RESUMO
Four lanthanide complexes with 8-hydroxyquinoline-2-aldehyde-2-hydrazinopyridine (H-L1), 8-hydroxyquinoline-2-aldehyde-2-hydrazimidazole (H-L2): [Sm(L1)2][Sm(L1)(NO3)3]·CHCl3·2CH3OH (1), [Gd(L1)2][Gd(L1)(NO3)3]·CHCl3·2CH3OH (2), [Sm(L2)(NO3)2]2·CH3OH (3), and [Eu(L2)(NO3)2]2·CH3OH (4) were synthesized and characterized. In vitro cytotoxicity evaluation showed that the ligands and four lanthanide complexes exhibited cytotoxicity to the five tested tumor cell lines. Among them, complex 1 showed the best antiproliferative activity against NCI-H460 tumor cells. Mechanistic studies demonstrated that complex 1 arrested the cell cycle of NCI-H460 cells in G1 phase and induced mitochondria-mediated apoptosis, which resulted in the loss of mitochondrial membrane potential, enhanced intracellular Ca2+ levels and reactive oxygen species generation. In addition, complex 1 affected the expression levels of intracellular apoptosis-related proteins and activated the caspase-3/9 in NCI-H460 cells. Therefore, complex 1 is a potential anticancer agent.
Assuntos
Antineoplásicos , Apoptose , Proliferação de Células , Oxiquinolina , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Oxiquinolina/farmacologia , Oxiquinolina/química , Linhagem Celular Tumoral , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Elementos da Série dos Lantanídeos/farmacologia , Elementos da Série dos Lantanídeos/química , Espécies Reativas de Oxigênio/metabolismo , Ciclo Celular/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacosRESUMO
A smartphone-assisted electrochemiluminescence (ECL) strategy based on Ru(bpy)2(L)4+ as chromophores confined with metal - organic frameworks (Ru(bpy)2(L)4+@MOF-5) for the signal-amplified detection of miRNA-21 was developed. We synthesized a derivative of tris(2,2'-bipyridyl)ruthenium(II) complex (Ru(bpy)2(L)4+) with high charges, which can be loaded into the MOF-5 by strong electrostatic interaction to prevent from leakage. In addition, nucleic acid cycle amplification was used to quench the signal of Ru(bpy)2(L)4+@MOF-5 by ferrocene. This method was applied to detect the concentration of miRNA-21 ranging from 1.0 × 10-14-1.0 × 10-9 M with a low LOD of 7.2 fM. This work demonstrated the construction of a signal quenching strategy ECL biosensor for miRNA using Ru(bpy)2(L)4+@MOF-5 systems and its application in smartphone-assisted ECL detection.
Assuntos
Técnicas Biossensoriais , Técnicas Eletroquímicas , Limite de Detecção , Medições Luminescentes , Estruturas Metalorgânicas , MicroRNAs , Smartphone , MicroRNAs/análise , MicroRNAs/sangue , Técnicas Biossensoriais/métodos , Medições Luminescentes/métodos , Técnicas Eletroquímicas/métodos , Técnicas Eletroquímicas/instrumentação , Estruturas Metalorgânicas/química , Humanos , Complexos de Coordenação/química , Compostos Organometálicos/químicaRESUMO
The novel structure of Hg(II) complexes including the pyridinium ylide C5H5NCHC(O)C6H4-m-Br (Y) were synthesized and reported in this study. In the first step, the pyridinium salt C5H5NCH2C(O)C6H4-m-Br (S) was produced by reacting 2,3'-dibromoactophenone and pyridine. then, treatment of S with K2CO3 gave the related pyridinium ylide Y. Finally, the reaction of Y with HgX2 and Hg(NO3)2·H2O leads to the formation of novel binuclear [HgY2][HgX4] (X=Cl (1); X=Br (2); X=I (3)) and polymeric [HgY(NO3)2]n (4) complexes. The structure of complex 2 was also determined by X-ray diffraction analysis. The obtained analyses proved the coordination through the ylidic carbon to metallic center. Additionally, Natural Bond Orbital (NBO), Energy Decomposition Analysis (EDA), and EDA-NOCV studies are also used to investigate the nature of metal-ligand bonding in the complexes. Finally, the antibacterial activity of 1-4 was also examined against Gram positive and negative represented significant levels of inhibitory potency respected to used standards.
