RESUMEN
Here, we have synthesized and characterized three visible light responsive terpyridine based-Re(I)-tricarbonyl complexes; [Re(CO)3(ph-tpy)Cl] (Retp1), [Re(CO)3(an-tpy)Cl] (Retp2), and [Re(CO)3(py-tpy)Cl] (Retp3) where ph-tpy = 4'-phenyl-2,2':6',2â³-terpyridine; an-tpy = 4'-anthracenyl-2,2':6',2â³-terpyridine, py-tpy = 4'-pyrenyl-2,2':6',2â³-terpyridine. The structures of Retp1 and Retp2 were confirmed from the SC-XRD data, indicating distorted octahedral structures. Unlike traditional PDT agents, these complexes generated reactive oxygen species (ROS) via type I and type II pathways and oxidized redox crucial NADH (reduced nicotinamide adenine dinucleotide) upon visible light exposure. Retp3 showed significant mitochondrial localization and demonstrated photoactivated anticancer activity (IC50 â¼ 2 µM) by inducing ROS-mediated cell death in cancer cells selectively (photocytotoxicity Index, PI > 28) upon compromising mitochondrial function in A549 cells. Their diagnostic capabilities were ultimately assessed using clinically relevant 3D multicellular tumor spheroids (MCTs).
Asunto(s)
Antineoplásicos , Complejos de Coordinación , NAD , Oxidación-Reducción , Piridinas , Especies Reactivas de Oxígeno , Renio , Humanos , Especies Reactivas de Oxígeno/metabolismo , NAD/química , NAD/metabolismo , Piridinas/química , Piridinas/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Renio/química , Renio/farmacología , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/síntesis química , Luz , Ensayos de Selección de Medicamentos Antitumorales , Fotoquimioterapia , Estructura Molecular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células A549 , Línea Celular TumoralRESUMEN
Microbes possessing electron transfer capabilities hold great promise for remediating subsurface contaminated by redox-active radionuclides such as technetium-99 (99TcO4-) through bio-transformation of soluble contaminants into their sparingly soluble forms. However, the practical application of this concept has been impeded due to the low electron transfer efficiency and long-term product stability under various biogeochemical conditions. Herein, we proposed and tested a pyrite-stimulated bio-immobilization strategy for immobilizing ReO4- (a nonradioactive analogue of 99TcO4-) using sulfate-reducing bacteria (SRB), with a focus on pure-cultured Desulfovibrio vulgaris. Pyrite acted as an effective stimulant for the bio-transformation of ReO4-, boosting the removal rate of ReO4- (50 mg/L) in a solution from 2.8 % (without pyrite) to 100 %. Moreover, the immobilized products showed almost no signs of remobilization during 168 days of monitoring. Dual lines of evidence were presented to elucidate the underlying mechanisms for the pyrite-enhanced bio-activity. Transcriptomic analysis revealed a global upregulation of genes associated with electron conductive cytochromes c network, extracellular tryptophan, and intracellular electron transfer units, leading to enhanced ReO4- bio-reduction. Spectroscopic analysis confirmed the long-term stability of the bio-immobilized products, wherein ReO4- is reduced to stable Re(IV) oxides and Re(IV) sulfides. This work provides a novel green strategy for remediation of radionuclides- or heavy metals-contaminated sites.
Asunto(s)
Sulfuros , Sulfuros/química , Renio/química , Oxidación-Reducción , Hierro/química , Biodegradación Ambiental , Desulfovibrio vulgarisRESUMEN
Cancer is a leading cause of death worldwide, accounting for about one among six deaths, so the quest for new and improved therapies is of crucial importance. The discovery of cisplatin as an anticancer agent has paved the way for the development of other metal-based therapeutic agents and Re(I)-based candidates have been recently found to show promising results. It is known as well that chirality plays a central role in the interactions of metal-based drugs with intrinsically chiral biomolecules such as membrane transport proteins or DNA. To further exploit this property, we have developed a series of diastereomeric dinuclear Re(I) complexes with chiral ligands containing pinene-bipyridine units. These complexes offer unique insights into the relation between stereochemistry and biological activity. Single-crystal X-ray diffraction studies, spectroscopic analysis, including UV-Vis and circular dichroism (CD), confirmed the chiral structures of these complexes. Biological activity assessments were carried out against various cancer cell lines, with a particular focus on breast and colon cancer. The diastereomers exhibited distinct anticancer activities, with some displaying promising results. Notably, one diastereomer showed exceptional cytotoxicity against HCT116 and MCF-7 cancer cells. This research underscores the significance of chirality in the design of novel anticancer agents, providing insights into the potential of dinuclear Re(I) complexes as effective candidates for cancer treatment.
