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1.
Org Lett ; 22(16): 6494-6499, 2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32806136

RESUMO

A simple and effective biocompatible domino reaction triggered by a model protease and leading to the formation of strongly fluorescent quinoxalin-2(1H)-one N-heterocycles is described. Some positive attributes including versatility and the ability to provide outstanding fluorescence "OFF-ON" responses were revealed by this work. They open the way for practical applications of this novel type of "covalent-assembly"-based fluorescent probe in the fields of sensing and bioimaging.


Assuntos
Corantes Fluorescentes/química , Peptídeo Hidrolases/química , Quinoxalinas/química , Estrutura Molecular , Peptídeo Hidrolases/genética , Peptídeo Hidrolases/metabolismo
2.
Dalton Trans ; 46(25): 8051-8056, 2017 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-28594007

RESUMO

Two new gold(i)-BODIPY-imidazole based trackable therapeutic bimetallic complexes have been synthesized and fully characterized. They display strong antiproliferative properties on several types of cancers including colon, breast, and prostate and one of them presents a significant anti-inflammatory effect. Additionally, the two compounds could be visualised in vitro by confocal microscopy in the submicromolar range.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Compostos de Boro/química , Complexos de Coordenação/farmacologia , Ouro/química , Imidazóis/química , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Descoberta de Drogas , Corantes Fluorescentes/química , Humanos
3.
Inorg Chem ; 55(5): 2544-57, 2016 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-26867101

RESUMO

A series of new heterodinuclear luminescent complexes with two different organic ligands have been synthesized and characterized. A luminescent Ru(II)(polypyridine) moiety and a metal-based anticancer fragment (AuCl, (p-cymene)RuCl2, (p-cymene)OsCl2, (Cp*)RhCl2, or Au-thioglucose) are the two general features of these complexes. All of the bimetallic compounds have been evaluated for their antiproliferative properties in vitro in human cancer cell lines. Only the complexes containing an Au(I) fragment exhibit antiproliferative activity in the range of cisplatin or higher. The photophysical and electrochemical properties of the bimetallic species have been investigated, and fluorescence microscopy experiments have been performed successfully. The most promising bimetallic cytotoxic complexes (i.e., with the Au-thioglucose scaffold) have shown to be easily taken up by cancer cells at 37 °C in the cytoplasm or in specific organelles. Interestingly, experiments repeated at 4 °C showed no uptake of the bimetallic species inside cells, which confirms involvement of active transport processes. To evaluate the role of glucose transporters in the cell uptake of the gold complexes, inhibition of the GluT-1 (glucose transporter isoform with high level of expression in cancer cells) was achieved, showing only scarce influence on the compounds' uptake. Finally, the observed absence of interactions with nucleic acid model structures suggests that the gold compounds may have different intracellular targets with respect to cisplatin.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Complexos de Coordenação/química , Metais/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA/efeitos dos fármacos , Humanos , Luminescência , Espectroscopia de Ressonância Magnética , Espectrofotometria Ultravioleta , Relação Estrutura-Atividade
4.
J Biol Inorg Chem ; 20(6): 1005-20, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26202908

RESUMO

While N-heterocyclic carbenes (NHC) are ubiquitous ligands in catalysis for organic or industrial syntheses, their potential to form transition metal complexes for medicinal applications has still to be exploited. Within this frame, we synthesized new homo- and heterobimetallic complexes based on the Au(I)-NHC scaffold. The compounds were synthesized via a microwave-assisted method developed in our laboratories using Au(I)-NHC complexes carrying a pentafluorophenol ester moiety and another Au(I) phosphane complex or a bipyridine ligand bearing a pendant amine function. Thus, we developed two different methods to prepare homo- and heterobimetallic complexes (Au(I)/Au(I) or Au(I)/Cu(II), Au(I)/Ru(II), respectively). All the compounds were fully characterized by several spectroscopic techniques including far infrared, and were tested for their antiproliferative effects in a series of human cancer cells. They showed moderate anticancer properties. Their toxic effects were also studied ex vivo using the precision-cut tissue slices (PCTS) technique and initial results concerning their reactivity with the seleno-enzyme thioredoxin reductase were obtained.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/uso terapêutico , Compostos Organoáuricos/síntese química , Tioglucosídeos/síntese química , Tioglucosídeos/uso terapêutico , Animais , Linhagem Celular Tumoral , Cobre , Glutationa Redutase/antagonistas & inibidores , Humanos , Compostos Organoáuricos/uso terapêutico , Ratos , Saccharomyces cerevisiae , Proteínas de Saccharomyces cerevisiae , Tiorredoxina Redutase 1/antagonistas & inibidores , Tiorredoxina Redutase 2/antagonistas & inibidores
5.
J Inorg Biochem ; 141: 10-16, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25172993