Assuntos
Antibacterianos , Mercúrio , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Mercúrio/química , Testes de Sensibilidade Microbiana , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Cristalografia por Raios X , Modelos Moleculares , Estrutura MolecularRESUMO
Cancer is a significant cause of death around the world, and for many varieties, treatment is not successful. Therefore, there is a need for the development of innovative, efficacious, and precisely targeted treatments. Here, we develop a series of Au(I) complexes (1-4) through rational manipulation of ligand structures, thereby achieving tumor cell specific targeting and orchestrated tumor eradication via chemo-phototherapy and induced immunogenic cell death. A comprehensive exploration based on in vitro and in vivo female mice experimentation shows that complex 4 exhibits proficiency in specific tumor imaging, endoplasmic reticulum targeting, and has robust therapeutic capabilities. Mechanistic elucidation indicates that the anticancer effect derives from the synergistic actions of thioredoxin reductase inhibition, highly efficient reactive oxygen species production and immunogenic cell death. This work presents a report on a robust Au(I) complex integrating three therapeutic modalities within a singular system. The strategy presented in this work provides a valuable reference for the development of high-performance therapeutic agents.
Assuntos
Ouro , Morte Celular Imunogênica , Espécies Reativas de Oxigênio , Animais , Ouro/química , Morte Celular Imunogênica/efeitos dos fármacos , Feminino , Camundongos , Humanos , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Tiorredoxina Dissulfeto Redutase/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias/terapia , Neoplasias/imunologia , Fototerapia/métodos , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêuticoRESUMO
Herein, the computer-guided design, chemical synthesis, and biological evaluation of a RuC polypyridine complex, that could eradicate cancerous cells upon excitation with red light at 630 nm, is reported.
Assuntos
Complexos de Coordenação , Luz , Fotoquimioterapia , Fármacos Fotossensibilizantes , Piridinas , Rutênio , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/síntese química , Humanos , Piridinas/química , Piridinas/farmacologia , Rutênio/química , Rutênio/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Desenho de Fármacos , Linhagem Celular Tumoral , Estrutura Molecular , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
In this paper, we firstly report the synthesis and structural characterization of a discrete coordination metallacycle complex, [CuI (bipy)]2 (1). The x-ray diffraction structure, temperature-dependent electronic absorption, and photoluminescence spectra have been investigated. The solid-state fluorescence at variable temperatures shows that complex 1 exhibits an obvious thermochromic fluorescence. At low temperature, the dual fluorescence with peaks at 590 and 694 nm was observed. The emission color significantly changes from red at 77 K to yellow at 200 K and blue-green at 330 K. The thermochromic fluorescent molecular materials show great potential as temperature sensing.
Assuntos
Cobre , Imidazóis , Temperatura , Cobre/química , Imidazóis/química , Imidazóis/síntese química , Fluorescência , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Estrutura Molecular , Espectrometria de FluorescênciaRESUMO
The synthesis and characterization of nine Schiff bases of pyrazolone ligands HLn (n = 1-9) and the corresponding zinc(II) complexes 1-9 of composition [Zn(Ln)2] (n = 1-9) are reported. The molecular structures of complexes 2, 3, 4, 8, and 9 were determined by single-crystal X-ray diffraction analysis, highlighting in all cases a distorted tetrahedral geometry around the Zn(II) ion. Density functional theory studies are performed on both the HLn ligands and the derived complexes. A mechanism of dissociation and hydrolyzation of the coordinated Schiff base ligands is suggested, confirmed experimentally by powder X-ray diffraction study and photophysical studies. Complexes 1-9 were investigated in vitro as anticancer agents, along with mutant p53 (mutp53) protein levels in human cancer cell lines carrying R175H and R273H mutp53 proteins. Only those complexes with the highest Zn(II) ion release via dissociation have shown a significant cytotoxic activity with reduction of mutp53 protein levels.
