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1.
Molecules ; 26(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206482

RESUMO

Gliomas and glioblastomas are very aggressive forms of brain tumors, prone to the development of a multitude of resistance mechanisms to therapeutic treatments, including cytoprotective autophagy. In this work, we investigated the role and mechanism of action of the combination of a ruthenacarborane derivative with 8-hydroxyquinoline (8-HQ), linked via an ester bond (complex 2), in rat astrocytoma C6 and human glioma U251 cells, in comparison with the two compounds alone, i.e., the free carboxylic acid (complex 1) and 8-HQ, and their non-covalent combination ([1 + 8-HQ], in 1:1 molar ratio). We found that only complex 2 was able to significantly affect cellular viability in glioma U251 cells (IC50 11.4 µM) via inhibition of the autophagic machinery, most likely acting at the early stages of the autophagic cascade. Contrary to 8-HQ alone, complex 2 was also able to impair cellular viability under conditions of glucose deprivation. We thus suggest different mechanisms of action of ruthenacarborane complex 2 than purely organic quinoline-based drugs, making complex 2 a very attractive candidate for evading the known resistances of brain tumors to chloroquine-based therapies.


Assuntos
Antineoplásicos , Astrocitoma , Neoplasias Encefálicas , Complexos de Coordenação , Quinolinas , Rutênio , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Astrocitoma/tratamento farmacológico , Astrocitoma/metabolismo , Astrocitoma/patologia , Morte Celular Autofágica , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Humanos , Quinolinas/química , Quinolinas/farmacologia , Ratos , Rutênio/química , Rutênio/farmacologia
2.
Molecules ; 26(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203562

RESUMO

Nucleic acids are essential biomolecules in living systems and represent one of the main targets of chemists, biophysics, biologists, and nanotechnologists. New small molecules are continuously developed to target the duplex (ds) structure of DNA and, most recently, RNA to be used as therapeutics and/or biological tools. Stimuli-triggered systems can promote and hamper the interaction to biomolecules through external stimuli such as light and metal coordination. In this work, we report on the interaction with ds-DNA and ds-RNA of two aza-macrocycles able to coordinate Zn2+ metal ions and form binuclear complexes. The interaction of the aza-macrocycles and the Zn2+ metal complexes with duplex DNA and RNA was studied using UV thermal and fluorescence indicator displacement assays in combination with theoretical studies. Both ligands show a high affinity for ds-DNA/RNA and selectivity for ds-RNA. The ability to interact with these duplexes is blocked upon Zn2+ coordination, which was confirmed by the low variation in the melting temperature and poor displacement of the fluorescent dye from the ds-DNA/RNA. Cell viability assays show a decrease in the cytotoxicity of the metal complexes in comparison with the free ligands, which can be associated with the observed binding to the nucleic acids.


Assuntos
Complexos de Coordenação , Citotoxinas , DNA/química , RNA de Cadeia Dupla/química , Zinco , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Citotoxinas/química , Citotoxinas/farmacologia , Humanos , Ligantes , Células Vero , Zinco/química , Zinco/farmacologia
3.
Molecules ; 26(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209921

RESUMO

Three novel gold(III) complexes (1-3) of general composition [Au(Bipydc)(S2CNR2)]Cl2 (Bipydc = 2,2'-bipyridine-3,3'-dicarboxylic acid and R = methyl for dimethyldithiocarbamate (DMDTC), ethyl for diethyldithiocarbamate (DEDTC), and benzyl for dibenzyldithiocarbamate (DBDTC)) have been synthesized and characterized by elemental analysis, FTIR and NMR spectroscopic techniques. The spectral results confirmed the presence of both the Bipydc and dithiocarbamate ligands in the complexes. The in vitro cytotoxic studies demonstrated that compounds 1-3 were highly cytotoxic to A549, HeLa, MDA-231, and MCF-7 cancer cells with activities much higher (about 25-fold) than cisplatin. In order to know the possible mode of cell death complex 2, [Au(Bipydc)(DEDTC)]Cl2 was further tested for induction of apoptosis towards the MCF-7 cells. The results indicated that complex 2 induces cell death through apoptosis.


