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1.
J Inorg Biochem ; 203: 110926, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31759264

RESUMO

Phosphonium salt (p-OCH3-Ph)2P(CH2OH)2Cl (MPOHC), derived phosphine ligands without and with SarGly (Sarcosine-Glycine) peptide carrier P(p-OCH3-Ph)2CH2OH (MPOH) and P(p-OCH3-Ph)2CH2SarGly (MPSG), respectively, and two copper(I) complexes [Cu(I)(dmp)(MPOH)] (1-MPOH; dmp = (2,9-dimethyl-1,10-phenanthroline)) and [Cu(I)(dmp)(MPSG)] (1-MPSG) were synthesized. The resulting compounds were characterized by elemental analysis, 1D and 2D NMR and UV-Vis absorption spectroscopies, mass spectrometry, cyclic voltammetry and by X-ray diffraction analysis. Cytotoxicity of all compounds was evaluated in vitro against colon, lung, breast, pancreatic, prostate tumor cell lines, as well as towards non-tumor cell lines: lung, kidney and keratinocyte. Stable in biological medium in the presence of atmospheric oxygen, Cu(I) complexes exerted a cytotoxic effect higher than that elicited by cisplatin against tested cancer cell lines. The introduction of methoxy group onto the phenyl rings of the phosphine ligand coordinated to the copper(I) ion resulted in a relevant increase of cytotoxicity in the case of breast, pancreatic and prostate tumor cell lines in vitro. Attachment of a peptide carrier significantly increased the selectivity towards cancer cells. Fluorescence spectroscopic data (calf thymus DNA: CT-DNA) titration), together with analysis of DNA fragmentation (gel electrophoresis) and molecular docking provided evidence for the multimodal interaction of copper compounds with DNA and showed their unusual low genotoxicity. Additionally, copper complexes were able to generate reactive oxygen species as a result of redox processes, proved by fluorescence spectroscopy and cyclic voltamperometry.

2.
Metallomics ; 11(11): 1800-1804, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31657408

RESUMO

Model peptides relevant to hCtr1 transchelate CuI from the anti-tumour [CuI(PTA)4]+ complex before metal internalization into tumor cells. ESI(+)MS experiments corroborated by DFT calculations indicate that tetracoordinated-CuII and linear-CuI arrangements of in situ generated copper-peptide products play a crucial role in promoting the transfer of copper from the terminal MDH portion into adjacent HSH peptide sequence.

3.
J Mass Spectrom ; 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31663260

RESUMO

Considering the high complexity of natural extracts, because of the presence of organic molecules of different chemical nature, the possibility of formation of noncovalent complexes should be taken into account. In a previous investigation, the formation of bimolecular complexes between caffeine and catechins in green tea extracts (GTE) has been experimentally proven by means of mass spectrometric and 1 H nuclear magnetic resonance experiments. The same approaches have been employed in the present study to evaluate the presence of bimolecular complexes in Ceylon tea and mate extracts. The obtained results show that in the case of Ceylon tea extracts, protonated theaflavin is detectable, together with theaflavin/caffein complexes, while caffeine/catechin complexes, already detected in green tea, are still present but at lower concentration. This aspect is evidenced by the comparison of precursor ion scans performed on protonated caffeine for the two extracts. The spectra obtained in these conditions for GTE and Ceylon tea show that the complexes of caffeine with epigallocatechin (EGC), epicatechin gallate (ECG), and epigallocatechin gallate (EGCG), highy abundant in the case of GTE (signal-to-chemical noise ratio in the range 50-100), are negligible (signal-to-chemical noise ratio in the range 2-3) in the case of Ceylon tea. Mate extracts show the formation of bimolecular complexes involving caffeine but not catechins, and chlorogenic acid becomes responsible for other complex formation. Under positive ion and negative ion conditions, accurate mass measurements allow the identification of malealdehyde, chlorogenic acid, caffeine, two isomers of dicaffeoylquinic acid, rutin, and kaempferol-3-O-rutinoside. These data indicate that the formation of complexes in natural extracts is a common behavior, and their presence must be considered in the description of natural extracts and, consequently, in their biological activity.