Asunto(s)
Antineoplásicos , Complejos de Coordinación , Renio , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/síntesis química , Estereoisomerismo , Renio/química , Renio/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Estructura Molecular , Supervivencia Celular/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
The Re(I) organometallic compounds [(Re(CO)3L1-6 )Cl], where Ligand(L) = Tryptanthrin derivatives were prepared and characterized by various spectroscopic techniques. To assess the binding capacities and binding manner, tests of Calf thymus DNA under the impact of organometallic complexes were conducted using absorption titration and viscosity measuring techniques. Data from the research mentioned above point to an intercalation type of binding, which was verified by the docking study. Swiss ADME tools carried out an ADME study. The work focuses on computing the molecular orbital energies for the synthesized compounds using the density functional theory (DFT). The compounds were tested against the MCF-7 cell line to determine their anticancer effects. It was observed that their IC50 values were equivalent to those of the standard medication, indicating that they had a similar antiproliferative impact.
Asunto(s)
Antineoplásicos , Renio , Renio/química , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Células MCF-7 , Proliferación Celular/efectos de los fármacos , Compuestos Organometálicos/farmacología , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Simulación del Acoplamiento Molecular , ADN/metabolismo , Complejos de Coordinación/farmacología , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Ensayos de Selección de Medicamentos Antitumorales , Teoría Funcional de la Densidad , Bovinos , Quinazolinonas/síntesis química , Quinazolinonas/farmacología , Quinazolinonas/química , Estructura Molecular , Animales , Indoles/farmacología , Indoles/química , Indoles/síntesis químicaRESUMEN
Benchtop 99Mo/99mTc and 188W/188Re generators enable economical production of molecular theranostic 99mTc and 188Re radiopharmaceuticals, provided that simple, kit-based chemistry exists to radiolabel targeting vectors with these radionuclides. We have previously described a diphosphine platform that efficiently incorporates 99mTc into receptor-targeted peptides. Here, we report its application to label a prostate-specific membrane antigen (PSMA)-targeted peptide with 99mTc and 188Re for diagnostic imaging and systemic radiotherapy of prostate cancer. Methods: Two diphosphine-dipeptide bioconjugates, DP1-PSMAt and DP2-PSMAt, were formulated into kits for radiolabeling with 99mTc and 188Re. The resulting radiotracers were studied in vitro, in prostate cancer cells, and in vivo in mouse xenograft models, to assess similarity of uptake and biodistribution for each 99mTc/188Re pair of agents. Results: Both DP1-PSMAt and DP2-PSMAt could be efficiently radiolabeled with 99mTc and 188Re using kit-based methods to furnish the isostructural compounds M-DP1-PSMAt and M-DP2-PSMAt (M = [99mTc]Tc, [188Re]Re). All 99mTc/188Re radiotracers demonstrated specific uptake in PSMA-expressing prostate cancer cells, with negligible uptake in prostate cancer cells that did not express PSMA or in which PSMA uptake was blocked. M-DP1-PSMAt and M-DP2-PSMAt also exhibited high tumor uptake (18-30 percentage injected dose per gram at 2 h after injection), low retention in nontarget organs, fast blood clearance, and excretion predominantly via a renal pathway. Importantly, each pair of 99mTc/188Re radiotracers showed near-identical biologic behavior in these experiments. Conclusion: We have prepared and developed novel pairs of isostructural PSMA-targeting 99mTc/188Re theranostic agents. These generator-based theranostic agents have potential to provide access to the benefits of PSMA-targeted diagnostic imaging and systemic radiotherapy in health care settings that do not routinely have access to either reactor-produced 177Lu radiopharmaceuticals or PET/CT infrastructure.