Assuntos
Antineoplásicos , Complexos de Coordenação , Ouro/química , Piridinas/química , Tiocarbamatos/química , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Células HeLa , Humanos , Células MCF-7
4.
Int J Mol Sci ; 22(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34206067

RESUMO

Nanozymes, nanomaterials with enzyme-like activities, are becoming powerful competitors and potential substitutes for natural enzymes because of their excellent performance. Nanozymes offer better structural stability over their respective natural enzymes. In consequence, nanozymes exhibit promising applications in different fields such as the biomedical sector (in vivo diagnostics/and therapeutics) and the environmental sector (detection and remediation of inorganic and organic pollutants). Prussian blue nanoparticles and their analogues are metal-organic frameworks (MOF) composed of alternating ferric and ferrous irons coordinated with cyanides. Such nanoparticles benefit from excellent biocompatibility and biosafety. Besides other important properties, such as a highly porous structure, Prussian blue nanoparticles show catalytic activities due to the iron atom that acts as metal sites for the catalysis. The different states of oxidation are responsible for the multicatalytic activities of such nanoparticles, namely peroxidase-like, catalase-like, and superoxide dismutase-like activities. Depending on the catalytic performance, these nanoparticles can generate or scavenge reactive oxygen species (ROS).


Assuntos
Ferrocianetos/química , Estruturas Metalorgânicas/química , Nanopartículas/química , Nanoestruturas/química , Catalase , Catálise , Complexos de Coordenação/química , Ferro/química , Oxirredução , Peroxidase , Espécies Reativas de Oxigênio
5.
Int J Mol Sci ; 22(10)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34068879

RESUMO

The redox chemistry of copper(II) is strongly modulated by the coordination to amyloid-ß peptides and by the stability of the resulting complexes. Amino-terminal copper and nickel binding motifs (ATCUN) identified in truncated Aß sequences starting with Phe4 show very high affinity for copper(II) ions. Herein, we study the oxidase activity of [Cu-Aß4-x] and [Cu-Aß1-x] complexes toward dopamine and other catechols. The results show that the CuII-ATCUN site is not redox-inert; the reduction of the metal is induced by coordination of catechol to the metal and occurs through an inner sphere reaction. The generation of a ternary [CuII-Aß-catechol] species determines the efficiency of the oxidation, although the reaction rate is ruled by reoxidation of the CuI complex. In addition to the N-terminal coordination site, the two vicinal histidines, His13 and His14, provide a second Cu-binding motif. Catechol oxidation studies together with structural insight from the mixed dinuclear complexes Ni/Cu-Aß4-x reveal that the His-tandem is able to bind CuII ions independently of the ATCUN site, but the N-terminal metal complexation reduces the conformational mobility of the peptide chain, preventing the binding and oxidative reactivity toward catechol of CuII bound to the secondary site.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Complexos de Coordenação/metabolismo , Cobre/metabolismo , Dopamina/metabolismo , Oxirredutases/metabolismo , Peptídeos beta-Amiloides/química , Complexos de Coordenação/química , Cobre/química , Dopamina/química , Histidina/química , Histidina/metabolismo , Modelos Moleculares , Conformação Molecular , Oxirredução , Oxirredutases/química
6.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070401

RESUMO

Transition metal coordination compounds play an important role in the treatment of neoplastic diseases. However, due to their low selectivity and bioavailability, as well as the frequently occurring phenomenon of drug resistance, new chemical compounds that could overcome these phenomena are still being sought. The solution seems to be the synthesis of new metal complexes conjugated with drug carriers, e.g., dendrimers. Numerous literature data have shown that dendrimers improve the bioavailability of the obtained metal complexes, solving the problem of their poor solubility and stability in an aqueous environment and also breaking down inborn and acquired drug resistance. Therefore, the aim of this study was to synthesize a novel imidazole platinum(II) complex conjugated with and without the second-generation PAMAM dendrimer (PtMet2-PAMAM and PtMet2, respectively) and to evaluate its antitumor activity. Cell viability studies indicated that PtMet2-PAMAM exhibited higher cytotoxic activity than PtMet2 in MCF-7 and MDA-MB-231 breast cancer cells at relatively low concentrations. Moreover, our results indicated that PtMet2-PAMAM exerted antiproliferative effects in a zebrafish embryo model. Treatment with PtMet2-PAMAM substantially increased apoptosis in a dose-dependent manner via caspase-9 (intrinsic pathway) and caspase-8 (extrinsic pathway) activation along with pro-apoptotic protein expression modulation. Additionally, we showed that apoptosis can be induced by activating POX, which induces ROS production. Furthermore, our results also clearly showed that the tested compounds trigger autophagy through p38 pathway activation and increase Beclin-1, LC3, AMPK, and mTOR inhibition. The high pro-apoptotic activity and the ability to activate autophagy by the imidazole platinum(II) complex conjugated with a dendrimer may be due to its demonstrated ability to reverse multidrug resistance (MDR) and thereby increase cellular accumulation in breast cancer cells.


