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1.
J Med Chem ; 67(11): 9662-9685, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38831692

RESUMO

The new ligand L2Ad, obtained by conjugating the bifunctional species bis(3,5-dimethylpyrazol-1-yl)-acetate and the drug amantadine, was used as a chelator for the synthesis of new Cu complexes 1-5. Their structures were investigated by synchrotron radiation-induced X-ray photoelectron spectroscopy (SR-XPS), near-edge X-ray absorption fine structure (NEXAFS) spectroscopy, and by combining X-ray absorption fine structure (XAFS) spectroscopy techniques and DFT modeling. The structure of complex 3 was determined by single-crystal X-ray diffraction analysis. Tested on U87, T98, and U251 glioma cells, Cu(II) complex 3 and Cu(I) complex 5 decreased cell viability with IC50 values significantly lower than cisplatin, affecting cell growth, proliferation, and death. Their effects were prevented by treatment with the Cu chelator tetrathiomolybdate, suggesting the involvement of copper in their cytotoxic activity. Both complexes were able to increase ROS production, leading to DNA damage and death. Interestingly, nontoxic doses of 3 or 5 enhanced the chemosensitivity to Temozolomide.


Assuntos
Adamantano , Antineoplásicos , Complexos de Coordenação , Cobre , Glioblastoma , Humanos , Cobre/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Glioblastoma/metabolismo , Ligantes , Adamantano/farmacologia , Adamantano/química , Adamantano/síntese química , Adamantano/análogos & derivados , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/síntese química , Sobrevivência Celular/efeitos dos fármacos , Teoria da Densidade Funcional , Ensaios de Seleção de Medicamentos Antitumorais , Espécies Reativas de Oxigênio/metabolismo , Estrutura Molecular , Quelantes/química , Quelantes/farmacologia , Quelantes/síntese química , Relação Estrutura-Atividade , Acetatos/química , Acetatos/farmacologia , Acetatos/síntese química
2.
Dalton Trans ; 53(10): 4526-4543, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38348686

RESUMO

A library of homoleptic mononuclear Ga(III) complexes of the general formula [Ga(DTC)3], where DTC is an alicyclic or a linear dithiocarbamate chelator, is reported. The complexes were prepared in high yields starting from Ga(NO3)3·6H2O and fully characterized by elemental analysis and IR and NMR spectroscopy. Crystals of five of these complexes were obtained. The antitumor activity of the newly synthesized compounds against a panel of human cancer cell lines was evaluated. The chemical nature of the DTC does not have a marked impact on the structural features of the final compound. X-ray crystal structure analyses revealed that all these complexes have a trigonal prismatic geometry with three identical chelating DTCs coordinating the Ga(III) ion. It is noteworthy that in complex 22, [Ga(NHEt)3] (NHEt = N-ethyldithiocarbamate), the asymmetric unit is formed by two independent and structurally different molecules. Cellular studies showed that all the synthesized Ga-DTC complexes exhibit marked cytotoxic activity, even against human colon cancer cells that are less sensitive to cisplatin. Among the tested compounds, 6 ([Ga(CEPipDTC)3], CEPipDTC = (ethoxycarbonyl)-piperidinedithiocarbamate) and 21 ([Ga(Pr-13)3], PR13 = 4 and N-(2-ethoxy-2-oxoethyl)-N-methyldithiocarbamate) are very promising derivatives, but they have no selectivity towards cancer cells. Nevertheless, the obtained data provide a foundation for developing gallium-dithiocarbamate complexes as anticancer agents.


Assuntos
Antineoplásicos , Complexos de Coordenação , Gálio , Neoplasias , Humanos , Gálio/farmacologia , Gálio/química , Antineoplásicos/química , Cisplatino , Quelantes/química , Complexos de Coordenação/química , Linhagem Celular Tumoral
3.
Molecules ; 25(8)2020 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-32316698