RESUMO

A series of mono- and heterodinuclear gold(I) and platinum(II) complexes with a new bipyridylamine-phosphine ligand have been synthesized and characterized. The X-ray structures of the ligand precursor 4-iodo-N,N-di(pyridin-2-yl)benzamide, and of one gold derivative are reported. All the complexes display antiproliferative properties in vitro in human cancer cells in the range of cisplatin or higher, which appear to correlate with compounds' uptake. Interestingly, studies of the interactions of the compounds with models of DNA indicate different mechanisms of actions with respect to cisplatin. The biological activity study of these complexes provides useful information about the interest of designing multimetallic complexes for enhanced cytotoxic properties.


Assuntos
Antineoplásicos/síntese química , Complexos de Coordenação/síntese química , Citotoxinas/síntese química , Compostos Organoáuricos/síntese química , Compostos Organoplatínicos/síntese química , Antineoplásicos/farmacologia , Benzamidas/química , Transporte Biológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Complexos de Coordenação/farmacologia , Citotoxinas/farmacologia , DNA/química , Humanos , Compostos Organoáuricos/farmacologia , Compostos Organoplatínicos/farmacologia , Fosfinas/química , Plasmídeos/química , Piridinas/química , Rutênio/química , Relação Estrutura-Atividade
6.
Dalton Trans ; 43(40): 15098-110, 2014 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-24819602

RESUMO

Terminal titanium imido complexes of the general formula [Ti(N(t)Bu)Cl{CH(Ph2PNR)2}] 4 (R = Ph, (i)Pr, (t)Bu) are reported. These compounds were synthesized from the corresponding Li adducts 3 of BIPMH (bis(iminophosphoranyl)methanide) and Mountford's complex [Ti(N(t)Bu)Cl2(Py)3]. The crystal structures of two of the Ti complexes (R = Ph, (t)Bu) and two of the Li compounds (R = (i)Pr, (t)Bu) are reported. Dynamic solution NMR spectroscopy reveals a dynamic isomerisation process in the case of the Ti complex 4c (R = (t)Bu). DFT studies showed that this dynamic process comes from steric repulsion between the imido ligand and the (t)Bu N-substituents on the BIPMH ligand. Complexes 4 were tested in alkyne hydroamination; 4a (R = Ph) displayed modest catalytic activity in the reaction of aniline with phenylacetylene.