Asunto(s)
Neoplasias de la Próstata , Radioisótopos , Renio , Tecnecio , Masculino , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/radioterapia , Neoplasias de la Próstata/metabolismo , Ratones , Renio/química , Animales , Humanos , Tecnecio/química , Radioisótopos/química , Línea Celular Tumoral , Distribución Tisular , Glutamato Carboxipeptidasa II/metabolismo , Antígenos de Superficie/metabolismo , Radiofármacos/química , Radiofármacos/farmacocinética , Nanomedicina Teranóstica , Péptidos/química , Medicina de PrecisiónRESUMEN
The toxicity profile of fac-[Re(CO)3(N-N)L]+ complexes against microbial and tumoral cells has been extensively studied, primarily focusing on modifications to the bidentate diimine (N-N) ligand. However, less attention has been paid to modifications of the axial ligand L, which is perpendicular to the Re-N-N plane. This study reveals that the high toxicity of the fac-[Re(CO)3(bpy)(Ctz)]+ complex may be attributed to the structural effect of the trityl (CPh3) group present in clotrimazole, as removal of phenyl rings causes a significant decrease in the activity against Staphylococcus aureus (S. aureus). Moreover, substitution of the 1-tritylimidazole ligand by the structurally related ligands PPh3 and PCy3 maintains similarly high activity levels. These findings contribute to understanding the interactions of toxic complexes with bacterial membranes, suggesting that the ligand structures play a crucial role in inhibiting cell wall synthesis processes, potentially including Lipid II synthesis. Compounds with Ph3E (E = C-imidazole; P) groups also showed to be 10 times more toxic than cisplatin against three mammalian cell lines (IC50: 2-4 µM). In contrast, the analogue 1-benzylimidazole and 1-tert-butylimidazole derivatives were as toxic as cisplatin. We observed that the decomposition of the [Re(I)(CO)3] fragment inside mammalian cell lines liberates CO, which is expected to exert biological effects. Therefore, compounds of this family possessing the structural motif Ph3E seem to combine high antimicrobial and antitumoral activities, the latter being much higher than that of cisplatin.
Asunto(s)
Antineoplásicos , Monóxido de Carbono , Complejos de Coordinación , Pruebas de Sensibilidad Microbiana , Renio , Staphylococcus aureus , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Staphylococcus aureus/efectos de los fármacos , Monóxido de Carbono/química , Monóxido de Carbono/farmacología , Renio/química , Renio/farmacología , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Línea Celular Tumoral , Estructura Molecular , Ligandos , Ensayos de Selección de Medicamentos Antitumorales , Supervivencia Celular/efectos de los fármacos , Relación Estructura-Actividad , Proliferación Celular/efectos de los fármacosRESUMEN
Pertechnetate (99TcO4-), a physiologically toxic radioactive anion, is of great concern due to its high mobility in environmental contamination remediation. Although the soluble oxyanion can be photoreduced to sparingly soluble TcO2·nH2O, its effective removal from a strongly acidic aqueous solution remains a challenge. Here, we found that low-crystalline nitrogen-doped titanium oxide (N-TiO2, 0.6 g L-1) could effectively uptake perrhenate (ReO4-, 10 mg L-1, a nonradioactive surrogate for TcO4-) with 50.8% during 360 min under simulated sunlight irradiation at pH 1.0, but P25 and anatase could not. The nitrogen active center formed by trace nitrogen doping in N-TiO2 can promote the separation and transfer of photogenerated carriers. The positive valence band value of N-TiO2 is slightly higher than those of P25 and anatase, which means that the photogenerated holes have a stronger oxidizability. These holes are involved in the formation of strong reducing â¢CO2- radicals from formic acid oxidation. The active radicals convert ReO4- to Re(VI), which is subsequently disproportionated to Re(IV) and Re(VII). Effective photocatalytic reduction/removal of Re(VII)/Tc(VII) is performed on the material, which may be considered a potential and convenient strategy for technetium decontamination and extraction in a strongly acidic aqueous solution.