RESUMO

Three new 6-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde-thiosemicarbazones-N-4-substituted pro-ligands and their Cu(II) complexes (1, -NH2; 2, -NHMe; 3, -NHEt) have been prepared and characterized. In both the X-ray structures of 1 and 3, two crystallographically independent complex molecules were found that differ either in the nature of weakly metal-binding species (water in 1a and nitrate in 1b) or in the co-ligand (water in 3a and methanol in 3b). Electron Paramagnetic Resonance (EPR) measurements carried out on complexes 1 and 3 confirmed the presence of such different species in the solution. The electrochemical behavior of the pro-ligands and of the complexes was investigated, as well as their biological activity. Complexes 2 and 3 exhibited a high cytotoxicity against human tumor cells and 3D spheroids derived from solid tumors, related to the high cellular uptake. Complexes 2 and 3 also showed a high selectivity towards cancerous cell lines with respect to non-cancerous cell lines and were able to circumvent cisplatin resistance. Via the Transmission Electron Microscopy (TEM) imaging technique, preliminary insights into the biological activity of copper complexes were obtained.


Assuntos
Técnicas de Química Sintética , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Cobre/química , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Complexos de Coordenação/química , Eletroquímica , Humanos , Ligantes , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Tiossemicarbazonas/química
4.
J Inorg Biochem ; 182: 18-28, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29407866

RESUMO

Three new 2-oxo-1,2-dihydrobenzo[h]quinoline-3-carbaldehyde terminal substituted aroylhydrazone ligands (2-Oxo-1,2-dihydrobenzo[h]quinoline-3-carbaldehyde(2'-hydroxybenzoyl)hydrazine, H2L1, 1, 2-Oxo-1,2-dihydrobenzo[h]quinoline-3-carbaldehyde(2'-hydroxybenzoyl)hydrazine, H2L2, 2, 2-Oxo-1,2-dihydrobenzo[h]quinoline-3-carbaldehyde(2'-hydroxybenzoyl)hydrazine, H2L3, 3) and the corresponding novel copper(II) complexes [Cu(L)(CH3OH)(NO3)](L = HL1 (4), HL2 (5), HL3 (6-6+), have been synthesized to compare their coordination behaviour and biological activity with respect to the presence of an OH group in different positions of the phenyl ring in the hydrazone moieties. The new ligands and their copper complexes were characterized by elemental analysis and spectroscopic techniques. The molecular structures of the new complexes 4 and 6-6+ were determined by single crystal X-ray diffraction. The interactions of the free ligands and their copper complexes with calf thymus DNA were tested by absorption measurements and ethidium bromide competitive studies which revealed that all compounds may interact with calf thymus DNA through intercalation. Furthermore, a comparative analysis of the cytotoxic effect of the compounds on a panel of human cancer cell lines showed that the copper complexes exhibited in vitro antitumor activity significantly higher than that of the free ligands and also of cisplatin.


Assuntos
Complexos de Coordenação/síntese química , Complexos de Coordenação/toxicidade , Cobre/química , Compostos Organometálicos/síntese química , Compostos Organometálicos/toxicidade , Quinolinas/química , Linhagem Celular Tumoral , Complexos de Coordenação/química , DNA/efeitos dos fármacos , DNA/genética , Clivagem do DNA/efeitos dos fármacos , Células HCT116 , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Compostos Organometálicos/química , Plasmídeos
5.
Inorg Chem ; 54(4): 1634-44, 2015 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-25588027

RESUMO

The coordination properties of isopropylxanthate (i-Pr-Tiox) and pyridine-2-thiolate (PyS) toward the [M(PS)2](+) moiety (M = Re and (99m)Tc; PS = phosphinothiolate) were investigated. Synthesis and full characterization of [Re(PS2)2(i-Pr-Tiox)] (Re1), [Re(PSiso)2(i-Pr-Tiox)] (Re2), [Re(PS2)2(PyS)] (Re3), and [Re(PSiso)2(PyS)] (Re4), where PS2 = 2-(diphenylphosphino)ethanethiolate and PSiso = 2-(diisopropylphosphino)ethanethiolate, and the structural X-ray analysis of complex Re3 were carried out. (99m)Tc analogues of complexes Re2 ((99m)Tc2) and Re4 ((99m)Tc4) were obtained in high radiochemical yield following a simple one-pot procedure. The chemical identity of the radiolabeled compounds was confirmed by chromatographic comparison with the corresponding rhenium complexes and by dual radio/UV HPLC analysis combined with ESI(+)-MS of (99g/99m)Tc complexes prepared in carrier-added conditions. The two radiolabeled complexes were stable with regard to trans chelation with cysteine, glutathione, and ethylenediaminotetraacetic acid and in rat and human sera. This study highlights the substitution-inert metal-fragment behavior of the [M(PS)2](+) framework, which reacts with suitable bidentate coligands to form stable hexacoordinated asymmetrical complexes. This feature makes it a promising platform on which to develop a new class of Re/Tc complexes that are potentially useful in radiopharmaceutical applications.