7.
Inorg Chem ; 53(4): 2296-303, 2014 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-24499428

RESUMO

A new series of gold(I) N-heterocyclic carbene (NHC) complexes based on xanthine ligands have been synthesized and characterized by mass spectrometry, NMR, and X-ray diffraction. The compounds have been tested for their antiproliferative properties in human cancer cells and nontumorigenic cells in vitro, as well as for their toxicity in healthy tissues ex vivo. The bis-carbene complex [Au(caffein-2-ylidene)2][BF4] (complex 4) appeared to be selective for human ovarian cancer cell lines and poorly toxic in healthy organs. To gain preliminary insights into their actual mechanism of action, two biologically relevant in cellulo targets were studied, namely, DNA (more precisely a higher-order DNA structure termed G-quadruplex DNA that plays key roles in oncogenetic regulation) and a pivotal enzyme of the DNA damage response (DDR) machinery (poly-(adenosine diphosphate (ADP)-ribose) polymerase 1 (PARP-1), strongly involved in the cancer resistance mechanism). Our results indicate that complex 4 acts as an efficient and selective G-quadruplex ligand while being a modest PARP-1 inhibitor (i.e., poor DDR impairing agent) and thus provide preliminary insights into the molecular mechanism that underlies its antiproliferative behavior.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Cafeína/química , Ouro/química , Metano/análogos & derivados , Animais , Antineoplásicos/síntese química , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Concentração Inibidora 50 , Ligantes , Metano/química , Estrutura Molecular , Xantina/química
8.
ChemMedChem ; 9(7): 1567-73, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24449620

RESUMO

A novel Ru(II) (arene) theranostic complex is presented. It is based on a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid macrocycle bearing a triarylphosphine and can be tracked in vivo by using the γ emission of (153) Sm atoms. Notably, the heteroditopic ligand can be selectively metalated with ruthenium at the phosphorus atom despite the presence of other functionalities that are prone to metal coordination. Subsequent labeling with radionuclides such as (153) Sm can then be performed easily. The resulting heterobimetallic complex exhibits favorable solubility and stability properties in biologically relevant media. It also shows in vitro cytotoxicity in line with that expected for this type of metallodrug, and is nontoxic to the organism as a whole. As a proof of concept, initial studies in healthy mice were performed to obtain information about the uptake, biodistribution, and excretion of the radiolabeled complex.


Assuntos
Complexos de Coordenação , Compostos Radiofarmacêuticos , Rutênio/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacocinética , Complexos de Coordenação/farmacologia , Compostos Heterocíclicos com 1 Anel/química , Humanos , Marcação por Isótopo , Camundongos , Fosfinas/química , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/farmacologia , Distribuição Tecidual , Água/química
9.
Dalton Trans ; 42(17): 6102-9, 2013 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-23232925

RESUMO

A new BODIPY-phosphane was synthesized and proved to be a versatile tool for imaging organometallic complexes. It also led to easy access to a new family of theranostics, featuring gold, ruthenium and osmium complexes. The compounds' cytotoxicity was tested on cancer cells, and their cell uptake was followed by fluorescence microscopy in vitro.


Assuntos
Compostos de Boro/química , Metais/química , Fosfinas/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , Ouro/química , Humanos , Microscopia Confocal , Osmio/química , Rutênio/química
10.
Chembiochem ; 13(13): 1905-12, 2012 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-22930447

RESUMO

The targeting of higher-order DNA structures has been thoroughly developed with G-quadruplex DNA but not with other structures like branched DNA (also known as DNA junctions). Because these alternative higher-order DNA architectures might be of high biological relevance, we implemented a high-throughput version of the FRET melting assay that enabled us to map the interactions of a candidate with four different DNA structures (duplex- and quadruplex DNA, three- and four-way junctions) in a rapid and reliable manner. We also introduce a novel index, the BONDS (branched and other noncanonical DNA selectivity) index, to conveniently quantify this differential affinity.


Assuntos
Cafeína/farmacologia , DNA/química , Conformação de Ácido Nucleico/efeitos dos fármacos , Compostos Organoáuricos/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Anticarcinógenos/química , Anticarcinógenos/farmacologia , Sequência de Bases , Cafeína/análogos & derivados , Transferência Ressonante de Energia de Fluorescência , Quadruplex G/efeitos dos fármacos , Modelos Moleculares , Compostos Organoáuricos/química , Bibliotecas de Moléculas Pequenas/química , Termodinâmica
11.
Inorg Chem ; 50(19): 9472-80, 2011 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-21875041