Asunto(s)
Titanio , Catálisis , Titanio/química , Oxidación-Reducción , Renio/química , Agua/química , Concentración de Iones de Hidrógeno , SolucionesRESUMEN
Rhenium complexes show great promise as anticancer drug candidates. Specifically, compounds with a Re(CO)3(NN)(py)+ core in their architecture have shown cytotoxicity equal to or greater than that of well-established anticancer drugs based on platinum or organic molecules. This study aimed to evaluate how the strength of the interaction between rhenium(I) tricarbonyl complexes fac-[Re(CO)3(NN)(py)]+, NN = 1,10-phenanthroline (phen), dipyrido[3,2-f:2',3'-h]quinoxaline (dpq) or dipyrido[3,2-a:2'3'-c]phenazine (dppz) and biomolecules (protein, lipid and DNA) impacted the corresponding cytotoxic effect in cells. Results showed that fac-[Re(CO)3(dppz)(py)]+ has higher Log Po/w and binding constant (Kb) with biomolecules (protein, lipid and DNA) compared to complexes of fac-[Re(CO)3(phen)(py)]+ and fac-[Re(CO)3(dpq)(py)]+. As consequence, fac-[Re(CO)3(dppz)(py)]+ exhibited the highest cytotoxicity (IC50 = 8.5 µM for HeLa cells) for fac-[Re(CO)3(dppz)(py)]+ among the studied compounds (IC50 > 15 µM). This highest cytotoxicity of fac-[Re(CO)3(dppz)(py)]+ are probably related to its lipophilicity, higher permeation of the lipid bilayers of cells, and a more potent interaction of the dppz ligand with biomolecules (protein and DNA). Our findings open novel avenues for rational drug design and highlight the importance of considering the chemical structures of rhenium complexes that strongly interact with biomolecules (proteins, lipids, and DNA).
Asunto(s)
Antineoplásicos , Complejos de Coordinación , ADN , Renio , Renio/química , Humanos , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , ADN/química , ADN/metabolismo , Fenantrolinas/química , Fenantrolinas/farmacología , Quinoxalinas/química , Quinoxalinas/farmacología , Fenazinas/química , Fenazinas/farmacología , Línea Celular Tumoral , Células HeLaRESUMEN
A stimuli-responsive drug delivery nanocarrier with a core-shell structure combining photothermal therapy and chemotherapy for killing cancer cells was constructed in this study. The multifunctional nanocarrier ReS2@mSiO2-RhB entails an ReS2 hierarchical nanosphere coated with a fluorescent mesoporous silica shell. The three-dimensional hierarchical ReS2 nanostructure is capable of effectively absorbing near-infrared (NIR) light and converting it into heat. These ReS2 nanospheres were generated by a hydrothermal synthesis process leading to the self-assembly of few-layered ReS2 nanosheets. The mesoporous silica shell was further coated on the surface of the ReS2 nanospheres through a surfactant-templating sol-gel approach to provide accessible mesopores for drug uploading. A fluorescent dye (Rhodamine B) was covalently attached to silica precursors and incorporated during synthesis in the mesoporous silica walls toward conferring imaging capability to the nanocarrier. Doxorubicin (DOX), a known cancer drug, was used in a proof-of-concept study to assess the material's ability to function as a drug delivery carrier. While the silica pores are not capped, the drug molecule loading and release take advantage of the pH-governed electrostatic interactions between the drug and silica wall. The ReS2@mSiO2-RhB enabled a drug loading content as high as 19.83 mg/g doxorubicin. The ReS2@mSiO2-RhB-DOX nanocarrier's cumulative drug release rate at pH values that simulate physiological conditions showed significant pH responsiveness, reaching 59.8% at pH 6.8 and 98.5% and pH 5.5. The in vitro testing using HeLa cervical cancer cells proved that ReS2@mSiO2-RhB-DOX has a strong cancer eradication ability upon irradiation with an NIR laser owing to the combined drug delivery and photothermal effect. The results highlight the potential of ReS2@mSiO2-RhB nanoparticles for combined cancer therapy in the future.