Assuntos
Compostos Organometálicos/química , Fosfinas/química , Piridinas/química , Rênio/química , Compostos de Sulfidrila/química , Tecnécio/química , Tionas/química , Cristalografia por Raios X , Modelos Moleculares , Estrutura Molecular , Compostos Organometálicos/síntese química
6.
J Inorg Biochem ; 141: 94-102, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25226437

RESUMO

New dinuclear di(N-heterocyclic carbene) silver(I), gold(I) and gold(III) complexes have been synthesised and their antiproliferative effects towards various cancer cell lines have been screened. The di(N-heterocyclic carbene) ligands have a propylene linker between the carbene moieties and the imidazole backbone has been functionalised with a 1-benzyl- or 1-PEG-1,2,3-triazole ring (PEG=poly(ethylene glycol)) via a CuAAC (copper azido alkyne cycloaddition) reaction. The resulting gold(I) and gold(III) complexes display an antiproliferative activity superior to that of the unfunctionalised pristine complexes together with a higher selectivity towards cancerous cells with respect to healthy cells.


Assuntos
Antineoplásicos/síntese química , Complexos de Coordenação/síntese química , Metano/análogos & derivados , Compostos Organoáuricos/síntese química , Prata/química , Antineoplásicos/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Complexos de Coordenação/farmacologia , Cobre/química , Reação de Cicloadição , Humanos , Imidazóis/química , Concentração Inibidora 50 , Ligantes , Metano/química , Especificidade de Órgãos , Compostos Organoáuricos/farmacologia , Polietilenoglicóis/química , Relação Estrutura-Atividade
7.
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
8.
J Inorg Biochem ; 129: 135-44, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24121303

RESUMO

The novel N-heterocyclic carbene ligand precursor NaHIm(PrSO3) (sodium 3,3'-(1H-imidazole-3-ium-1,3-diyl)dipropane-1-sulfonate) and the related silver carbene complex [Na4(Im(PrSO3))2]AgCl have been synthesized and characterized. Recrystallization of the analogous [Im(AcEt)]AgCl complex allowed the development of X-ray analysis which led to achieve relevant structural information concerning this silver(I) derivative. Both sulfonate- and ester-functionalized silver(I) N-heterocyclic carbenes (NHCs) were evaluated for their antiproliferative activities in a wide panel of human cancer cells. Complex [Na4(Im(PrSO3))2]AgCl showed a significant in vitro antiproliferative activity that was correlated with its strong ability to inhibit thioredoxin reductase. The inhibition of this selenoenzyme determined an alteration of the cellular redox environment thus leading to the induction of the apoptotic cell death through the activation of the ASK-1 pathway.


Assuntos
Antineoplásicos , Proliferação de Células/efeitos dos fármacos , Compostos Heterocíclicos com 1 Anel , Metano/análogos & derivados , Neoplasias/tratamento farmacológico , Prata , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Compostos Heterocíclicos com 1 Anel/síntese química , Compostos Heterocíclicos com 1 Anel/química , Compostos Heterocíclicos com 1 Anel/farmacologia , Humanos , MAP Quinase Quinase Quinase 5/metabolismo , Metano/síntese química , Metano/química , Metano/farmacologia , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Oxirredução/efeitos dos fármacos , Selenoproteínas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Prata/química , Prata/farmacologia , Solubilidade , Tiorredoxina Dissulfeto Redutase/metabolismo , Água/química
9.
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
10.
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
11.
Inorg Chem ; 51(9): 5409-16, 2012 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-22515419

RESUMO

Highly versatile coordinating ligands are designed and synthesized with two ß-diketonate groups linked at the carbon 3 through a phenyl ring. The rigid aromatic spacer is introduced in the molecules to orient the two acetylacetone units along different angles and coordination vectors. The resulting para, meta, and ortho bis-(3-acetylacetonate)benzene ligands show efficient chelating properties toward Cu(II) ions. In the presence of 2,2'-bipyridine, they promptly react and yield three dimers, 1, 2, and 3, with the bis-acetylacetonate unit in bridging position between two metal centers. X-ray single crystal diffraction shows that the compounds form supramolecular chains in the solid state because of intermolecular interactions. Each of the dinuclear complexes shows a magnetic behavior which is determined by the combination of structural parameters and spin polarization effects. Notably, the para derivative (1) displays a moderate antiferromagnetic coupling (J = -3.3 cm(-1)) along a remarkably long Cu···Cu distance (12.30 Å).