Assuntos
Antineoplásicos , Neoplasias da Mama , Complexos de Coordenação , Dendrímeros , Imidazóis , Platina , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacocinética , Complexos de Coordenação/farmacologia , Dendrímeros/química , Dendrímeros/farmacocinética , Dendrímeros/farmacologia , Feminino , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Imidazóis/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células MCF-7 , Proteínas de Neoplasias/metabolismo , Platina/química , Platina/farmacocinética , Platina/farmacologia
7.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069455

RESUMO

In this work, we report solvent-induced complexation properties of a new N2S2 tetradentate bis-thiosemicarbazone ligand (H2LI), prepared by the condensation of 4-phenylthiosemicarbazide with bis-aldehyde, namely 2,2'-(ethane-1,2-diylbis(oxy)dibenzaldehyde, towards nickel(II). Using ethanol as a reaction medium allowed the isolation of a discrete mononuclear homoleptic complex [NiLI] (1), for which its crystal structure contains three independent molecules, namely 1-I, 1-II, and 1-III, in the asymmetric unit. The doubly deprotonated ligand LI in the structure of 1 is coordinated in a cis-manner through the azomethine nitrogen atoms and the thiocarbonyl sulfur atoms. The coordination geometry around metal centers in all the three crystallographically independent molecules of 1 is best described as the seesaw structure. Interestingly, using methanol as a reaction medium in the same synthesis allowed for the isolation of a discrete mononuclear homoleptic complex [Ni(LII)2] (2), where LII is a monodeprotonated ligand 2-(2-(2-(2-(dimethoxymethyl)phenoxy)ethoxy)benzylidene)-N-phenylhydrazine-1-carbothioamide (HLII). The ligand LII was formed in situ from the reaction of LI with methanol upon coordination to the metal center under synthetic conditions. In the structure of 2, two ligands LII are coordinated in a trans-manner through the azomethine nitrogen atom and the thiocarbonyl sulfur atom, also yielding a seesaw coordination geometry around the metal center. The charge and energy decomposition scheme ETS-NOCV allows for the conclusion that both structures are stabilized by a bunch of London dispersion-driven intermolecular interactions, including predominantly N-H∙∙∙S and N-H∙∙∙O hydrogen bonds in 1 and 2, respectively; they are further augmented by less typical C-H∙∙∙X (where X = S, N, O, π), CH∙∙∙HC, π∙∙∙π stacking and the most striking, attractive long-range intermolecular C-H∙∙∙Ni preagostic interactions. The latter are found to be determined by both stabilizing Coulomb forces and an exchange-correlation contribution as revealed by the IQA energy decomposition scheme. Interestingly, the analogous long-range C-H∙∙∙S interactions are characterized by a repulsive Coulomb contribution and the prevailing attractive exchange-correlation constituent. The electron density of the delocalized bonds (EDDB) method shows that the nickel(II) atom shares only ~0.8|e| due to the σ-conjugation with the adjacent in-plane atoms, demonstrating a very weak σ-metalloaromatic character.


