and TAC, indicative of the role of metal-induced oxidative stress as a prominent phenomenon associated with the pathophysiology of the underlying PCOS. Data obtained in the study suggest toxic metals as risk factors causing PCOS, and thus protective measures should be considered to minimize exposure to prevent such reproductive anomalies.
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Metales Pesados , Síndrome del Ovario Poliquístico , Humanos , Femenino , Antioxidantes/metabolismo , Síndrome del Ovario Poliquístico/metabolismo , Antimonio , Telurio , Talio , Osmio , Estrés Oxidativo , Oxidación-Reducción , Glutatión/metabolismoRESUMEN
Nanoformulation of an osmium photosensitizer within liposomes and micelles is used to improve the water-solubility of this highly lipophilic molecule. This highlight report describes a recent paper by Cameron, Obaid and McFarland on this topic and discusses the context for this report. Nanoformulation has been explored as a strategy before, but this represents the first usage of this strategy with highly potent metal-based photosensitizers having phototherapeutic indices (PIs) in excess of 104 . The nanoformulation strategy is effective due to reducing aggregation and self-quenching of the photosensitizer molecules.
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Liposomas , Fotoquimioterapia , Micelas , Fármacos Fotosensibilizantes , Osmio , Reproducibilidad de los ResultadosRESUMEN
Osmium (Os) based photosensitizers (PSs) are a unique class of nontetrapyrrolic metal-containing PSs that absorb red light. We recently reported a highly potent Os(II) PS, rac-[Os(phen)2 (IP-4T)](Cl)2 , referred to as ML18J03 herein, with light EC50 values as low as 20 pm. ML18J03 also exhibits low dark toxicity and submicromolar light EC50 values in hypoxia in some cell lines. However, owing to its longer oligothiophene chain, ML18J03 is not completely water soluble and forms 1-2 µm sized aggregates in PBS containing 1% DMSO. This aggregation causes variability in PDT efficacy between assays and thus unreliable and irreproducible reports of in vitro activity. To that end, we utilized PEG-modified DPPC liposomes (138 nm diameter) and DSPE-mPEG2000 micelles (10.2 nm diameter) as lipid nanoformulation vehicles to mitigate aggregation of ML18J03 and found that the spectroscopic properties important to biological activity were maintained or improved. Importantly, the lipid formulations decreased the interassay variance between the EC50 values by almost 20-fold, with respect to the unformulated ML18J03 when using broadband visible light excitation (P = 0.0276). Herein, lipid formulations are presented as reliable platforms for more accurate in vitro photocytotoxicity quantification for PSs prone to aggregation (such as ML18J03) and will be useful for assessing their in vivo PDT effects.
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Fotoquimioterapia , Fármacos Fotosensibilizantes , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Osmio , Luz , Liposomas/química , LípidosRESUMEN
G-quadruplexes are emerging targets in cancer research and understanding how diagnostic probes bind to DNA G-quadruplexes in solution is critical to the development of new molecular tools. In this study the binding of an enantiopure NIR emitting [Os(TAP)2 (dppz)]2+ complex to different G-quadruplex structures formed by human telomer (hTel) and cMYC sequences in solution is reported. The combination of NMR and time-resolved infrared spectroscopic techniques reveals the sensitivity of the emission response to subtle changes in the binding environment of the complex. Similar behaviour is also observed for the related complex [Os(TAP)2 (dppp2)]2+ upon quadruplex binding.
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G-Cuádruplex , Osmio , Humanos , ADN/química , Espectroscopía de Resonancia Magnética/métodos , Imagen por Resonancia MagnéticaRESUMEN
Postfixation with osmium tetroxide and Epon embedding are essential for the preservation and visualization of subcellular ultrastructures via electron microscopy. These chemical treatments diminish the fluorescent intensity of most fluorescent proteins in cells, creating a problem for the in-resin correlative light-electron microscopy (CLEM) of Epon-embedded mammalian cultured cells. We found that two green and two far-red fluorescent proteins retain their fluorescence after chemical fixation with glutaraldehyde, osmium tetroxide-staining, dehydration, and polymerization of Epon resins. Consequently, we could observe the fluorescence of fluorescent proteins in ultrathin sections of Epon-embedded cells via fluorescence microscopy, investigate ultrastructures of the cells in the same sections via electron microscopy, and correlate the fluorescent image with the electron microscopic image without chemical or physical distortion of the cells. In other words, referred as "in-resin CLEM" of Epon-embedded samples. This technique also improves the Z-axis resolution of fluorescent images. In this chapter, we introduce the detailed protocol for in-resin CLEM of Epon-embedded mammalian cultured cells using these fluorescent proteins.
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Tetróxido de Osmio , Osmio , Animales , Células Cultivadas , Electrones , Glutaral , Mamíferos , Microscopía ElectrónicaRESUMEN
Transmission electron microscopy and the use of glutaraldehyde-osmium fixation allow to distinguish norepinephrine from epinephrine granules in the adrenochromaffin cells, a difficult distinction with histochemical methods if both types of granules are present in the same cell. Here we describe all the steps necessary to process the adrenochromaffin tissue for the transmission electron microscopy; this protocol is suitable for any kind of adrenal tissue, and personally we used it in mammals, reptiles, and amphibians.