Asunto(s)
Doxorrubicina , Liberación de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Ensayo de Materiales , Nanopartículas , Tamaño de la Partícula , Terapia Fototérmica , Renio , Dióxido de Silicio , Dióxido de Silicio/química , Humanos , Doxorrubicina/farmacología , Doxorrubicina/química , Concentración de Iones de Hidrógeno , Nanopartículas/química , Renio/química , Renio/farmacología , Disulfuros/química , Porosidad , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Materiales Biocompatibles/síntesis química , Supervivencia Celular/efectos de los fármacos , Antineoplásicos/química , Antineoplásicos/farmacología , Portadores de Fármacos/química , Células HeLaRESUMEN
Analogous to thermal ablation techniques in clinical settings, cell necrosis induced during tumor photothermal therapy (PTT) can provoke an inflammatory response that is detrimental to the treatment of tumors. In this study, we employed a straightforward one-step liquid-phase reduction process to synthesize uniform RhRe nanozymes with an average hydrodynamic size of 41.7 nm for non-inflammatory photothermal therapy. The obtained RhRe nanozymes showed efficient near-infrared (NIR) light absorption for effective PTT, coupled with a remarkable capability to scavenge reactive oxygen species (ROS) for anti-inflammatory treatment. After laser irradiation, the 4T1 tumors were effectively ablated without obvious tumor recurrence within 14 days, along with no obvious increase in pro-inflammatory cytokine levels. Notably, these RhRe nanozymes demonstrated high biocompatibility with normal cells and tissues, both in vitro and in vivo, as evidenced by the lack of significant toxicity in female BALB/c mice treated with 10 mg/kg of RhRe nanozymes over a 14 day period. This research highlights RhRe alloy nanoparticles as bioactive nanozymes for non-inflammatory PTT in tumor therapy.
Asunto(s)
Aleaciones , Ratones Endogámicos BALB C , Terapia Fototérmica , Renio , Rodio , Animales , Rodio/química , Rodio/farmacología , Ratones , Aleaciones/química , Aleaciones/farmacología , Femenino , Renio/química , Renio/farmacología , Línea Celular Tumoral , Humanos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Herein, we have compared the effectivity of light-based photoactivated cancer therapy and ultrasound-based sonodynamic therapy with Re(I)-tricarbonyl complexes (Re1-Re3) against cancer cells. The observed photophysical and TD-DFT calculations indicated the potential of Re1-Re3 to act as good anticancer agents under visible light/ultrasound exposure. Re1 did not display any dark- or light- or ultrasound-triggered anticancer activity. However, Re2 and Re3 displayed concentration-dependent anticancer activity upon light and ultrasound exposure. Interestingly, Re3 produced 1O2 and OH⢠on light/ultrasound exposure. Moreover, Re3 induced NADH photo-oxidation in PBS and produced H2O2. To the best of our knowledge, NADH photo-oxidation has been achieved here with the Re(I) complex for the first time in PBS. Additionally, Re3 released CO upon light/ultrasound exposure. The cell death mechanism revealed that Re3 produced an apoptotic cell death response in HeLa cells via ROS generation. Interestingly, Re3 showed slightly better anticancer activity under light exposure compared to ultrasound exposure.
Asunto(s)
Antineoplásicos , Fenantrolinas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Ligandos , Células HeLa , Fenantrolinas/química , Fenantrolinas/farmacología , Renio/química , Renio/farmacología , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Complejos de Coordinación/efectos de la radiación , Apoptosis/efectos de los fármacos , Luz , Especies Reactivas de Oxígeno/metabolismo , Terapia por Ultrasonido , Fotoquimioterapia , Ensayos de Selección de Medicamentos Antitumorales , Neoplasias/tratamiento farmacológicoRESUMEN
Metal-based complexes with their unique chemical properties, including multiple oxidation states, radio-nuclear capabilities and various coordination geometries yield value as potential pharmaceuticals. Understanding the interactions between metals and biological systems will prove key for site-specific coordination of new metal-based lead compounds. This study merges the concepts of target coordination with fragment-based drug methodologies, supported by varying the anomalous scattering of rhenium along with infrared spectroscopy, and has identified rhenium metal sites bound covalently with two amino acid types within the model protein. A time-based series of lysozyme-rhenium-imidazole (HEWL-Re-Imi) crystals was analysed systematically over a span of 38 weeks. The main rhenium covalent coordination is observed at His15, Asp101 and Asp119. Weak (i.e. noncovalent) interactions are observed at other aspartic, asparagine, proline, tyrosine and tryptophan side chains. Detailed bond distance comparisons, including precision estimates, are reported, utilizing the diffraction precision index supplemented with small-molecule data from the Cambridge Structural Database. Key findings include changes in the protein structure induced at the rhenium metal binding site, not observed in similar metal-free structures. The binding sites are typically found along the solvent-channel-accessible protein surface. The three primary covalent metal binding sites are consistent throughout the time series, whereas binding to neighbouring amino acid residues changes through the time series. Co-crystallization was used, consistently yielding crystals four days after setup. After crystal formation, soaking of the compound into the crystal over 38 weeks is continued and explains these structural adjustments. It is the covalent bond stability at the three sites, their proximity to the solvent channel and the movement of residues to accommodate the metal that are important, and may prove useful for future radiopharmaceutical development including target modification.