Assuntos
Níquel/química , Tiossemicarbazonas/química , Aldeídos/química , Compostos Azo/química , Complexos de Coordenação/química , Cristalografia por Raios X/métodos , Ligação de Hidrogênio , Ligantes , Modelos Moleculares , Estrutura Molecular , Solventes/química , Tiossemicarbazonas/metabolismo
8.
Nat Commun ; 12(1): 3363, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099651

RESUMO

Impaired wound healing and ulcer complications are a leading cause of death in diabetic patients. In this study, we report the design and synthesis of a cyclometalated iridium(III) metal complex 1a as a stabilizer of hypoxia-inducible factor-1α (HIF-1α). In vitro biophysical and cellular analyses demonstrate that this compound binds to Von Hippel-Lindau (VHL) and inhibits the VHL-HIF-1α interaction. Furthermore, the compound accumulates HIF-1α levels in cellulo and activates HIF-1α mediated gene expression, including VEGF, GLUT1, and EPO. In in vivo mouse models, the compound significantly accelerates wound closure in both normal and diabetic mice, with a greater effect being observed in the diabetic group. We also demonstrate that HIF-1α driven genes related to wound healing (i.e. HSP-90, VEGFR-1, SDF-1, SCF, and Tie-2) are increased in the wound tissue of 1a-treated diabetic mice (including, db/db, HFD/STZ and STZ models). Our study demonstrates a small molecule stabilizer of HIF-1α as a promising therapeutic agent for wound healing, and, more importantly, validates the feasibility of treating diabetic wounds by blocking the VHL and HIF-1α interaction.


Assuntos
Complexos de Coordenação/farmacologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Complexos de Coordenação/química , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/patologia , Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Irídio/química , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ligação Proteica/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Cicatrização/genética
9.
Inorg Chem ; 60(12): 8826-8837, 2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34060309

RESUMO

How to deliver nitric oxide (NO) to a physiological target and control its release quantitatively is a key issue for biomedical applications. Here, a water-soluble nitrosylruthenium complex, [(CH3)4N][RuCl3(5cqn)(NO)] (H5cqn = 5-chloro-8-quinoline), was synthesized, and its structure was confirmed with 1H NMR and X-ray crystal diffraction. Photoinduced NO release was investigated with time-resolved Fourier transform infrared and electron paramagnetic resonance (EPR) spectroscopies. The binding constant of the [RuCl3(5cqn)(NO)]- complex with human serum albumin (HSA) was determined by fluorescence spectroscopy, and the binding mode was identified by X-ray crystallography of the HSA and Ru-NO complex adduct. The crystal structure reveals that two molecules of the Ru-NO complex are located in the subdomain IB, which is one of the major drug binding regions of HSA. The chemical structures of the Ru complexes were [RuCl3(5cqn)(NO)]- and [RuCl3(Glycerin)NO]-, in which the electron densities for all ligands to Ru are unambiguously identified. EPR spin-trapping data showed that photoirradiation triggered NO radical generation from the HSA complex adduct. Moreover, the near-infrared image of exogenous NO from the nitrosylruthenium complex in living cells was observed using a NO-selective fluorescent probe. This study provides a strategy to design an appropriate delivery system to transport NO and metallodrugs in vivo for potential applications.


Assuntos
Complexos de Coordenação/metabolismo , Óxido Nítrico/metabolismo , Compostos de Rutênio/metabolismo , Albumina Sérica Humana/metabolismo , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cristalografia por Raios X , Corantes Fluorescentes/química , Células HeLa , Humanos , Modelos Moleculares , Estrutura Molecular , Óxido Nítrico/química , Imagem Óptica , Processos Fotoquímicos , Compostos de Rutênio/química , Albumina Sérica Humana/química , Células Tumorais Cultivadas
10.
Inorg Chem ; 60(12): 9199-9211, 2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34102841

RESUMO

The radionuclide 213Bi can be applied for targeted α therapy (TAT): a type of nuclear medicine that harnesses α particles to eradicate cancer cells. To use this radionuclide for this application, a bifunctional chelator (BFC) is needed to attach it to a biological targeting vector that can deliver it selectively to cancer cells. Here, we investigated six macrocyclic ligands as potential BFCs, fully characterizing the Bi3+ complexes by NMR spectroscopy, mass spectrometry, and elemental analysis. Solid-state structures of three complexes revealed distorted coordination geometries about the Bi3+ center arising from the stereochemically active 6s2 lone pair. The kinetic properties of the Bi3+ complexes were assessed by challenging them with a 1000-fold excess of the chelating agent diethylenetriaminepentaacetic acid (DTPA). The most kinetically inert complexes contained the most basic pendent donors. Density functional theory (DFT) and quantum theory of atoms in molecules (QTAIM) calculations were employed to investigate this trend, suggesting that the kinetic inertness is not correlated with the extent of the 6s2 lone pair stereochemical activity, but with the extent of covalency between pendent donors. Lastly, radiolabeling studies of 213Bi (30-210 kBq) with three of the most promising ligands showed rapid formation of the radiolabeled complexes at room temperature within 8 min for ligand concentrations as low as 10-7 M, corresponding to radiochemical yields of >80%, thereby demonstrating the promise of this ligand class for use in 213Bi TAT.