RESUMO

An unprecedented series of titanocene-gold bi- and trimetallic complexes of the general formula [[(η(5)-C(5)H(5))(µ-η(5):κ(1)-C(5)H(4)(CH(2))(n)PPh(2))TiCl(2)](m)AuCl(x)](q+) (n = 0, 2, or 4; m = 1, x = 1, q = 0 or m = 2, x = 0, q = 1) have been prepared and characterized spectroscopically. The luminescence spectroscopy and photophysics of one of the compounds, [[(η(5)-C(5)H(5))(µ-η(5):κ(1)-C(5)H(4)PPh(2))TiCl(2)](2)Au]PF(6), have been investigated in 2MeTHF solution and in the solid state at 77 and 298 K. Evidence for interfragment interactions based on the comparison of electronic band positions and emission lifetimes, namely, triplet energy transfer (ET) from the Au- to the Ti-containing chromophores, is provided. The cytotoxicity of the complexes was evaluated on A2780 ovarian cancer cells and on their cisplatin-resistant cell line A2780cisR; the compounds showed activity in the low micromolar range that was markedly more active than the corresponding titanocene-phosphine precursors [(η(5)-C(5)H(5))(η(5)-C(5)H(4)(CH(2))(n)PPh(2))TiCl(2)], cisplatin, and, for some of them, the gold analogue [(PPh(3))AuCl]. In an attempt to draw preliminary structure-activity relationships, cell uptake measurements and interaction studies with plasmid DNA and the model protein ubiquitin (Ub) have been undertaken on some of the compounds.


Assuntos
Antineoplásicos/química , Ouro/química , Compostos Organometálicos/química , Titânio/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Ouro/farmacologia , Humanos , Luminescência , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Compostos Organometálicos/síntese química , Compostos Organometálicos/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Ultravioleta , Relação Estrutura-Atividade , Titânio/farmacologia
12.
J Med Chem ; 53(19): 6923-33, 2010 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-20822096

RESUMO

A series of bimetallic titanium-ruthenium complexes of general formula [(η(5)-C(5)H(5))(µ-η(5):κ(1)-C(5)H(4)(CR(2))(n)PR'R'')TiCl(2)](η(6)-p-cymene)RuCl(2) (n = 0, 1, 2 or 4; R = H or Me; R' = H, Ph, or Cy; R'' = Ph or Cy) have been synthesized, including two novel compounds as well as two cationic derivatives of formula [(η(5)-C(5)H(5))(µ-η(5):κ(1)-C(5)H(4)(CH(2))(n)PPh(2))TiCl(2)] [(η(6)-p-cymene)RuCl](BF(4)) (n = 0 or 2). The solid state structure of two of these compounds was also established by X-ray crystallography. The complexes showed a cytotoxic effect on human ovarian cancer cells and were markedly more active than their Ti or Ru monometallic analogues titanocene dichloride and RAPTA-C, respectively. Studies of cathepsin B inhibition, an enzyme involved in cancer progression, showed that enzyme inhibition by the bimetallic complexes is influenced by the length of the alkyl chain in between the metal centers. Complementary ESI-MS studies provided evidence for binding of a Ru(II) fragment to proteins.


Assuntos
Antineoplásicos/síntese química , Complexos de Coordenação/síntese química , Rutênio , Titânio , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Catepsina B/antagonistas & inibidores , Bovinos , Linhagem Celular Tumoral , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Cristalografia por Raios X , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Ligação Proteica , Relação Estrutura-Atividade
13.
J Phys Chem B ; 114(12): 4276-82, 2010 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-20218577

RESUMO

The complexation of UO(2)(2+) with NO(3)(-) has been investigated in the ionic liquid 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide by UV-vis spectroscopy at T = 18.5 degrees C. The complexation is evidenced through the appearance of four peaks at 425, 438, 453, and 467 nm. EXAFS data indicate that the trinitrato complex, UO(2)(NO(3))(3)(-), is dominating the speciation for a reagent ratio of [NO(3)(-)]/[UO(2)(2+)] > 3. Assuming three successive complexation steps, the conditional stability constants are calculated, the individual absorption spectra are derived, and a speciation plot is presented.