Assuntos
Antineoplásicos , Complexos de Coordenação , Pirazolonas , Proteína Supressora de Tumor p53 , Zinco , Humanos , Pirazolonas/farmacologia , Pirazolonas/química , Pirazolonas/síntese química , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Zinco/química , Zinco/farmacologia , Zinco/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Linhagem Celular Tumoral , Mutação , Bases de Schiff/química , Bases de Schiff/farmacologia , Bases de Schiff/síntese química , Relação Estrutura-Atividade , Ensaios de Seleção de Medicamentos Antitumorais , Modelos Moleculares , Cristalografia por Raios XRESUMO
The synthesis and characterization of metal complexes have garnered significant attention due to their versatile applications in scientific and biomedical fields. In this research, two novel copper (Cu) complexes, [Cu(L)(L')(H2O)2] (1) and [Cu(L)(Im)H2O] (2), where L = pyridine-2,6-dicarboxylic acid, L' = 2,4-diamino-6-hydroxypyrimidine, and Im = imidazole, were investigated concerning their sonochemical synthesis, spectroscopic analysis, and biological activity. The complexes' structural characterization was achieved using analytical techniques, including single-crystal X-ray structure determination, FTIR, PXRD, TGA and DTA, SEM, TEM, and EDS. Complex (1) displayed a six-coordinated Cu2+ ion, while complex (2) exhibited a five-coordinated Cu2+ ion. The crystal structures revealed monoclinic (C2/c) and triclinic (P-1) space groups, respectively. Both complexes showcased zero-dimensional (0D) supramolecular networks, primarily driven by hydrogen bonding and π-π stacking interactions, which played pivotal roles in stabilizing the structures and shaping the unique supramolecular architecture. Both complexes demonstrated significant antioxidant activity, suggesting their capability to neutralize free radicals and mitigate oxidative stress-related diseases. Hemolysis percentages were less than 2%, per the ASTM F756-00 standard, indicating non-hemolytic behavior. Low cytotoxicity was observed against fibroblast and MCF-7 cell lines. They do not exhibit antibacterial activity against Escherichia coli and Staphylococcus aureus. These findings suggest that the synthesized Cu2+âcomplexes hold considerable promise for applications in drug delivery and cancer treatment. This research contributes to the advancement of supramolecular chemistry and the development of multifunctional materials for diverse scientific and medical applications.
Assuntos
Complexos de Coordenação , Cobre , Cobre/química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Humanos , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Cristalografia por Raios X , Antioxidantes/farmacologia , Antioxidantes/química , Antioxidantes/síntese química , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Células MCF-7 , Hemólise/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese químicaRESUMO
As the most frequent and deadly type of cancer in women, breast cancer has a high propensity to spread to the brain, bones, lymph nodes, and lungs. The discovery of cisplatin marked the beginning of the development of anticancer metal-based medications, although the drug's severe side effects have limited its usage in clinical settings. The remarkable antimetastatic and anticancer activity of different ruthenium complexes such as NAMI-A, KP1019, KP1339, etc. reported in the 1980s has bolstered the discovery of ruthenium complexes with various types of ligands for anticancer applications. The review meticulously elucidates the cytotoxic and antimetastatic potential of reported ruthenium complexes against breast cancer cells. Notably, arene-based and cyclometalated ruthenium complexes emerge as standout candidates, showcasing remarkable potency with notably low IC50 values. These findings underscore the promising therapeutic avenues offered by ruthenium-based compounds, particularly in addressing the challenges posed by conventional treatments in refractory or aggressive breast cancer subtypes. Moreover, the review comprehensively integrates a spectrum of ruthenium complexes, spanning traditional metal complexes to nano-based formulations and light-activated variants, underscoring the versatility and adaptability of ruthenium chemistry in breast cancer therapy.