Assuntos
Bismuto/uso terapêutico , Quelantes/uso terapêutico , Complexos de Coordenação/uso terapêutico , Éteres de Coroa/uso terapêutico , Neoplasias/tratamento farmacológico , Compostos Radiofarmacêuticos/uso terapêutico , Bismuto/química , Quelantes/síntese química , Quelantes/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Éteres de Coroa/química , Teoria da Densidade Funcional , Humanos , Cinética , Ligantes , Estrutura Molecular , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química
11.
Inorg Chem ; 60(12): 8651-8664, 2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34110140

RESUMO

Four high-spin Fe(III) macrocyclic complexes, including three dinuclear and one mononuclear complex, were prepared toward the development of more effective iron-based magnetic resonance imaging (MRI) contrast agents. All four complexes contain a 1,4,7-triazacyclononane macrocyclic backbone with two hydroxypropyl pendant groups, an ancillary aryl or biphenyl group, and a coordination site for a water ligand. The pH potentiometric titrations support one or two deprotonations of the complexes, most likely deprotonation of hydroxypropyl groups at near-neutral pH. Variable-temperature 17O NMR studies suggest that the inner-sphere water ligand is slow to exchange with bulk water on the NMR time scale. Water proton T1 relaxation times measured for solutions of the Fe(III) complexes at pH 7.2 showed that the dinuclear complexes have a 2- to 3-fold increase in r1 relaxivity in comparison to the mononuclear complex per molecule at field strengths ranging from 1.4 T to 9.4 T. The most effective agent, a dinuclear complex with macrocycles linked through para-substitution of an aryl group (Fe2(PARA)), has an r1 of 6.7 mM-1 s-1 at 37 °C and 4.7 T or 3.3 mM-1 s-1 per iron center in the presence of serum albumin and shows enhanced blood pool and kidney contrast in mice MRI studies.


Assuntos
Meios de Contraste/química , Complexos de Coordenação/química , Compostos Férricos/química , Compostos Macrocíclicos/química , Imageamento por Ressonância Magnética , Animais , Meios de Contraste/síntese química , Meios de Contraste/farmacocinética , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacocinética , Compostos Férricos/farmacocinética , Humanos , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacocinética , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Albumina Sérica Humana/química
12.
Inorg Chem ; 60(12): 8710-8721, 2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34110143

RESUMO

A handful of oxygen-activating enzymes has recently been found to contain Fe/Mn active sites, like Class 1c ribonucleotide reductases and R2-like ligand-binding oxidase, which are closely related to their better characterized diiron cousins. These enzymes are proposed to form high-valent intermediates with Fe-O-Mn cores. Herein, we report the first examples of synthetic Fe/Mn complexes that mimic doubly bridged intermediates proposed for enzymatic oxygen activation. Fe K-edge extended X-ray absorption fine structure (EXAFS) analysis has been used to characterize the structures of each of these compounds. Linear compounds accurately model the Fe···Mn distances found in Fe/Mn proteins in their resting states, and doubly bridged diamond core compounds accurately model the distances found in high-valent biological intermediates. Unlike their diiron analogues, the paramagnetic nature of Fe/Mn compounds can be analyzed by EPR, revealing S = 1/2 signals that reflect antiferromagnetic coupling between the high-spin Fe(III) and Mn(III) units of heterobimetallic centers. These compounds undergo electron transfer with various ferrocenes, linear compounds being capable of oxidizing diacetyl ferrocene, a weak reductant, and diamond core compounds being capable of oxidizing acetyl ferrocene. Diamond core compounds can also perform HAT reactions from substrates with X-H bonds with bond dissociation free energies (BDFEs) up to 75 kcal/mol and are capable of oxidizing TEMPO-H at rates of 0.32-0.37 M-1 s-1, which are comparable to those reported for some mononuclear FeIII-OH and MnIII-OH compounds. However, such reactivity is not observed for the corresponding diiron compounds, a difference that Nature may have taken advantage of in evolving enzymes with heterobimetallic active sites.