4.
Nanomaterials (Basel) ; 9(5)2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31137492

RESUMO

Gold nanoparticles (AuNPs), which are strongly hydrophilic and dimensionally suitable for drug delivery, were used in loading and release studies of two different copper(I)-based antitumor complexes, namely [Cu(PTA)4]+ [BF4]- (A; PTA = 1, 3, 5-triaza-7-phosphadamantane) and [HB(pz)3Cu(PCN)] (B; HB(pz)3 = tris(pyrazolyl)borate, PCN = tris(cyanoethyl)phosphane). In the homoleptic, water-soluble compound A, the metal is tetrahedrally arranged in a cationic moiety. Compound B is instead a mixed-ligand (scorpionate/phosphane), neutral complex insoluble in water. In this work, the loading procedures and the loading efficiency of A and B complexes on the AuNPs were investigated, with the aim to improve their bioavailability and to obtain a controlled release. The non-covalent interactions of A and B with the AuNPs surface were studied by means of dynamic light scattering (DLS), UV-Vis, FT-IR and high-resolution x-ray photoelectron spectroscopy (HR-XPS) measurements. As a result, the AuNPs-A system proved to be more stable and efficient than the AuNPs-B system. In fact, for AuNPs-A the drug loading reached 90%, whereas for AuNPs-B it reached 65%. For AuNPs-A conjugated systems, a release study in water solution was performed over 4 days, showing a slow release up to 10%.

5.
J Nat Prod ; 81(11): 2338-2347, 2018 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-30372064

RESUMO

A hypothesis on the peculiar pharmacological behavior of biologically active natural compounds is based on the occurrence of molecular interactions originating from the high complexity of the natural matrix, following the rules of supramolecular chemistry. In this context, some investigations were performed to establish unequivocally the presence of caffeine/catechin complexes in green tea extracts (GTEs). 1H NMR spectroscopy was utilized to compare profiles from GTEs with caffeine/catechin mixtures in different molar ratios, showing that peaks related to caffeine in GTEs are generally upfield shifted compared to those of free caffeine. On the other hand, ESIMS experiments performed on GTE, by means of precursor ion scan and neutral loss scan experiments, proved unequivocally the presence of caffeine/catechin complexes. Further investigations were performed by an LC-MS method operating at high-resolution conditions. The reconstructed ion chromatograms of the exact mass ions corresponding to caffeine/catechin species have been obtained, showing the presence of complexes of caffeine with gallate-type catechins. Furthermore, this last approach evidenced the presence of the same complex with different structures, consequently exhibiting different retention times. Both MSE and product ion MS/MS methods confirm the nature of caffeine/catechin complexes of the detected ions, showing the formation of protonated caffeine.


Assuntos
Cafeína/análise , Camellia sinensis/química , Catequina/análise , Extratos Vegetais/química , Cafeína/química , Catequina/química , Cromatografia Líquida , Estrutura Molecular , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray
6.
J Inorg Biochem ; 188: 50-61, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30121398

RESUMO

The chemistry of copper(I) with water-soluble phosphines is an emergent area of study which has the objective of finding ligands that stabilize copper in its lower oxidation state. Cu(I) has been found relevant in the mechanism of copper transports into cells, and the accessibility of this oxidation state has implications in oxidative stress processes. For these reasons the possibility to deal with stable, water soluble copper(I) is an attractive approach for devising new biologically relevant metal-based drugs and chelating agents. Here we present the X-ray absorption spectroscopy (XAS) and UV-visible spectrophotometric study of the [Cu(PTA)4]BF4 complex (PTA = aminophosphine­1,3,5­triaza­7­phosphaadamantane). In particular, we have studied the stability of the [Cu(PTA)n]+ species (n = 2-4) in aqueous medium, and their speciation as a function of the total [Cu(PTA)4]BF4 concentration by means of competitive UV-visible spectrophotometric titrations using metallochromic indicators. Also, the structure in solution of the Cu(I)/PTA species and the nature of the first coordination sphere of the metal were studied by transformed XAS. Both techniques allowed to study samples with total [Cu(PTA)4]BF4 concentration down to 68-74 µM, possibly relevant for biological applications. Overall, our data suggest that the [Cu(PTA)n]+ species are stable in solution, among which [Cu(PTA)2]+ has a remarkable thermodynamic stability. The tendency of this last complex to form adducts with N-donor ligands is demonstrated by the spectrophotometric data. The biological relevance of PTA towards Cu(I), especially in terms of chemotreatments and chelation therapy, is discussed on the basis of the speciation model the Cu(I)/PTA system.