Assuntos
Antineoplásicos , Neoplasias da Mama , Complexos de Coordenação , Rutênio , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Rutênio/química , Rutênio/farmacologia , Feminino , Desenho de FármacosRESUMO
Fourteen cobalt(II) complexes with the non-steroidal anti-inflammatory drugs sodium meclofenamate, tolfenamic acid, mefenamic acid, naproxen, sodium diclofenac, and diflunisal were prepared in the presence or absence of a series of nitrogen-donors (namely imidazole, pyridine, 3-aminopyridine, neocuproine, 2,2'-bipyridine, 1,10-phenanthroline and 2,2'-bipyridylamine) as co-ligands and were characterised by spectroscopic and physicochemical techniques. Single-crystal X-ray crystallography was employed to determine the crystal structure of eight complexes. The biological profile of the complexes was investigated regarding their interaction with serum albumins and DNA, and their antioxidant potency. The interaction of the compounds with calf-thymus DNA takes place via intercalation. The ability of the complexes to cleave pBR322 plasmid DNA at the concentration of 500 µM is rather low. The complexes demonstrated tight and reversible binding to human and bovine serum albumins and the binding site of bovine serum albumin was also examined. In order to assess the antioxidant activity of the compounds, the in vitro scavenging activity towards free radicals, namely 1,1-diphenyl-picrylhydrazyl and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid), and their ability to reduce H2O2 were studied.
Assuntos
Anti-Inflamatórios não Esteroides , Cobalto , Complexos de Coordenação , DNA , Ácido Mefenâmico , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Cobalto/química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Humanos , DNA/química , DNA/metabolismo , Bovinos , Animais , Ácido Mefenâmico/química , Ácido Mefenâmico/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Diflunisal/química , Diflunisal/farmacologia , Ácido Meclofenâmico/química , Ácido Meclofenâmico/farmacologia , Cristalografia por Raios X , Soroalbumina Bovina/química , Soroalbumina Bovina/metabolismo , Diclofenaco/química , Diclofenaco/farmacologia , Naproxeno/química , Naproxeno/farmacologia , ortoaminobenzoatos/química , ortoaminobenzoatos/farmacologiaRESUMO
Cyclometalated iridium(III) compounds have been widely explored due to their outstanding photo-physical properties and multiple anticancer activities. In this paper, three cyclometalated iridium(III) compounds [Ir(ppy)2(DBDIP)]PF6 (5a), [Ir(bzq)2(DBDIP)]PF6 (5b), and [Ir(piq)2(DBDIP)]PF6 (5c) (ppy: 2-phenylpyridine; bzq: benzo[h]quinoline; piq: 1-phenylisoquinoline, and DBDIP: 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-imidazo[4,5-f][1,10]phenanthroline) were synthesized and the mechanism of antitumor activity was investigated. Compounds photoactivated by visible light show strong cytotoxicity against tumor cells, especially toward A549 cells. Biological experiments such as migration, cellular localization, mitochondrial membrane potential and permeability, reactive oxygen species (ROS) and calcium ion level detection were performed, and they demonstrated that the compounds induced the apoptosis of A549 cells through a mitochondrial pathway. At the same time, oxidative stress caused by ROS production increases the release of damage-related molecules and the expression of porogen gasdermin D (GSDMD), and the content of LDH released from damaged cell membranes also increased. Besides, the content of the lipid peroxidation product, malondialdehyde (MDA), increased and the expression of GPX4 decreased. These indicate that the compounds promote cell death by combining ferroptosis and pyroptosis. The results reveal that cyclometalated iridium(III) compounds 5a-5c may be a potential chemotherapeutic agent for photodynamic therapy of cancers.