Assuntos
Complexos de Coordenação/metabolismo , Compostos Férricos/metabolismo , Manganês/metabolismo , Ribonucleotídeo Redutases/metabolismo , Sítios de Ligação , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Compostos Férricos/química , Manganês/química , Modelos Moleculares , Estrutura Molecular , Oxigênio/química , Oxigênio/metabolismo , Ribonucleotídeo Redutases/química
13.
Inorg Chem ; 60(13): 9233-9237, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34111354

RESUMO

Two new desoxo molybdenum(V) complexes have been synthesized and characterized as models for the paramagnetic high-g split intermediate observed in the catalytic cycle of dimethyl sulfoxide reductase (DMSOR). Extended X-ray absorption fine structure (EXAFS) and electron paramagnetic resonance (EPR) data are used to provide new insight into the geometric and electronic structures of high-g split and other EPR-active type II/III DMSOR family enzyme forms. The results support a 6-coordinate [(PDT)2Mo(OH)(OSer)]- structure (PDT = pyranopterin dithiolene) for a high-g split with four S donors from two PDT ligands, a coordinated hydroxyl ligand, and a serinate O donor. This geometry orients the redox orbital toward the substrate access channel for the two-electron reduction of substrates.


Assuntos
Complexos de Coordenação/metabolismo , Proteínas Ferro-Enxofre/metabolismo , Oxirredutases/metabolismo , Serina/metabolismo , Biocatálise , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Proteínas Ferro-Enxofre/química , Ligantes , Modelos Moleculares , Estrutura Molecular , Molibdênio/química , Molibdênio/metabolismo , Oxirredução , Oxirredutases/química , Serina/química
14.
Inorg Chem ; 60(13): 9805-9819, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34115482

RESUMO

A series of nine RuII arene complexes bearing tridentate naphthoquinone-based N,O,O-ligands was synthesized and characterized. Aqueous stability and their hydrolysis mechanism were investigated via UV/vis photometry, HPLC-MS, and density functional theory calculations. Substituents with a positive inductive effect improved their stability at physiological pH (7.4) intensely, whereas substituents such as halogens accelerated hydrolysis and formation of dimeric pyrazolate and hydroxido bridged dimers. The observed cytotoxic profile is unusual, as complexes exhibited much higher cytotoxicity in SW480 colon cancer cells than in the broadly chemo- (incl. platinum-) sensitive CH1/PA-1 teratocarcinoma cells. This activity pattern as well as reduced or slightly enhanced ROS generation and the lack of DNA interactions indicate a mode of action different from established or previously investigated classes of metallodrugs.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Naftoquinonas/farmacologia , Rutênio/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cristalografia por Raios X , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Naftoquinonas/química , Rutênio/química , Água/química
15.
Inorg Chem ; 60(13): 9880-9898, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34130457

RESUMO

In the search for potential new metal-based antitumor agents, two series of nonclassical palladium(II) pincer complexes based on functionalized amides with S-modified cysteine and homocysteine residues have been prepared and fully characterized by 1D and 2D NMR (1H, 13C, COSY, HMQC or HSQC, 1H-13C, and 1H-15N HMBC) and IR spectroscopy and, in some cases, X-ray diffraction. Most of the resulting complexes exhibit a high level of cytotoxic activity against several human cancer cell lines, including colon (HCT116), breast (MCF7), and prostate (PC3) cancers. Some of the compounds under consideration are also efficient in both native and doxorubicin-resistant transformed breast cells HBL100, suggesting the prospects for the creation of therapeutic agents based on the related compounds that would be able to overcome drug resistance. An analysis of different aspects of their biological effects on living cells has revealed a remarkable ability of the S-modified derivatives to induce cell apoptosis and efficient cellular uptake of their fluorescein-conjugated counterpart, confirming the high anticancer potential of Pd(II) pincer complexes derived from functionalized amides with S-donor amino acid pendant arms.