Assuntos
Derivados de Benzeno/química , Técnicas de Química Sintética , Cobre/química , Fenômenos Magnéticos , Compostos Organometálicos/química , Compostos Organometálicos/síntese química , Isomerismo , Modelos Moleculares , Conformação Molecular
12.
Dalton Trans ; 41(17): 5307-18, 2012 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-22391922

RESUMO

Following an increasing interest in the gold drug therapy field, nine new neutral azolate gold(I) phosphane compounds have been synthesized and tested as anticancer agents. The azolate ligands used in this study are pyrazolates and imidazolates substituted with deactivating groups such as trifluoromethyl, nitro or chloride moieties, whereas the phosphane co-ligand is the triphenylphosphane or the more hydrophilic TPA (TPA = 1,3,5-triazaphosphaadamantane). The studied gold(I) complexes are: (3,5-bis-trifluoromethyl-1H-pyrazolate-1-yl)-triphenylphosphane-gold(I) (1), (3,5-dinitro-1H-pyrazolate-1-yl)-triphenylphosphane-gold(I) (2), (4-nitro-1H-pyrazolate-1-yl)-triphenylphosphane-gold(I) (5), (4,5-dichloro-1H-imidazolate-1-yl)-triphenylphosphane-gold(I) (7), with the related TPA complexes (3), (4), (6) and (8) and (1-benzyl-4,5-di-chloro-2H-imidazolate-2-yl)-triphenylphosphane-gold(I) (9). The presence of deactivating groups on the azole rings improves the solubility of these complexes in polar media. Compounds 1-8 contain the N-Au-P environment, whilst compound 9 is the only one to contain a C-Au-P environment. Crystal structures for compounds 1 and 2 have been obtained and discussed. Interestingly, the newly synthesized gold(I) compounds were found to possess a pronounced cytotoxic activity on several human cancer cells, some of which were endowed with cis-platin or multidrug resistance. In particular, among azolate gold(I) complexes, 1 and 2 proved to be the most promising derivatives eliciting an antiproliferative effect up to 70 times higher than cis-platin. Mechanistic experiments indicated that the inhibition of thioredoxin reductase (TrxR) might be involved in the pharmacodynamic behavior of these gold species.


Assuntos
Técnicas de Química Sintética/métodos , Compostos Organoáuricos/síntese química , Compostos Organoáuricos/farmacologia , Fosfinas/química , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glutationa Redutase/antagonistas & inibidores , Humanos , Compostos Organoáuricos/química
13.
Dalton Trans ; 40(38): 9877-88, 2011 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-21709917