Assuntos
Adamantano/análogos & derivados , Complexos de Coordenação/química , Cobre/química , Modelos Moleculares , Compostos Organofosforados/química , Termodinâmica , Adamantano/química , Oxirredução
7.
Rapid Commun Mass Spectrom ; 32(15): 1199-1206, 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-29740881

RESUMO

RATIONALE: fac-[Re(CO)3 (PO)(X)]-type complexes (PO = chelated bidentate tertiary phosphine (1-), X = various neutral, mono-dentate ligands) represent a class of compounds that meets the synthetic criteria for the preparation of potential carbon monoxide (CO) release molecules (CORMs) for medicinal application. The aim of our investigation was to achieve qualitative information whether the nature of the ancillary X ligand might influence the release of CO. METHODS: The release of CO has been investigated by means of product ion spectrometry of electrospray ionization (ESI)-generated [M + H]+ species, produced by multiple collisional experiments, using an ion trap mass spectrometer. RESULTS: Tandem mass spectrometry applied to the protonated species [Re(CO)3 (PO)(X) + H]+ of seven complexes (those including X = OH2 (1), isonitrile (2, 3), imidazole (4), pyridine (5) and phosphine (6, 7)) shows initial loss of coordinated water (1) or pyridine (5), whereas the majority of investigated entries display initial, sequential release of CO groups. The energetics of CO release have been investigated by breakdown curves for selected collisionally activated decomposition processes involving CO, and compared with those involving X groups. CONCLUSIONS: The nature of the co-ligand X drives the primary loss in the MSn processes of [Re(CO)3 (PO)(X) + H]+ compounds. When X = solvent, the energetics of these decompositions follow the trend H2 O < MeOH < CO. In each case, loss of CO is a favored fragmentation route with associated energies following the trend: N-py ≤ P-phosphine < C-isonitrile. Overall, MSn pathways indicate that [Re(PO)] (Re with chelated PO phosphine) constitutes the residual moiety. This behavior indicates that the presence of a functionalized phosphine is essential for a sequential, controlled release of CO.

8.
Eur J Med Chem ; 146: 709-746, 2018 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-29407992

RESUMO

Within the research field of antitumor metal-based agents alternative to platinum drugs, gold(I/III) coordination complexes have always been in the forefront due mainly to the familiarity of medicinal chemists with gold compounds, whose application in medicine goes back in the ancient times, and to the rich chemistry shown by this metal. In the last decade, N-heterocyclic carbene ligands (NHC), a class of ligands that largely resembles the chemical properties of phosphines, became of interest for gold(I) medicinal applications, and since then, the research on NHC-gold(I/III) coordination complexes as potential antiproliferative agents boosted dramatically. Different classes of gold(I/III)-NHC complexes often showed an outstanding in vitro antiproliferative activity, however up to now very few in vivo data have been reported to corroborate the in vitro results. This review summarizes all achievements in the field of gold (I/III) complexes comprising NHC ligands proposed as potential antiproliferative agents in the period 2004-2016, and critically analyses biological data (mainly IC50 values) in relation to the chemical structures of Au compounds. The state of art of the in vivo studies so far described is also reported.


Assuntos
Antineoplásicos/farmacologia , Ouro/farmacologia , Compostos Heterocíclicos/farmacologia , Metano/análogos & derivados , Animais , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ouro/química , Compostos Heterocíclicos/química , Humanos , Metano/química , Metano/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade
9.
Sci Rep ; 7(1): 13936, 2017 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-29066771

RESUMO

[Cu(thp)4][PF6] (HydroCuP) is a phosphino copper(I) complex highly soluble and stable in physiological media that has been developed as a possible viable alternative to platinum-based drugs for anticancer therapy. HydroCuP potently inhibited the growth of human cancer cells derived from solid tumors by inducing endoplasmatic reticulum (ER) stress thus leading to cell death through paraptosis with a preferential efficacy against cancer rather than non-cancer cells. Aim of the present study was to assess the therapeutic potential of HydroCuP in vivo, in syngenic and xenograft murine models of solid tumors by triggering the Unfolded Protein Response (UPR) pathway. With respect to platinum drugs, HydroCuP induced a markedly higher reduction of tumor growth associated with minimal animal toxicity. In human colorectal cancer xenografts, chemotherapy with HydroCuP was extremely effective in both oxaliplatin-sensitive and resistant models. The favorable in vivo tolerability of HydroCuP was also correlated to an encouraging biodistribution profile. Additionally, no signs of drug-related neurotoxicity and nephrotoxicity were observed. Altogether, these results demonstrate that HydroCuP appears worth of further investigation to evaluate its therapeutic activity towards a broad spectrum of solid malignancies.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Cobre/química , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Fosfinas/química , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Camundongos , Compostos Organometálicos/efeitos adversos , Compostos Organometálicos/farmacocinética , Distribuição Tecidual , Resposta a Proteínas não Dobradas/efeitos dos fármacos
10.
Dalton Trans ; 46(5): 1455-1466, 2017 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-28074209