Assuntos
Antineoplásicos , Complexos de Coordenação , Ensaios de Seleção de Medicamentos Antitumorais , Irídio , Espécies Reativas de Oxigênio , Humanos , Irídio/química , Irídio/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Espécies Reativas de Oxigênio/metabolismo , Células A549 , Apoptose/efeitos dos fármacos , Luz , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Estrutura Molecular , Cálcio/metabolismo , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Processos Fotoquímicos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/síntese químicaRESUMO
A novel lipoformulation was developed by encapsulating cationic (S^C)-cyclometallated gold(III) complex [Au(dppta)(N2Py-PZ-dtc)]+ (AuPyPZ) in liposomes. The liposomal form of compound AuPyPZ has a bactericidal action similar to that of the free drug without any appreciable effect on the viability of mammalian cells. Furthermore, the nanoformulation reduces metalloantibiotic-induced inhibition of hERG and the inhibition of cytochromes, significantly decreasing the potential liabilities of the metallodrug. The obtained metalloantibiotic liposomal formulation shows high stability and suitable properties for drug delivery, representing an effective strategy to fight against drug-resistant bacteria.
Assuntos
Antibacterianos , Ouro , Lipossomos , Testes de Sensibilidade Microbiana , Lipossomos/química , Antibacterianos/química , Antibacterianos/farmacologia , Antibacterianos/síntese química , Ouro/química , Ouro/farmacologia , Humanos , Farmacorresistência Bacteriana/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Compostos Organoáuricos/química , Compostos Organoáuricos/farmacologia , Compostos Organoáuricos/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese químicaRESUMO
The N-truncation of amyloid beta (Aß) peptides could lead to peptide sequences with the histidine residue at the second and third positions, creating His-2 and His-3 motifs, known as high-affinity Cu(II) binding sites. In such complexes, the Cu(II) ion is arrested in a rigid structure of a square-planar arrangement of nitrogen donors, which highly limits its susceptibility to Cu(II) reduction. Cu(II) reduction fuels the Cu(II)/Cu(I) redox cycle, which is engaged in the production of reactive oxygen species (ROS). Employing electrochemical techniques, cyclic voltammetry (CV) and differential pulse voltammetry (DPV), together with UV-vis spectroscopy, we showed that low-molecular-weight (LMW) substances, such as imidazole, histamine, and histidine, could enhance the redox activity of Cu(II) complexes of three models of N-truncated Aß peptides, Aß4-9, Aß5-9, and Aß12-16, identifying three main mechanisms. LMW compounds could effectively compete with Aß peptides for Cu(II) ions, forming Cu(II)/LMW species, which are more prone to Cu(II) reduction. LMW substances could also shift the equilibrium between the Cu(II)/Aß species towards the species with higher susceptibility to Cu(II) reduction. Finally, the presence of LMW molecules could promote Cu(I) reoxidation in ternary Cu(II)/Aß/LMW systems. The obtained results raise further questions regarding the Cu(II) redox activity in Alzheimer's disease.
Assuntos
Peptídeos beta-Amiloides , Complexos de Coordenação , Cobre , Técnicas Eletroquímicas , Histamina , Histidina , Imidazóis , Cobre/química , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Histidina/química , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Imidazóis/química , Histamina/química , OxirreduçãoRESUMO
Photodynamic therapy delivers more targeted cell killing than classical chemotherapy. It uses light-absorbing compounds, photosensitizers (PSs), to generate lethal reactive oxygen species (ROS) at sites of localized irradiation. Transition metal complexes are attractive PSs due to their photostability, visible-light absorption, and high ROS yields. Here, we introduce a low-molecular weight, photostable iridium complex, [Ir(thpy)2(benz)]Cl, 1, that localizes to the Golgi apparatus, mitochondria, and endoplasmic reticulum, absorbs visible light, phosphoresces strongly, generates 1O2 with 43% yield, and undergoes cellular elimination after 24 h. 1 shows low dark toxicity and under remarkably low doses (3 min, 20-30 mJ s-1 cm-2) of 405 or 455 nm light, it causes killing of bladder (EJ), malignant melanoma (A375), and oropharyngeal (OPSCC72) cancer cells, with high phototoxic indices > 100-378. 1 is also an efficient PS in 3D melanoma spheroids, with repeated short-time irradiation causing cumulative killing.