Asunto(s)
Muramidasa , Compuestos Organometálicos , Renio , Renio/química , Muramidasa/química , Muramidasa/metabolismo , Compuestos Organometálicos/química , Compuestos Organometálicos/metabolismo , Desarrollo de Medicamentos/métodos , Cristalografía por Rayos X , Sitios de Unión , Complejos de Coordinación/química , Imidazoles/química , Imidazoles/metabolismo , Modelos MolecularesRESUMEN
Rhenium(I) tricarbonyl complexes are widely studied for their cell imaging properties and anti-cancer and anti-microbial activities, but the complexes with S-donor ligands remain relatively unexplored. A series of six fac-[Re(NN)(CO)3(SR)] complexes, where (NN) is 2,2'-bipyridyl (bipy) or 1,10-phenanthroline (phen), and RSH is a series of thiocarboxylic acid methyl esters, have been synthesized and characterized. Cellular uptake and anti-proliferative activities of these complexes in human breast cancer cell lines (MDA-MB-231 and MCF-7) were generally lower than those of the previously described fac-[Re(NN)(CO)3(OH2)]+ complexes; however, one of the complexes, fac-[Re(CO)3(phen)(SC(Ph)CH2C(O)OMe)] (3b), was active (IC50 â¼ 10 µM at 72 h treatment) in thiol-depleted MDA-MB-231 cells. Moreover, unlike fac-[Re(CO)3(phen)(OH2)]+, this complex did not lose activity in the presence of extracellular glutathione. Taken together these properties show promise for further development of 3b and its analogues as potential anti-cancer drugs for co-treatment with thiol-depleting agents. Conversely, the stable and non-toxic complex, fac-[Re(bipy)(CO)3(SC(Me)C(O)OMe)] (1a), predominantly localized in the lysosomes of MDA-MB-231 cells, as shown by live cell confocal microscopy (λex = 405 nm, λem = 470-570 nm). It is strongly localized in a subset of lysosomes (25 µM Re, 4 h treatment), as shown by co-localization with a Lysotracker dye. Longer treatment times with 1a (25 µM Re for 48 h) resulted in partial migration of the probe into the mitochondria, as shown by co-localization with a Mitotracker dye. These properties make complex 1a an attractive target for further development as an organelle probe for multimodal imaging, including phosphorescence, carbonyl tag for vibrational spectroscopy, and Re tag for X-ray fluorescence microscopy.
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Antineoplásicos , Proliferación Celular , Complejos de Coordinación , Renio , Azufre , Humanos , Renio/química , Renio/farmacología , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Ligandos , Azufre/química , Azufre/farmacología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Estructura MolecularRESUMEN
The hypoxic microenvironment of solid tumors severely lowers the efficacy of oxygen-dependent photodynamic therapy (PDT). The development of hypoxia-tolerant photosensitizers for PDT is an urgent requirement. In this study, a novel rhenium complex (Re-TTPY) to develop a "closed-loop" therapy based on PDT-induced ferroptosis and immune therapy is reported. Due to its electron donor-acceptor (D-A) structure, Re-TTPY undergoes energy transfer and electron transfer processes under 550 nm light irradiation and displays hypoxia-tolerant type I/II combined PDT capability, which can generate 1O2, O2 -, and ·OH simultaneously. Further, the reactive oxygen species (ROSs) leads to the depletion of 1,4-dihydronicotinamide adenine dinucleotide (NADH), glutathione peroxidase 4 (GPX4), and glutathione (GSH). As a result, ferroptosis occurs in cells, simultaneously triggers immunogenic cell death (ICD), and promotes the maturation of dendritic cells (DCs) and infiltration of T cells. The release of interferon-γ (IFN-γ) by CD8+ T cells downregulates the expression of GPX4, further enhancing the occurrence of ferroptosis, and thereby, forming a mutually reinforcing "closed-loop" therapeutic approach.