RESUMO

The complexes of Cu(i) and Ag(i) with 1,3,5-triaza-7-phosphadamantane (PTA) are currently studied for their potential clinical use as anticancer agents, given the cytotoxicity they exhibited in vitro towards a panel of several human tumor cell lines. These metallodrugs are prepared in the form of [M(PTA)4]+ (M = Cu+, Ag+) compounds and dissolved in physiological solution for their administration. However, the nature of the species involved in the cytotoxic activity of the compounds is often unknown. In the present work, the thermodynamics of formation of the complexes of Cu(i) and Ag(i) with PTA in aqueous solution is investigated by means of potentiometric, spectrophotometric and microcalorimetric methods. The results show that both metal(i) ions form up to four successive complexes with PTA. The formation of Ag(i) complexes is studied at 298.15 K in 0.1 M NaNO3 whereas the formation of the Cu(i) one is studied in 1 M NaCl, where Cu(i) is stabilized by the formation of three successive chloro-complexes. Therefore, for this latter system, conditional stability constants and thermodynamic data are obtained. To estimate the affinity of Cu(i) for PTA in the absence of chloride, Density Functional Theory (DFT) calculations have been done to obtain the stoichiometry and the relative stability of the possible Cu/PTA/Cl species. Results indicate that one chloride ion is involved in the formation of the first two complexes of Cu(i) ([CuCl(PTA)] and [CuCl(PTA)2]) whereas it is absent in the successive ones ([Cu(PTA)3]+ and [Cu(PTA)4]+). The combination of DFT results and thermodynamic experimental data has been used to estimate the stability constants of the four [Cu(PTA)n]+ (n = 1-4) complexes in an ideal non-complexing medium. The calculated stability constants are higher than the corresponding conditional values and show that PTA prefers Cu(i) to the Ag(i) ion. The approach used here to estimate the hidden role of chloride on the conditional stability constants of Cu(i) complexes may be applied to any Cu(i)/ligand system, provided that the stoichiometry of the species in NaCl solution is known. The speciation for the two systems shows that the [M(PTA)4]+ (M = Cu+, Ag+) complexes present in the metallodrugs are dissociated into lower stoichiometry species when diluted to the micromolar concentration range, typical of the in vitro biological testing. Accordingly, [Cu(PTA)2]+, [Cu(PTA)3]+ and [Ag(PTA)2]+ are predicted to be the species actually involved in the cytotoxic activity of these compounds.

11.
Rapid Commun Mass Spectrom ; 31(2): 179-192, 2017 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-27806439

RESUMO

RATIONALE: [Cu(P)4 ][BF4 ]-type complexes (P = tertiary phosphine) have shown significant antitumor activity. This biological property appears to be activated via formation of coordinative unsaturated [Cu(P)n ]+ species (n < 4), that may interact with various molecules starting from the solvent(s) in which they are dissolved. Aim of our study was to investigate the interaction of these species with different solvent mixtures. METHODS: The interaction has been investigated by electrospray ionization mass spectrometry, and the interaction products have been characterized by multiple collisional experiments, using an ion trap mass instrument. Density functional theory (DFT) calculation studies, using a meta-hybrid exchange correlation (xc) functional and an implicit solvent model, were employed to investigate the equilibrium distribution of species in solution. RESULTS: Depending on the nature of the solvent mixture and coordinated phosphine, three [Cu(P)4 ][BF4 ]-type complexes undergo dissociation with formation of [Cu(P)2 ]+ , [Cu(P)(solv)]+ and [Cu(solv)2 ]+ species (solv = solvent). Preferred collisional-induced fragmentation pathways provide qualitative information on the selectivity of [Cu(P)n ]+ for specific solvents and donor atoms. Formation free energies and equilibrium constants pertaining to [CuI (PTA)n ]+ , [CuI/II (solv)n ]m+ (n ≤ 4; m = 1, 2) and [CuI (PTA)2-k (sol)k ]+ (k = 1, 2) provide a comprehensive picture of equilibria in solution. CONCLUSIONS: Dimethyl sulfoxide (DMSO) and acetonitrile (MeCN) strongly affect [Cu(P)n ]+ assemblies producing mixed-ligand [Cu(P)(DMSO)]+ and [Cu(P)(MeCN)]+ species. Excess of both DMSO and MeCN solvents are able to fully displace coordinated phosphines giving [Cu(solv)2 ]+ -type adducts. The presence of phosphines in the native complex is mandatory to retain the reduced oxidation state of copper. Instead, the more labile [CuI (MeCN)4 ]+ complex dissolved in DMSO and MeCN displays a combination of Cu(I) and Cu(II) adducts. Copyright © 2016 John Wiley & Sons, Ltd.