Assuntos
Complexos de Coordenação , Irídio , Luz , Fotoquimioterapia , Fármacos Fotossensibilizantes , Humanos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/síntese química , Irídio/química , Irídio/farmacologia , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/efeitos da radiação , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Espécies Reativas de Oxigênio/metabolismoRESUMO
We report the synthesis, characterization, and in vitro biological activities of [Re(η6-arene)2]+-terpyridine conjugates and their CuII complexes. The terpyridine (terpy) chelators were attached to the [Re(η6-arene)2]+ scaffold via secondary amine linkers allowing for heteroleptic mono- and homoleptic bis-terpyridine-substituted chelators. Complexation with CuCl2 afforded the respective square pyramidal [Cu(terpy)Cl2] complexes hosted on the [Re(η6-arene)2]+ scaffold. The chelator conjugates and their respective complexes were found to be remarkably cytotoxic against malignant HT29 and A549 human cancer cell lines in vitro with IC50 values in the low micromolar range. Mitochondrial respiration disruption was identified as a possible mode of action of these novel drug candidates. Crucially, the [Re(η6-arene)2]+ hosts delivered water solubility of the otherwise insoluble [Cu(terpy)Cl2] motif. Importantly, the homoleptic [99mTc(η6-arene)2]+-terpyridine conjugate is available in a single step, which enables the presented system to be used as a theranostic approach to modern medicinal inorganic chemistry.
Assuntos
Antineoplásicos , Complexos de Coordenação , Cobre , Ensaios de Seleção de Medicamentos Antitumorais , Piridinas , Rênio , Humanos , Piridinas/química , Piridinas/farmacologia , Piridinas/síntese química , Cobre/química , Cobre/farmacologia , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Rênio/química , Rênio/farmacologia , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular , Células A549 , Tecnécio/química , Linhagem Celular Tumoral , Quelantes/química , Quelantes/síntese química , Quelantes/farmacologia , Relação Estrutura-AtividadeRESUMO
Sonodynamic therapy (SDT) can generate reactive oxygen species (ROS) to combat multidrug-resistant biofilms, which pose significant challenges to human health. As the key to producing ROS in SDT, the design of sonosensitizers with optimal molecular structures for sufficient ROS generation and activity in complex biofilm matrix is essential. In this study, we propose a π-expansion strategy and synthesize a series of small-molecule metal Ru(II) complexes (Ru1-Ru4) as sonosensitizers (Ru1-Ru4) to enhance the efficacy of SDT. Among these complexes, Ru4 demonstrates remarkable ROS generation capability (â¼65.5-fold) that surpasses most commercial sonosensitizers (1.3- to 6.7-fold). Through catalyzing endogenous H2O2 decomposition, Ru4 facilitates the production of abundant O2 as a resource for 1O2 and the generation of new ROS (i.e., â¢OH) for improving SDT. Furthermore, Ru4 maintains the sustained ROS activity via consuming the interferences (e.g., glutathione) that react with ROS. Due to these unique advantages, Ru4 exhibits potent biofilm eradication ability against methicillin-resistant Staphylococcus aureus (MRSA) both in vitro and in vivo, underscoring its potential use in clinical settings. This work introduces a new approach for designing effective sonosensitizers to eliminate biofilm infections, addressing a critical need in healthcare management.