Assuntos
Amidas/farmacologia , Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Cisteína/farmacologia , Paládio/farmacologia , Amidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cisteína/análogos & derivados , Cisteína/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Paládio/química
16.
Inorg Chem ; 60(13): 9529-9541, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34156246

RESUMO

Four bipyridine-type ligands variably derivatized with two bioactive groups (taken from ethacrynic acid, flurbiprofen, biotin, and benzylpenicillin) were prepared via sequential esterification steps from commercial 2,2'-bipyridine-4,4'-dicarboxylic acid and subsequently coordinated to ruthenium(II) p-cymene and iridium(III) pentamethylcyclopentadienyl scaffolds. The resulting complexes were isolated as nitrate salts in high yields and fully characterized by analytical and spectroscopic methods. NMR and MS studies in aqueous solution and in cell culture medium highlighted a substantial stability of ligand coordination and a slow release of the bioactive fragments in the latter case. The complexes were assessed for their antiproliferative activity on four cancer cell lines, showing cytotoxicity to the low micromolar level (equipotent with cisplatin). Additional biological experiments revealed a multimodal mechanism of action of the investigated compounds, involving DNA metalation and enzyme inhibition. Synergic effects provided by specific combinations of metal and bioactive fragments were identified, pointing toward an optimal ethacrynic acid/flurbiprofen combination for both Ru(II) and Ir(III) complexes.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Irídio/farmacologia , Piridinas/farmacologia , Rutênio/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Dano ao DNA , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Irídio/química , Ligantes , Estrutura Molecular , Piridinas/química , Rutênio/química , Células Tumorais Cultivadas
17.
Nat Commun ; 12(1): 3898, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162854

RESUMO

One topical area of supramolecular chemistry is the binding of anionic species but despite the importance of anions in diverse cellular processes and for cancer development, anion receptors or 'binders' have received little attention as potential anti-cancer therapeutics. Here we report self-assembling trimetallic cryptands (e.g. [L2(Metal)3]6+ where Metal = Cu2+, Zn2+ or Mn2+) which can encapsulate a range of anions and which show metal-dependent differences in chemical and biological reactivities. In cell studies, both [L2Cu3]6+ and [L2Zn3]6+ complexes are highly toxic to a range of human cancer cell lines and they show significant metal-dependent selective activity towards cancer cells compared to healthy, non-cancerous cells (by up to 2000-fold). The addition of different anions to the complexes (e.g. PO43-, SO42- or PhOPO32-) further alters activity and selectivity allowing the activity to be modulated via a self-assembly process. The activity is attributed to the ability to either bind or hydrolyse phosphate esters and mechanistic studies show differential and selective inhibition of multiple kinases by both [L2Cu3]6+ and [L2Zn3]6+ complexes but via different mechanisms.


Assuntos
Ânions/química , Antineoplásicos/química , Complexos de Coordenação/química , Metais/química , Células A549 , Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Western Blotting , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Cristalografia por Raios X , Células HCT116 , Células HT29 , Humanos , Concentração Inibidora 50 , Neoplasias/metabolismo , Neoplasias/patologia , Fosfotransferases/antagonistas & inibidores , Fosfotransferases/metabolismo
18.
Nat Commun ; 12(1): 3706, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34140488

RESUMO

Organometallic complexes are ubiquitous in chemistry and biology. Whereas their preparation has historically relied on ligand synthesis followed by coordination to metal centers, the ability to efficiently diversify their structures remains a synthetic challenge. A promising yet underdeveloped strategy involves the direct manipulation of ligands that are already bound to a metal center, also known as chemistry-on-the-complex. Herein, we introduce a versatile platform for on-the-complex annulation reactions using transient aryne intermediates. In one variant, organometallic complexes undergo transition metal-catalyzed annulations with in situ generated arynes to form up to six new carbon-carbon bonds. In the other variant, an organometallic complex bearing a free aryne is generated and intercepted in cycloaddition reactions to access unique scaffolds. Our studies, centered around privileged polypyridyl metal complexes, provide an effective strategy to annulate organometallic complexes and access complex metal-ligand scaffolds, while furthering the synthetic utility of strained intermediates in chemical synthesis.