12.
Eur J Mass Spectrom (Chichester) ; 22(5): 275-287, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27882894

RESUMO

Tetrahedral [Cu(P)4][BF4]-type complexes (P = tertiary phosphine) are a class of monopositively charged compounds that have shown notable antitumor activity in both in vitro and in vivo tests. This biological property appears to be related to the peculiar physicochemical characteristics of these compounds. Although thermodynamically stable, they are labile at micromolar concentrations. Such a behavior allows the Cu(I) ion in [Cu(P)n]+ assemblies (n < 4) to interact with surrounding molecules, including the rich peptide/protein environment that metal complexes have to face in the physiological milieu on the way to tumor cells. The scope of this investigation was to study the interaction products that originate from the treatment in water/methanol mixtures of representative phosphino Cu(I) compounds with an excess of individual amino acids (AAs) selected on the basis of the donor atom likely involved in metal coordination (i.e. O-glycine, S-methionine and N-histidine). These interactions have been investigated in electrospray ionization mass spectrometry (ESI-MS), mainly in the positive ion mode [ESI(+)MS], and the interaction products have been characterized by sequential collisional experiments, performed by an ion trap instrument. Histidine and methionine, but not glycine, were able to mine Cu(I) from [Cu(P)n]+ assemblies through the formation of mixed [CuI(P)(AA)]+ and eventually [CuI(AA)2]+ adducts. The ability to substitute phosphine(s) by AAs and the strongest affinity for Cu(I) was proved by the study of the energetics of collisional-induced decomposition (CID) reactions [CuI(P)(AA)]+ → CuI(AA) + P]+. Among the investigated AAs, histidine displayed the strongest affinity for Cu(I). Transchelation of Cu(I) was similarly observed when [Cu(P)n]+ species were treated with the model tripeptide GlyGlyHis (GGH), the most investigated member of the amino terminal Cu(II) and Ni(II) (ATCUN) peptide family. GGH was able to form robust metal adducts not only with Cu(II) and the related divalent Zn(II) and Ni(II) ions, but also with monovalent ions, including Cu(I) and Ag(I). CID pathways of [CuI(GGH)]+ and [AgI(GGH)]+ were qualitatively superimposable and proceeded through losses of neutral fragments. Similar losses of neutral fragments were observed from [ZnII(GGH)] and [NiII(GGH)]. CID pathways of [CuII(GGH)]-/+ adducts instead took place mainly through intramolecular electron-transfer reactions comprising the reduction of Cu(II) to Cu(I) and the formation of fragment radical cations.


Assuntos
Aminoácidos/química , Cobre/química , Citotoxinas/química , Peptídeos/química , Fosfinas/química , Espectrometria de Massas por Ionização por Electrospray/métodos , Aminoácidos/análise , Sítios de Ligação , Cobre/análise , Citotoxinas/análise , Peptídeos/análise , Fosfinas/análise , Ligação Proteica
13.
J Inorg Biochem ; 165: 80-91, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27449160

RESUMO

The phosphane Cu(I) complex [Cu(thp)4][PF6], 1 (thp=tris(hydroxymethyl)phosphane) shows notable in vitro antitumour activity against a wide range of solid tumours. Uptake experiments performed in 1-treated colon cancer cells by atomic absorption spectrometry, reveal that the antiproliferative activity is consistent with the intracellular copper content. The solution chemistry of this agent, investigated by means of X-ray Absorption Spectroscopy and spectrophotometric titrations in aqueous media, indicates that 1 is labile giving coordinative unsaturated [Cu(thp)n]+ species (n=3 and 2) at micromolar concentrations. [Cu(thp)n]+ are reactive species that yield the mixed-ligand complex [Cu(thp)2(BCS)]- (BCS: bathocuproinedisulphonate(2-)) upon interaction with N,N-diimine. Analogously, [Cu(thp)n]+ interact with the methionine-rich peptide sequence (Ac-MMMMPMTFK-NH2; Pep1), relevant in the recruiting of physiological copper, giving [Cu(thp)(Pep1)]+ and [Cu(Pep1)]+ species. The formation of these adducts was assessed by electrospray mass spectrometry in the positive ion mode and validated by density functional theory investigations. The possibility to trans-chelate Cu(I) from pure inorganic [Cu(thp)n]+ assemblies into more physiological adducts represents a pathway that complex 1 might follow during the internalization process into cancer cells.