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Médula Suprarrenal , Células Cromafines , Médula Suprarrenal/metabolismo , Animales , Células Cromafines/metabolismo , Epinefrina/metabolismo , Glutaral , Mamíferos/metabolismo , Microscopía Electrónica de Transmisión , Norepinefrina , OsmioRESUMEN
The concentrations of specific macromolecular species can be quantified using diagnostic tools that rely on molecular recognition by nucleic acid aptamers. One such approach involves the formation of osmium tetroxide 2,2'-bipyridine protein adducts, followed by electrochemical detection of analytes that bind specifically to electrode-tethered aptamers. In conjunction with a 27-mer DNA aptamer that binds specifically to exosite II on human alpha thrombin, this technique permits, in theory, a highly sensitive diagnostic tool for the quantification of serum thrombin levels. However, thrombin's aptamer binding site is lined by two tryptophan residues and the conjugation of bulky osmium groups to these residues weakens aptamer binding by an estimated 4 to 12 kcal/mol, undermining detection sensitivity. Therefore, we have rationally modified this DNA aptamer to strengthen its thrombin binding in the presence of conjugated osmium. Specifically, aptamers carrying long hydrophobic thymine derivatives in place of guanine 21 have binding affinities for osmium-conjugated thrombin that are enhanced by 10 to 15 kcal/mol, suggesting that these modified aptamers may be effective in a highly sensitive electrochemical sensor for the quantification of low concentrations of thrombin. Our approach of using molecular simulation to subtly re-engineer a DNA aptamer may be generally applicable for the optimization of other macromolecular binding interfaces.Communicated by Ramaswamy H. Sarma.
Asunto(s)
Aptámeros de Nucleótidos , Humanos , Aptámeros de Nucleótidos/química , Trombina/química , Osmio , Simulación por Computador , Sitios de UniónRESUMEN
OBJECTIVE: To study the impact of heavy metals especially tellurium, thallium, and osmium, in recurrent pregnancy loss (RPL) and to study their association with antioxidant status and DNA damage. METHODS: This case-control study included women with RPL (n = 30) and healthy pregnant women as control (n = 30). Following blood collection, serum levels of thallium, tellurium, osmium, lead, mercury, and cadmium were estimated by inductively coupled plasma mass spectrophotometer. RESULTS: Women with RPL exhibited significantly higher levels of heavy metals (P < 0.001) when compared with control women. Intriguingly, increased levels of serum thallium, tellurium, osmium, and lead were negatively correlated with total antioxidant status (P < 0.05). Further, the RPL group demonstrated strong positive correlation between heavy metals (thallium, tellurium, osmium, lead) and DNA damage (P < 0.05). No significant correlation between other heavy metals and markers of cellular damage was noted. CONCLUSION: Enhanced levels of heavy metals in women with RPL and correlation of thallium, tellurium, osmium, and lead with markers of cellular damage reflect the role of heavy metal poisoning, especially thallium, tellurium, and osmium, as potential risk factor in the etiology underlying recurrent miscarriage.
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Metales Pesados , Talio , Femenino , Humanos , Embarazo , Telurio , Osmio , Antioxidantes , Estudios de Casos y Controles , Metales Pesados/efectos adversosRESUMEN
Influence of the metal center on hydrolysis of organometallic anticancer complexes containing an N-phenyl-2-pyridinecarbothioamide (PCA) ligand, [M(η6-p-cymene)(N-phenyl-2-pyridinecarbothioamide)Cl]+ (M = RuII, 1A, and OsII, 2A), as well as their N-fluorophenyl derivatives [M(η6-p-cymene)(N-fluorophenyl-2-pyridinecarbothioamide)Cl]+ (M = RuII, 1B, and OsII, 2B) have been investigated using the DFT method in aqueous medium. The activation energy barriers for the hydrolysis of 1A (21.5 kcal/mol) and 1B (20.7 kcal/mol) are found to be significantly lower than those of their corresponding osmium analogs 2A (28.6 kcal/mol) and 2B (27.5 kcal/mol). DFT evaluated results reveal the inertness of Os(II)-PCA complex toward the hydrolysis that rationalizes the experimental observations. However, the incorporation of fluoride substituent slightly decreases the activation energy for the hydrolysis of Ru(II)- and Os(II)-PCA. In addition, the interaction of hydrolyzed Ru(II)-PCAs (1AH and 1BH) and Os(II)-PCAs (2AH and 2BH) complexes with the histidine (Hist) have also been investigated. The aquated 1BH and 2BH show an enhanced propensity toward the interaction with histidine, and their activation Gibbs free energies are calculated to be 15.9 and 18.9 kcal/mol, respectively. ONIOM (QM/MM) study of the resulting aquated complexes inside histone protein shows the maximum stability of the 2BH complex having a binding energy of -43.6 kcal/mol.
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Antineoplásicos , Compuestos Organometálicos , Rutenio , Osmio/química , Rutenio/química , Histidina , Hidrólisis , Antineoplásicos/farmacología , Antineoplásicos/química , Compuestos Organometálicos/químicaRESUMEN
Interest in the third-row transition metal osmium and its compounds as potential anticancer agents has grown in recent years. Here, we synthesized the osmium(VI) nitrido complex Na[OsVI(N)(tpm)2] (tpm = [5-(Thien-2-yl)-1H-pyrazol-3-yl]methanol), which exhibited a greater inhibitory effect on the cell viabilities of the cervical, ovarian, and breast cancer cell lines compared with cisplatin. Proteomics analysis revealed that Na[OsVI(N)(tpm)2] modulates the expression of protein-transportation-associated, DNA-metabolism-associated, and oxidative-stress-associated proteins in HepG2 cells. Perturbation of protein expression activity by the complex in cancer cells affects the functions of the mitochondria, resulting in high levels of cellular oxidative stress and low rates of cell survival. Moreover, it caused G2/M phase cell cycle arrest and caspase-mediated apoptosis of HepG2 cells. This study reveals a new high-valent osmium complex as an anticancer agent candidate modulating protein homeostasis.