Assuntos
Derivados de Benzeno/química , Complexos de Coordenação/química , Metais/química , Compostos Organometálicos/química , Carbono/química , Catálise , Complexos de Coordenação/síntese química , Ligantes , Compostos Organometálicos/síntese química , Paládio/química , Rutênio/química , Elementos de Transição/química
19.
Int J Mol Sci ; 22(9)2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-34063691

RESUMO

The constantly growing resistance of bacteria to antibiotics and other antibacterial substances has led us to an era in which alternative antimicrobial therapies are urgently required. One promising approach is to target bacterial pathogens using metal complexes. Therefore, we investigated the possibility of utilizing series of manganese(II) complexes with heteroaromatic ligands: Alcohol, aldehyde, ketone, and carboxylic acid as inhibitors for biofilm formation of Pseudomonas aeruginosa. To complete the series mentioned above, Mn-dipyCO-NO3 with dipyridin-2-ylmethanone (dipyCO) was isolated, and then structurally (single-crystal X-ray analysis) and physicochemically characterized (FT-IR, TG, CV, magnetic susceptibility). The antibacterial activity of the compounds against representative Gram-negative and Gram-positive bacteria was also evaluated. It is worth highlighting that the results of the cytotoxicity assays performed (MTT, DHI HoloMonitorM4) indicate high cell viability of the human fibroblast (VH10) in the presence of the Mn(II) complexes. Additionally, the inhibition effect of catalase activity by the complexes was studied. This paper focused on such aspects as studying different types of intermolecular interactions in the crystals of the Mn(II) complexes as well as their possible effect on anti-biofilm activity, the structure-activity relationship of the Mn(II) complexes, and regularity between the electrochemical properties of the Mn(II) complexes and anti-biofilm activity.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Complexos de Coordenação/química , Manganês/química , Álcoois/química , Aldeídos/química , Antibacterianos/química , Ácidos Carboxílicos/química , Complexos de Coordenação/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Cetonas/química , Testes de Sensibilidade Microbiana , Oxirredução/efeitos dos fármacos , Pseudomonas aeruginosa , Espectroscopia de Infravermelho com Transformada de Fourier
20.
Nat Commun ; 12(1): 3393, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099712

RESUMO

The iron gall ink-triggered chemical corrosion of hand-written documents is a big threat to Western cultural heritages, which was demonstrated to result from the iron gall (GA-Fe) chelate-promoted reactive oxygen species generation. Such a phenomenon has inspired us to apply the pro-oxidative mechanism of GA-Fe to anticancer therapy. In this work, we construct a composite cancer nanomedicine by loading gallate into a Fe-engineered mesoporous silica nanocarrier, which can degrade in acidic tumor to release the doped Fe3+ and the loaded gallate, forming GA-Fe nanocomplex in situ. The nanocomplex with a highly reductive ligand field can promote oxygen reduction reactions generating hydrogen peroxide. Moreover, the resultant two-electron oxidation form of GA-Fe is an excellent Fenton-like agent that can catalyze hydrogen peroxide decomposition into hydroxyl radical, finally triggering severe oxidative damage to tumors. Such a therapeutic approach by intratumoral synthesis of GA-Fe nano-metalchelate may be instructive to future anticancer researches.


Assuntos
Antineoplásicos/administração & dosagem , Ácido Gálico/administração & dosagem , Ferro/administração & dosagem , Nanopartículas Metálicas/administração & dosagem , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Catálise , Complexos de Coordenação/administração & dosagem , Complexos de Coordenação/química , Complexos de Coordenação/metabolismo , Portadores de Fármacos/química , Feminino , Ácido Gálico/química , Ácido Gálico/metabolismo , Células HeLa , Células Endoteliais da Veia Umbilical Humana , Humanos , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/metabolismo , Concentração de Íons de Hidrogênio , Radical Hidroxila/química , Radical Hidroxila/metabolismo , Injeções Intravenosas , Ferro/química , Ferro/metabolismo , Ligantes , Nanopartículas Metálicas/química , Camundongos , Neoplasias/patologia , Oxirredução , Oxigênio/metabolismo , Dióxido de Silício/química , Ensaios Antitumorais Modelo de Xenoenxerto
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