Assuntos
Antineoplásicos , Cobre , Citotoxinas , Neoplasias/tratamento farmacológico , Compostos de Fósforo , Antineoplásicos/química , Antineoplásicos/farmacologia , Células CACO-2 , Quelantes/química , Quelantes/farmacologia , Cobre/química , Cobre/farmacologia , Citotoxinas/química , Citotoxinas/farmacologia , Células HeLa , Células Hep G2 , Humanos , Células MCF-7 , Neoplasias/metabolismo , Neoplasias/patologia , Compostos de Fósforo/química , Compostos de Fósforo/farmacologia
14.
Rapid Commun Mass Spectrom ; 29(3): 253-62, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26411623

RESUMO

RATIONALE: The cytotoxic activity of the copper(I) complex [Cu(thp)4][PF6] (CP) (thp = tris(hydroxymethyl) phosphine) is correlated with its high accumulation in cancer cells. Human copper transporter 1 (hCtr1) has been described as the main trans-membrane protein involved in cellular trafficking of physiological copper. Methionine-rich peptide sequences incorporated in the extracellular domain of hCtr1 play a key role in the cellular internalization of copper. We wish to investigate the interaction of CP with model peptides that mimic the extracellular domain of hCtr1. METHODS: The interaction of CP with methionine-rich and methionine-free model peptides has been investigated by electrospray ionization mass spectrometry and the interaction products have been characterized by multiple collisional experiments, using an ion trap mass instrument. RESULTS: The interaction of CP with selected methionine-rich model peptides, Ac-MMMMPMTFK-NH2 (P1) and Ac-MGMSYMDSK-NH2 (P2), shows that the native copper complex, after sequential loss of phosphines, induces the formation of [Cu(P1)(thp)](+) and [Cu(P1/P2)](+) adducts reasonably by inclusion of the Cu(I) ion in the peptide framework. Collisionally induced fragmentations (MS(n)) of [Cu(P1/P2)](+) give evidence that the metal is coordinated by the thioether-S of two adjacent methionine residues. Interaction of the same peptides with the isostructural complex [Ag(thp)4](+) or AgNO3 yields similar experimental evidence, leading to [Ag(P1/P2)](+). CONCLUSIONS: Methionine sequences incorporated in model peptides are crucial for the recruitment of copper from CP. Such a metal-peptide interaction does not take place when methionine-free Ac-NleGNleSYNleDSK-NH2 (P3) is utilized. A mechanism for tumor cell internalization of CP involving: (i) chemically driven sequential loss of phosphines from the native tetrahedral complex, followed by (ii) transfer of Cu(I) to the methionine-rich sequences typical of the hCtr1 transporter, is proposed.


Assuntos
Antineoplásicos/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Complexos de Coordenação/metabolismo , Cobre/metabolismo , Peptídeos/metabolismo , Fosfinas/metabolismo , Sequência de Aminoácidos , Antineoplásicos/química , Proteínas de Transporte de Cátions/química , Complexos de Coordenação/química , Cobre/química , Transportador de Cobre 1 , Humanos , Metionina/química , Metionina/metabolismo , Peptídeos/química , Fosfinas/química , Espectrometria de Massas por Ionização por Electrospray
15.
J Med Chem ; 57(11): 4745-60, 2014 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-24793739

RESUMO

Tetrahedral copper(I) TpCuP complexes 1-15, where Tp is a N,N,N-tris(azolyl)borate and P is a tertiary phosphine, have been synthesized and characterized by means of NMR, ESI-MS, and XAS-EXAFS, and X-ray diffraction analyses on the representative complexes 1 and 10, respectively. All copper(I) complexes were evaluated for their antiproliferative activity against a panel of human cancer cell lines (including cisplatin and multidrug-resistant sublines). The two most effective complexes [HB(pz)3]Cu(PCN), 1, and [HB(pz)3]Cu(PTA), 2, showed selectivity toward tumor vs normal cells, inhibition of 26S proteasome activity associated with endoplasmic reticulum (ER) stress, and unfolded protein response (UPR) activation. No biochemical hallmarks of apoptosis were detected, and morphology studies revealed an extensive cytoplasmic vacuolization coherently with a paraptosis-like cell death mechanism. Finally, the antitumor efficacy of complex 1 was validated in the murine Lewis Lung Carcinoma (LLC) model.