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Ferroptosis , Inmunoterapia , Fotoquimioterapia , Fármacos Fotosensibilizantes , Renio , Ferroptosis/efectos de los fármacos , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Animales , Ratones , Humanos , Inmunoterapia/métodos , Fotoquimioterapia/métodos , Renio/química , Renio/farmacología , Línea Celular Tumoral , Especies Reactivas de Oxígeno/metabolismo , Células Dendríticas/metabolismo , Células Dendríticas/efectos de los fármacos , Femenino , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Ratones Endogámicos C57BLRESUMEN
Cancer is one of the deadliest diseases worldwide. Chemotherapy remains one of the most dominant forms for anticancer treatment. Despite their clinical success, the used chemotherapeutic agents are associated with severe side effect and pharmacological limitations. To overcome these drawbacks there is a need for the development of new types of chemotherapeutic agents. Herein, the chemical synthesis and biological evaluation of dinuclear rhenium(I) complexes as potential chemotherapeutic drug candidates are proposed. The metal complexes were found to be internalized by an energy dependent endocytosis pathway, primary accumulating in the mitochondria. The rhenium(I) complexes demonstrated to induce cell death against a variety of cancer cells in the micromolar range through apoptosis. The lead compound showed to eradicate a pancreatic carcinoma multicellular tumor spheroid at micromolar concentrations.
Asunto(s)
Antineoplásicos , Apoptosis , Complejos de Coordinación , Renio , Renio/química , Humanos , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular/efectos de los fármacosRESUMEN
A series of rhenium(I) complexes of the type fac-[Re(CO)3(N^N)L]0/+, Re1-Re9, was synthesized, where N^N = benzimidazole-derived bidentate ligand with an ester functionality and L = chloride or pyridine-type ligand. The new compounds demonstrated potent activity toward ovarian A2780 cancer cells. The most active complexes, Re7-Re9, incorporating 4-NMe2py, exhibited remarkable activity in 3D HeLa spheroids. The emission in the red region of Re9, which contains an electron-deficient benzothiazole moiety, allowed its operability as a bioimaging tool for in vitro and in vivo visualization. Re9 effectivity was tested in two different C. elegans tumoral strains, JK1466 and MT2124, to broaden the oncogenic pathways studied. The results showed that Re9 was able to reduce the tumor growth in both strains by increasing the ROS production inside the cells. Moreover, the selectivity of the compound toward cancerous cells was remarkable as it did not affect neither the development nor the progeny of the nematodes.
Asunto(s)
Antineoplásicos , Caenorhabditis elegans , Complejos de Coordinación , Renio , Animales , Caenorhabditis elegans/efectos de los fármacos , Renio/química , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Complejos de Coordinación/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Línea Celular Tumoral , Nanomedicina Teranóstica , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular/efectos de los fármacosRESUMEN
The main goal of this work was to elucidate the potential relevance of (radio)metal chelates of 99mTc and Re targeting G-quadruplex structures for the design of new tools for cancer theranostics. 99mTc provides the complexes with the ability to perform single-photon-emission computed tomography imaging studies, while the Re complexes should act as anticancer agents upon interaction with specific G4 DNA or RNA structures present in tumor tissues. Towards this goal, we have developed isostructural 99mTc(I) and Re(I) tricarbonyl complexes anchored by a pyrazolyl-diamine (Pz) chelator carrying a pendant pyridostatin (PDS) fragment as the G4-binding motif. The interaction of the PDF-Pz-Re (8) complex with different G4-forming oligonucleotides was studied by circular dichroism, fluorescence spectroscopy and FRET-melting assays. The results showed that the Re complex retained the ability to bind and stabilize G4-structures from different DNA or RNA sequences, namely those present on the SRC proto-oncogene and telomeric RNA (TERRA sequence). PDF-Pz-Re (8) showed low to moderate cytotoxicity in PC3 and MCF-7 cancer cell lines, as typically observed for G4-binders. Biodistribution studies of the congener PDF-Pz-99mTc (12) in normal mice showed that the complex undergoes a fast blood clearance with a predominant hepatobiliary excretion, pointing also for a high inâ vitro stability.