RESUMO

New nitroimidazole and glucosamine conjugated heteroscorpionate ligands, namely 2,2-bis(3,5-dimethyl-1H-pyrazol-1-yl)-N-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)acetamide (L(MN)) and 1,3,4,6-tetra-O-acetyl-2-{[bis(3,5-dimethyl-1H-pyrazol-1-yl)acetyl]amino}-2-deoxy-ß-D-glucopyranose (L(DAC)), respectively, were synthesized by direct coupling of preformed side chain acid and amine components. The related copper(II) complexes {[(L(MN))(2)Cu]Cl(2)}, and {[(L(DAC))(2)Cu]Cl(2)} have been prepared from the reaction of CuCl(2)*2H(2)O with L(MN) or L(DAC) ligand in methanol solution. Single crystal structural characterization was undertaken for the L(MN) ligand. In the absence of a coordinated metal core, the overall arrangement of the ligand is determined by some loose intra- and inter-molecular nonbonding contacts. X-Ray Absorption Spectroscopy (XAS) has been used to probe the local structure of the two copper(II) complexes, {[(L(MN))(2)Cu]Cl(2)} and {[(L(DAC))(2)Cu]Cl(2)}. The EXAFS analysis has permitted the identification of the local environment of the copper site. Copper interacts with 2 units of ligand in both complexes, and it is found to be 6-fold coordinated. Its local structure is described by four Cu-N and two Cu-O interactions to form a pseudo-octahedron core, with a 0.14 Å lengthening of the Cu-O bond length in the case of L(DAC) complex with respect to the L(MN) one, likely due to the higher steric hindrance of the glucosamine moiety. The XANES analysis agrees with these results, also confirming the Cu(II) formal copper oxidation state for both complexes. The new copper(II) complexes {[(L(MN))(2)Cu]Cl(2)} and {[(L(DAC))(2)Cu]Cl(2)} as well as the corresponding uncoordinated ligands were evaluated for their cytotoxic activity towards a panel of several human tumour cell lines. The results reported here indicate that both copper(II) complexes show similar spectra of cytotoxicity and very low resistance factors (RF < 2) against C13* ovarian cancer cells which have acquired resistance to cisplatin.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Cobre/química , Glucosamina/química , Compostos Heterocíclicos/química , Nitroimidazóis/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Teoria Quântica , Estereoisomerismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Espectroscopia por Absorção de Raios X
14.
J Biol Inorg Chem ; 16(1): 137-55, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20924624

RESUMO

This study presents the first application of a general procedure based on the use of the [Tc(N)Cl(PS)(PPh(3))] species (PS is an alkyl phosphinothiolate ligand) for the preparation of Tc(N) target-specific compounds. [Tc(N)Cl(PS)(PPh(3))] selectively reacts with an appropriate dithiocarbamate ligand (S(∧)Y) to give [Tc(N)(PS)(S(∧)Y)] compounds. 1-(2-Methoxyphenyl)piperazine, which displays a potent and specific affinity for 5HT(1A) receptors, was selected as a functional group and conjugated to the dithiocarbamate unit through different spacers (L( n )). [(99m)Tc(N)(PS)(L( n ))] complexes were prepared in high yield (more than 90%). The chemical identity of (99m)Tc complexes was determined by high performance liquid chromatography comparison with the corresponding (99g)Tc complexes. All complexes were found to be inert toward transchelation with an excess of glutathione and cysteine. No notable biotransformation of the native compound into different species by the in vitro action of the serum and liver enzymes was shown. Nanomolar affinity for the 5HT(1A) receptor was obtained for [(99m)Tc(N)(PSiso)L(3)] (IC(50) = 1.5 nM); a reduction of the affinity was observed for the other complexes as a function of the shortening of the alkyl chain interposed between the dithiocarbamate and the pharmacophore. Negligible brain uptake was found from in vivo distribution data of [(99m)Tc(N)(PSiso)L(3)]. The key finding of this study is that the complexes maintained good affinity and selectivity for 5HT(1A) receptors, and the IC(50) value for [(99g)Tc(N)(PSiso)L(3)] being comparable to the IC(50) value found for WAY 100635. This result confirmed the possibility of preparing [(99m)Tc(N)(PS)]-based target-specific compounds without affecting the affinity and selectivity of the bioactive molecules for the corresponding receptors.


Assuntos
Desenho de Fármacos , Compostos de Organotecnécio/farmacocinética , Piperazinas/química , Compostos Radiofarmacêuticos/farmacocinética , Compostos de Sulfidrila/química , Tecnécio/química , Tiocarbamatos/química , Animais , Ligantes , Estrutura Molecular , Compostos de Organotecnécio/síntese química , Compostos de Organotecnécio/química , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Ratos , Receptor 5-HT1A de Serotonina/química , Distribuição Tecidual
15.
J Med Chem ; 46(18): 3800-10, 2003 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-12930143

RESUMO

This study reports the synthesis of tetrahydrobenzo- (4-6) and benzopsoralen (7-9) derivatives obtained by condensing the fourth ring to the pyrone side of the tricyclic psoralen moiety. The new compounds are characterized by having a methoxy, a hydroxy, or a dimethylaminopropoxy side chain inserted at position 8 of the psoralen chromophore. The evaluation of the photoantiproliferative activity on human tumor cell lines along with skin phototoxicity on guinea pigs revealed an interesting photobiological pattern for the dimethylaminopropoxy derivatives 6 and 9: they are in fact able to exert an antiproliferative effect up to 1 order of magnitude higher than that of the well-known drug 8-MOP, but they are devoid of skin phototoxicity. The ability of both 6 and 9 to photoadd to DNA is demonstrated by the isolation and characterization of the 4',5'-monoadducts. AM1 calculations were also performed to gain further insight into the molecular basis of their photobiological behavior.