Assuntos
Antineoplásicos/síntese química , Azóis/química , Boratos/química , Quelantes/química , Complexos de Coordenação/síntese química , Cobre , Fosfinas/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Estresse do Retículo Endoplasmático , Camundongos , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/síntese química , Inibidores de Proteassoma/química , Inibidores de Proteassoma/farmacologia , Relação Estrutura-Atividade , Resposta a Proteínas não Dobradas
17.
Rapid Commun Mass Spectrom ; 27(17): 2019-27, 2013 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-23939970

RESUMO

RATIONALE: To try to find a correlation between the antiproliferative activity of a series of [M(I)(P)4](+) complexes (M = Cu, Ag and Au; P = tertiary phosphine) and their stability at micromolar concentration under mass spectrometric conditions. METHODS: [M(I)(P)4](+) complexes were investigated by positive ion electrospray ionization mass spectrometry with multiple collisional experiments using an ion trap mass spectrometer. RESULTS: The displacement of P from native [M(I)(P)4](+), previously described for the copper derivative, is common for the triad complexes leading to the formation of [M(P)3](+) and [M(P)2](+) adducts. Further dissociation of [M(P)2](+) depends on the nature of the metal (Cu ~ Ag > Au). More labile [Cu(P)2](+) and [Ag(P)2](+) are more cytotoxic against HCT-15 human colon carcinoma cells compared to less labile [Au(P)2](+) species. CONCLUSIONS: The dissociation of P ligand(s) from the [M(I)(P)4](+) complexes is the driving force for the triggering of the antiproliferative activity. The more favored is the displacement of P from the [M(P)2](+) active form, the more favored is in turn the possibility for the metal to interact with biological substrates related to cancer proliferation.


Assuntos
Cobre/química , Ouro/química , Fosfinas/química , Fosfinas/toxicidade , Prata/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cobre/toxicidade , Ouro/toxicidade , Humanos , Prata/toxicidade , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade
18.
J Med Chem ; 56(18): 7416-30, 2013 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-23964823

RESUMO

Novel tetrahedral copper(I) mixed-ligand complexes of the type [Cu(X)(N(∩)N)(PCN)], 3-10, where X = Cl or Br, N(∩)N = 2,2'-bipyridine (bipy), 1,10-phenanthroline (phen), 5,6-dimethyl-1,10-phenanthroline (dmp), and dipyrido-[3,2-d:2',3'-f]-quinoxaline (dpq), and PCN = tris-(2-cyanoethyl)phosphine, have been synthetized and characterized by NMR, ESI-MS, and X-ray diffraction on two representative examples, [CuCl(phen)(PCN)]·DMF (5·DMF) and [CuBr(dpq)(PCN)]·2DMF (10·2DMF). Cu(I) complexes were evaluated for their in vitro antitumor properties against a panel of human cancer cell lines, including cisplatin- and multidrug-resistant sublines. The most effective complex, [CuCl(dpq)(PCN)] (9), exhibited nanomolar cytotoxicity toward both sensitive and resistant cancer cells, but it significantly inhibited the growth of cultured normal cells. In vitro DNA assays and single cell gel electrophoresis revealed that 9 induced DNA fragmentation resulting in cell apoptosis. In parallel, fluorescence in situ hybridization (FISH) micronucleus assay attested high levels of genotoxicity following treatment of peripheral blood lymphocytes with complex 9, suggesting that the potential risk posed by diimine metal complexes should be carefully reconsidered.


Assuntos
Cobre/química , Iminas/química , Compostos Organometálicos/efeitos adversos , Compostos Organometálicos/farmacologia , Aneugênicos/efeitos adversos , Aneugênicos/química , Aneugênicos/metabolismo , Aneugênicos/farmacologia , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Transporte Biológico , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , DNA/genética , DNA/metabolismo , Fragmentação do DNA/efeitos dos fármacos , Humanos , Ligantes , Testes para Micronúcleos , Modelos Moleculares , Conformação Molecular , Compostos Organometálicos/química , Compostos Organometálicos/metabolismo , Relação Estrutura-Atividade
19.
Eur J Med Chem ; 59: 218-26, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23229057