14.
Inorg Chem ; 48(3): 1236-42, 2009 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-19117419

RESUMO

The reaction between two 1,3-dialkylimidazolium-2-carboxylates 1a and 1b and two different dichlorophosphines (RPCl(2), with R = Ph and NEt(2)) led to new donor-stabilized phosphenium adducts. When the reaction was performed with the 1,3-dimethylimidazolium-2-carboxylate 1a and PhPCl(2) in a 2:1 ratio, the phosphine 4a, bearing two imidazolium moieties, was obtained and led to 5a, after an anion exchange reaction with KPF(6), the latter being fully characterized by an X-ray structure analysis. In similar conditions, the bis-imidazolium phosphine or phosphene-di-ium, 4b, which is analogous to 4a, has been obtained by the addition of PhPCl(2) to the 1-dodecyl-3-methylimidazolium-2-carboxylate 1b. However, by the use of dichloro(diethylamino)phosphine, (Et(2)N)PCl(2), instead of PhPCl(2), the reaction with 1a did not afford the biscationic phosphorus product 6a, an analogue to 4a, but, instead, the water-soluble mixed mono-imidazolium chlorophosphine 7a. Subsequently, additional kinetic experiments have been investigated to rationalize the different reactivities observed with imidazolium-2-carboxylates and the phosphorus halide derivatives. We, thus, found that the bis-imidazolium phosphine 4b was very rapidly formed in the above-mentioned reaction and was slowly converted, thereafter, back to the mixed mono-imidazolium chlorophosphine 8b in the presence of the residual starting dichlorophosphine. Additionally, the addition of PhPCl(2) to the phosphene-di-ium 4b represents, to our knowledge, the first example of a P-substituent exchange reaction involving a P-C bond formation in imidazolium phosphines. On the other hand, the air stability and the solubility of these new cationic functional phosphines in different media render such ligands very appealing in coordination chemistry for catalysis in mono- or biphasic media.

15.
J Phys Chem B ; 113(4): 1085-99, 2009 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-19128051

RESUMO

Several earlier studies of the electrochemical oxidation of ferrocene (Fc) in room-temperature ionic liquids revealed an essentially nonlinear dependence of the oxidation current on the Fc concentration in its relatively dilute solutions, with its formally calculated diffusion coefficient strongly increasing with the concentration. Since no plausible mechanism leading to this very unusual finding had been proposed, our study of Fc solutions in 1-butyl-3-methylimidazolium triflimide, [BMIM][NTf(2)], was performed to verify whether the above observation originated from an incorrect determination of the dissolved Fc concentration. Our observations have demonstrated that reliable control of the Fc concentration in solution is complicated by factors such as the low amount of Fc used to prepare small-volume solutions or the great difficulty to dissolve completely a solid powder in a solvent with an extremely high viscosity. An unexpected additional complication is related to a sufficiently high volatility of Fc which manifests itself even at room temperature and especially at elevated temperatures or/and in the course of vacuum treatment of its solutions or its solid powder. Parallel measurements of electrochemical responses and UV-visible spectra for several series of Fc solutions of various concentrations (prepared with the use of different procedures) have shown a perfect parallelism between the peak current and the intensity of the absorption band in the range of 360-550 nm, leading us to the conclusion of a linear relationship between the oxidation current and the molecularly dissolved Fc concentration. The relations of these measured characteristics with the estimated Fc concentration in these solutions have demonstrated a much greater dispersion (attributed to the difficulty of a precise measurement of the latter) but without a significant deviation from the linearity in general. This finding has allowed us to estimate the diffusion coefficient of this species: D = (1.7 +/- 0.2) x 10(-7) cm(2)/s. The extinction coefficients for the maximum of the absorption band (at 440 nm) of Fc have been compared for a series of solvents: [BMIM][NTf(2)], acetonitrile, THF, heptane, CH(2)Cl(2), ethanol, and toluene. A simple method to estimate reliably the concentration of solute Fc in ionic liquids based on spectroscopic measurements has been proposed, owing to the proximity of Fc absorption properties for a great variety of solvents.

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