Assuntos
Antineoplásicos/síntese química , Cumarínicos/síntese química , Cicloexanos/síntese química , Furanos/síntese química , Furocumarinas/síntese química , Pironas/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Dicroísmo Circular , Cumarínicos/química , Cumarínicos/farmacologia , Reagentes de Ligações Cruzadas/síntese química , Reagentes de Ligações Cruzadas/química , Cicloexanos/química , Cicloexanos/farmacologia , Cicloexenos , Adutos de DNA/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/química , Furanos/farmacologia , Furocumarinas/química , Furocumarinas/farmacologia , Cobaias , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Modelos Moleculares , Terapia PUVA , Pironas/química , Pironas/farmacologia , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Raios Ultravioleta
16.
Inorg Chem ; 42(4): 950-9, 2003 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-12588125

RESUMO

The PN(2)S chelate N-[N-(3-diphenylphosphinopropionyl)glycyl]-S-tritylcysteine methyl ester [PN(2)S(Trt)-OMe] was synthesized and reacted with ReOCl(3)(PPh(3))(2) and Ph(4)P[ReOCl(4)]. The reactions of both tritylated and detritylated ligands with Re(V)O precursors gave two diastereomers, 9a and 9b, of the ReO(PN(2)S-OMe) complex. The two isomers, produced in a 1:1 molar ratio, are stable and do not interconvert. They were separated by reverse-phase HPLC and characterized by NMR, FT-IR, and UV-visible spectroscopy and electrospray mass spectrometry. X-ray analysis established for 9a the presence in the solid of the syn isomer. Compound 9a, C(21)H(23)N(2)O(5)PSRe, crystallized from warm acetonitrile in the triclinic space group Ponemacr;, a = 9.828(2) A, b = 11.163(2) A, c = 11.641(2) A, alpha = 106.48(3) degrees, beta = 109.06(3) degrees, gamma = 102.81(3) degrees, V = 1085.7(4) A(3), Z = 2. The PN(2)S coordination set is in the equatorial plane, and the complex shows a distorted square pyramidal coordination. The anti configuration assigned to 9b is consistent with all the available physicochemical data. Follow-up of the reaction of the detritylated ligand with Ph(4)P[ReOCl(4)] in ethanol or acetonitrile indicated that the phosphorus atom of the chelate binds first to the metal and that this bond acts as the driving force for coordination.


Assuntos
Quelantes/síntese química , Dipeptídeos/síntese química , Compostos Organometálicos/síntese química , Compostos Radiofarmacêuticos/síntese química , Rênio/química , Catálise , Quelantes/química , Química Orgânica/métodos , Cristalografia por Raios X , Dipeptídeos/química , Glicina/química , Ligantes , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Compostos Organometálicos/química , Compostos Radiofarmacêuticos/química , Espectroscopia de Infravermelho com Transformada de Fourier
17.
J Pept Sci ; 8(7): 373-81, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12148786

RESUMO

A novel CCK8 derivative bearing a chelating agent at its N- end and its oxo-rhenium(V) complex have been synthesized and characterized. The chelating agent N-[N-13-(diphenylphosphino)propionyl]glycyl]cysteine (PN2S) ligand, the coordination set of which is made by the phosphorus atom of phosphine, the nitrogen atoms of the two amido groups and the sulphur atom of cysteine, has been used due to its high affinity towards the oxo-rhenium(V) moiety. Molecular modelling studies indicate that the CCK8 peptide adopts the right conformation for cholecystokinin receptor binding, and that modifications on the N-terminal side of CCK8 obtained by introducing chelating agents and its metal complexes should not affect the interaction with CCK(A) receptor.


Assuntos
Colecistocinina/química , Colecistocinina/síntese química , Marcação por Isótopo/métodos , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/síntese química , Fenóis/química , Fosfinas/química , Rênio/química , Sequência de Aminoácidos , Modelos Moleculares , Estrutura Molecular , Conformação Proteica
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