RESUMO

Ligand-exchange reactions of copper(I) precursors ([Cu(CH(3)CN)(4)]BF(4), CuCl) with a panel of bis(azolyl)borates or poly(pyrazolyl)methanes and a tertiary monodentate phosphine (PTA = 1,3,5-triaza-7-phosphaadamantane, PCN = tris(cyanoethyl)phosphine) produced two series of heteroleptic, either '2 + 1 + 1'- or '3 + 1'-type complexes, which have been characterized by elemental analysis, FT-IR, ESI-MS and multinuclear (31)P and (1)H NMR. '2 + 1 + 1'-type complexes include a N,N-bidentate chelate and two monodentate phosphines (1-8) and '3 + 1'-type complexes comprise a N,N,O- or N,N,N-tridentate chelate and one monodentate phosphine (9-12). All these complexes adopt a four-coordinate, tetrahedral geometry. '3 + 1' complexes show better red-ox stability and a greater tendency to retain the native '3 + 1' mixed-ligand structure. Conversely, '2 + 1 + 1' complexes exhibit increased propensity to dissociation as shown by ESI-MS measurements and X-ray structure determination at low temperature (150 K) of the polymeric complex {[H(2)B(tz(NO2))(2)]Cu[PCN]}(n)6b. In this complex, either the bis(triazolyl)borate and the PCN ligands act as bidentate, with PCN being also the µ(2)-bridiging linker between adjacent monomers. Compound 6b is the first reported example of a polymeric PCN compound with a tetra-coordinate metal centre. Cytotoxic activity of all compounds has been evaluated by MTT test against a panel of several human tumor cell lines including examples of breast (MCF-7), colon (HCT-15 and LoVo), lung (A549), cervix (A431) and ovarian (2008 and its cisplatin resistant variant, C13*) carcinoma, melanoma (A375) and promyelocytic leukemia (HL60). Copper complexes generally show in vitro antitumour activity comparable to that of cisplatin. In particular, neutral '3 + 1'-type complexes 9 and 10, show IC(50) values appreciably lower than those exhibited by the reference metallodrug.


Assuntos
Antineoplásicos , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Cobre/química , Cobre/farmacologia , Fosfinas/química , Fosfinas/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Humanos , Concentração Inibidora 50 , Ligantes , Estrutura Molecular
20.
Nucl Med Biol ; 39(3): 335-46, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22136886

RESUMO

INTRODUCTION: The neutral complex [(99m)Tc(N)(NOEt)(2)], often referred to as TcN-NOET [NOEt=N-ethoxy,N-ethyldithiocarbamate(1-)], was proposed several years ago as a myocardial imaging agent. Despite some favorable clinical properties evidenced during phase I and phase II studies, the overall results of the European and American phase III clinical studies have been judged insufficient for a successful approval process by the regulatory agencies. METHODS: Non-carrier-added and carrier-added experiments using short-lived (99m)Tc and long-lived (99g)Tc have been utilized to prepare a series of bis-substituted [Tc(N)(DTC)(2)] complexes [DTC=dithiocarbamate(1-)]. They have been purified by means of chromatographic techniques (high-performance liquid chromatography and thin-layer chromatography) and identified via double detection (UV-vis and radiometry) by comparison with authenticated samples of (99g)Tc compounds prepared by conventional coordination chemistry procedures. RESULTS: The molecular structure of the lipophilic, neutral complex cis-[Tc(N)(NOEt)(2)] has been assigned by comparison with similar nitrido-Tc(V) complexes already reported in the literature. Novel bis-substituted nitrido-Tc complexes containing hydrolyzed portions of coordinated NOEt, namely, N-ethyldithiocarbamate [NHEt(1-)] and N-hydroxy, N-ethyldithiocarbamate [NOHEt(1-)], have been prepared and characterized by means of multinuclear nuclear magnetic resonance spectroscopy and mass spectrometry. CONCLUSIONS: Despite the identification of these "hydrolyzed" species, it is still unclear whether the failure to reach the clinical goal of the perfusion tracer [(99m)Tc(N)(NOEt)(2)] is related to the degradation processes evidenced in this study or is the result of the mediocre imaging properties of the tracer.


Assuntos
Compostos de Organotecnécio/química , Compostos de Organotecnécio/metabolismo , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/metabolismo , Tiocarbamatos/química , Tiocarbamatos/metabolismo , Cromatografia em Camada Delgada , Coração/diagnóstico por imagem , Espectrometria de Massas , Estrutura Molecular , Imagem de Perfusão do Miocárdio , Compostos de Organotecnécio/síntese química , Compostos de Organotecnécio/isolamento & purificação , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/isolamento & purificação , Tiocarbamatos/síntese química , Tiocarbamatos/isolamento & purificação
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