Assuntos
Antibacterianos , Biofilmes , Complexos de Coordenação , Staphylococcus aureus Resistente à Meticilina , Espécies Reativas de Oxigênio , Rutênio , Biofilmes/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Rutênio/química , Rutênio/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Animais , Camundongos , Terapia por Ultrassom , Humanos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Testes de Sensibilidade MicrobianaRESUMO
Ruthenium(II) polypyridyl complexes are being tested as potential anticancer agents in different therapies, which include conventional chemotherapy and light-activated approaches. A mechanistic study on a recently synthesized dual-action Ru(II) complex [Ru(bpy)2(sora)Cl]+ is described here. It is characterized by two mono-dentate leaving ligands, namely, chloride and sorafenib ligands, which make it possible to form a di-aquo complex able to bind DNA. At the same time, while the released sorafenib can induce ferroptosis, the complex is also able to act as a photosensitizer according to type II photodynamic therapy processes, thus generating one of the most harmful cytotoxic species, 1O2. In order to clarify the mechanism of action of the drug, computational strategies based on density functional theory are exploited. The photophysical properties of the complex, which include the absorption spectrum, the kinetics of ISC, and the character of all the excited states potentially involved in 1O2 generation, as well as the pathway providing the di-aquo complex, are fully explored. Interestingly, the outcomes show that light is needed to form the mono-aquo complex, after releasing both chloride and sorafenib ligands, while the second solvent molecule enters the coordination sphere of the metal once the system has come back to the ground-state potential energy surface. In order to simulate the interaction with canonical DNA, the di-aquo complex interaction with a guanine nucleobase as a model has also been studied. The whole study aims to elucidate the intricate details of the photodissociation process, which could help with designing tailored metal complexes as potential anticancer agents.
Assuntos
Antineoplásicos , Complexos de Coordenação , Rutênio , Sorafenibe , Sorafenibe/química , Sorafenibe/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Rutênio/química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Humanos , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologiaRESUMO
Radiopharmaceuticals are currently a key tool in cancer diagnosis and therapy. Metal-based radiopharmaceuticals are characterized by a radiometal-chelator moiety linked to a bio-vector that binds the biological target (e.g., a protein overexpressed in a particular tumor). The right match between radiometal and chelator influences the stability of the complex and the drug's efficacy. Therefore, the coupling of the radioactive element to the correct chelator requires consideration of several features of the radiometal, such as its oxidation state, ionic radius, and coordination geometry. In this work, we systematically investigated about 120 radiometal-chelator complexes taken from the Cambridge Structural Database. We considered 25 radiometals and about 30 chelators, featuring both cyclic and acyclic geometries. We used quantum mechanics methods at the density functional theoretical level to generate the general AMBER force field parameters and to perform 1 µs-long all-atom molecular dynamics simulations in explicit water solution. From these calculations, we extracted several key molecular descriptors accounting for both electronic- and dynamical-based properties. The whole workflow was carefully validated, and selected test-cases were investigated in detail. Molecular descriptors and force field parameters for the complexes considered in this study are made freely available, thus enabling their use in predictive models, molecular modelling, and molecular dynamics investigations of the interaction of compounds with macromolecular targets. Our work provides new insights in understanding the properties of radiometal-chelator complexes, with a direct impact for rational drug design of this important class of drugs.
Assuntos
Quelantes , Simulação de Dinâmica Molecular , Teoria Quântica , Quelantes/química , Compostos Radiofarmacêuticos/química , Complexos de Coordenação/química , Estrutura MolecularRESUMO
Calcium phosphates (CaPs) and their substituted derivatives encompass a large number of compounds with a vast presence in nature that have aroused a great interest for decades. In particular, hydroxyapatite (HAp, Ca10(OH)2(PO4)6) is the most abundant CaP mineral and is significant in the biological world, at least in part due to being a major compound in bones and teeth. HAp exhibits excellent properties, such as safety, stability, hardness, biocompatibility, and osteoconductivity, among others. Even some of its drawbacks, such as its fragility, can be redirected thanks to another essential feature: its great versatility. This is based on the compound's tendency to undergo substitutions of its constituent ions and to incorporate or anchor new molecules on its surface and pores. Thus, its affinity for biomolecules makes it an optimal compound for multiple applications, mainly, but not only, in biological and biomedical fields. The present review provides a chemical and structural context to explain the affinity of HAp for biomolecules such as proteins and nucleic acids to generate hybrid materials. A size-dependent criterium of increasing complexity is applied, ranging from amino acids/nucleobases to the corresponding macromolecules. The incorporation of metal ions or metal complexes into these functionalized compounds is also discussed.