Asunto(s)
Aminoquinolinas , G-Cuádruplex , Neoplasias , Ácidos Picolínicos , Renio , Ratones , Animales , Tecnecio/química , Distribución Tisular , ADN/química , Quelantes/química , Tomografía Computarizada de Emisión de Fotón Único , ARN , Renio/química , Radiofármacos/químicaRESUMEN
We report on interactions of different types of DNA molecules including double-stranded and plasmid DNA as well as polynucleotides (poly[dGdC]2 and poly[dAdT]2) with fac-[ReI(CO)3(pterin)(H2O)] (or Reptr) complex. The interaction was characterized spectroscopically and changes in the plasmid structure were verified by both electrophoresis and AFM microscopy. For comparative reasons, two others related tricarbonyl rhenium(I) complexes, fac-[(4,4'-bpy)ReI(CO)3(dppz)]+ (or Redppz) and fac-[(CF3SO3)ReI(CO)3(2,2'-bpy)] (or Rebpy) were also studied to further explore the influence of the different co-ligands on the interaction and DNA (photo)damage. Data reported herein suggests that DNA molecules can be structurally modified either by direct interaction with Re(I) complexes in their ground states inducing DNA relaxation, and/or through photoinduced cross-linking processes. The chemical nature of the co-ligands modulates the extent of the damage observed.
Asunto(s)
Pterinas , Renio , Renio/química , ADN/química , Plásmidos , LigandosRESUMEN
In an effort to develop new potent anticancer agents, two Schiff base rhenium(I) tricarbonyl complexes, containing the ubiquitous aminoquinoline scaffold, were synthesized. Both aminoquinoline ligands and Re(I) complexes showed adequate stability over a 48-h incubation period. Furthermore, the cytotoxic activity of the precursor ligands and rhenium(I) complexes were evaluated against the hormone-dependent MCF-7 and hormone-independent triple negative MDA-MB-231 breast cancer cell lines. Inclusion of the [Re(CO)3Cl]+ entity significantly enhanced the cytotoxicity of the aminoquinoline Schiff base ligands against the tested cancer cell lines. Remarkably, the incorporation of the Schiff-base iminoquinolyl entity notably enhanced the cytotoxic activity of the Re(I) complexes, in comparison with the iminopyridyl entity. Notably, the quinolyl-substituted complex showed up to three-fold higher activity than cisplatin against breast cancer cell lines, underpinning the significance of the quinoline pharmacophore in rational drug design. In addition, the most active Re(I) complex showed better selectivity towards the breast cancer cells over non-tumorigenic FG-0 cells. Western blotting revealed that the complexes increased levels of γH2AX, a key DNA damage response protein. Moreover, apoptosis was confirmed in both cell lines due to the detection of cleaved PARP. The complexes show favourable binding affinities towards both calf thymus DNA (CT-DNA), and bovine serum albumin (BSA), and the order of their interactions align with their cytotoxic effects. The in silico molecular simulations of the complexes were also performed with CT-DNA and BSA targets.
Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Complejos de Coordinación , Renio , Humanos , Femenino , Bases de Schiff/farmacología , Bases de Schiff/química , Renio/química , ADN/metabolismo , Células MCF-7 , Albúmina Sérica Bovina/química , Hormonas , Aminoquinolinas/farmacología , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Antineoplásicos/química , LigandosRESUMEN
Morpholine motifs have been used extensively as targeting moieties for lysosomes, primarily in fluorescence imaging agents. Traditionally these imaging agents are based on organic molecules which have several shortcomings including small Stokes shifts, short emission lifetimes, and susceptibility to photobleaching. To explore alternative lysosome targeting imaging agents we have used a rhenium based phosphorescent platform which has been previously demonstrated to have an improved Stokes shift, a long lifetime emission, and is highly photostable. Rhenium complexes containing morpholine substituted ligands were designed to accumulate in acidic compartments. Two of the three complexes prepared exhibited bright emission in cells, when incubated at low concentrations (20 µM) and were non-toxic at concentrations as high as 100 µM, making them suitable for live cell imaging. We show that the rhenium complexes are amenable to chemical modification and that the morpholine targeted derivatives can be used for live cell confocal fluorescence imaging of endosomes-lysosomes.