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1.
Food Chem ; 301: 125254, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31398672

RESUMO

Researches based on metal complexes of plant-derived phenolic acids have attracted much attention due to their beneficial applications in the development of functional food products, dietary supplements and pharmacology. Binding of phenolic acids with serum proteins greatly influences their pharmacological properties. In this context, interactions of a naturally occurring phenolic acid, sinapic acid (SA) and its Cu2+ complex with a model transport protein, bovine serum albumin (BSA), have been explored by means of different spectroscopic and theoretical tools. Spectroscopic studies revealed that the interaction of SA and its Cu2+ complex with BSA occurred through quenching of intrinsic fluorescence of BSA. Site-specific experimental and docking studies were performed to predict the binding site. The geometies of bound Cu2+ and interacting residues of protein were predicted from a solution dynamics study. Interestingly, the complexation of SA with Cu2+ enhanced the antioxidant activity of SA.


Assuntos
Cobre/química , Ácidos Cumáricos/química , Ácidos Cumáricos/metabolismo , Simulação de Acoplamento Molecular , Compostos Organometálicos/química , Compostos Organometálicos/metabolismo , Soroalbumina Bovina/metabolismo , Animais , Sítios de Ligação , Bovinos , Ligação Proteica , Conformação Proteica , Soroalbumina Bovina/química , Espectrometria de Fluorescência , Termodinâmica
2.
J Sci Food Agric ; 99(14): 6582-6588, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31328268

RESUMO

BACKGROUND: This study was conducted to investigate effects of dietary zinc methionine (Zn-Met) supplementation on laying performance, zinc (Zn) status, intestinal morphology, and Zn transporters in laying hens compared with zinc sulfate (ZnSO4 ). A total of 384 Hyline Grey laying hens (38 weeks old) with similar performance (1.42 ± 0.07 kg) were randomly allotted to four dietary treatments and fed with a basal diet (control) or the basal diet supplemented with Zn, either as Zn-Met at 40 and 80 mg Zn/kilogram diet or as ZnSO4 at 80 mg Zn/kilogram diet, for 10 weeks. RESULTS: There was no difference in egg weight, egg production, feed intake, and feed conversation ratio among all groups (P > 0.05). Compared with the control, Zn contents were increased (P < 0.05) in the liver, duodenum, and jejunum of laying hens fed diets supplemented with different Zn sources. There was no difference (P > 0.05) in Zn contents in liver, duodenum, and jejunum between diets supplemented with Zn-Met or ZnSO4 at 80 mg Zn/kilogram diet. Compared with the control and the ZnSO4 group (80 mg Zn/kilogram diet), supplementation with Zn-Met of 80 mg Zn/kilogram diet increased (P < 0.05) villus height, villus area, and villus height/crypt depth ratio but reduced (P < 0.05) crypt depth in jejunum. Expression of metallothionein messenger RNA of jejunum in the group fed a diet containing Zn-Met (80 mg Zn/kilogram diet) was higher (P < 0.05) than that in the control. CONCLUSION: These results indicated that Zn-Met has positive effects on the Zn status of liver, duodenum, and jejunum, intestinal morphology, and metallothionein messenger RNA expression in jejunum of laying hens compared with ZnSO4 . © 2019 Society of Chemical Industry.


Assuntos
Proteínas de Transporte/genética , Galinhas/crescimento & desenvolvimento , Galinhas/metabolismo , Intestinos/crescimento & desenvolvimento , Metionina/análogos & derivados , Compostos Organometálicos/administração & dosagem , Zinco/metabolismo , Ração Animal/análise , Animais , Proteínas de Transporte/metabolismo , Galinhas/genética , Suplementos Nutricionais/análise , Ovos/análise , Feminino , Intestinos/efeitos dos fármacos , Metionina/administração & dosagem , Metionina/metabolismo , Compostos Organometálicos/metabolismo , Zinco/análise
3.
Clin Nucl Med ; 44(10): 795-796, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31306201

RESUMO

A 61-year-old man, with a history of prior clear cell renal cell carcinoma in remission, was referred to Ga-DOTATATE PET/CT for the further evaluation of pancreatic tail mass. Ga-DOTATATE PET/CT showed pathologically intense uptake on the pancreatic mass; subsequent biopsy of the pancreatic mass confirmed the diagnosis of clear cell renal cell carcinoma metastasis. Ga-DOTATATE uptake is not specific for neuroendocrine tumors. In the presence of prior malignancy, it should be kept in mind that malignancies apart from neuroendocrine tumors express somatostatin receptors, and they can show Ga-DOTATATE uptake.


Assuntos
Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Tumores Neuroendócrinos/diagnóstico por imagem , Compostos Organometálicos/metabolismo , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/secundário , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Transporte Biológico , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptores de Somatostatina/metabolismo
4.
Clin Nucl Med ; 44(10): 810-811, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31306203

RESUMO

Ga-DOTATATE PET/CT, a functional imaging modality for assessment of well-differentiated neuroendocrine tumors, targeting the somatostatin receptors, has essentially replaced the conventional gamma camera-based imaging with In-labeled octreotide. Physiologic distribution, normal variations, and common pitfalls with Ga-DOTATATE imaging have been well described in the literature. Here, we describe uptake of Ga-DOTATATE in 2 different patients at cervicothoracic junction within the stellate ganglia.


Assuntos
Compostos Organometálicos/metabolismo , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Gânglio Estrelado/diagnóstico por imagem , Gânglio Estrelado/metabolismo , Transporte Biológico , Humanos , Pessoa de Meia-Idade , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Receptores de Somatostatina/metabolismo
6.
Dalton Trans ; 48(22): 7644-7658, 2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31049548

RESUMO

In the search for a more effective chemotherapy for the treatment of Chagas' disease and human African trypanosomiasis, caused by Trypanosoma cruzi and Trypanosoma brucei parasites, respectively, the use of organometallic compounds may be a promising strategy. In this work, eight new heterobimetallic compounds are described including four 5-nitrofuryl containing thiosemicarbazones as bioactive ligands (HL1-HL4) and dppf = 1,1'-bis(diphenylphosphino) ferrocene as an organometallic co-ligand. Complexes of the formula [MII(L)(dppf)](PF6) with M = Pd or Pt were synthesized and fully characterized in the solid state and in solution, including the determination of the molecular structure of four of them by single crystal X-ray diffraction methods. Most compounds showed activity in the low micromolar or submicromolar range against both parasites, with the platinum compounds being more active than the palladium analogues. Activity was significantly increased by generation of the M-dppf compounds (3-24 fold increase with respect to free ligands HL for T. cruzi and up to 99 fold increase with respect to HL for T. brucei). The inclusion of the organometallic co-ligand also led to lower toxicity in mammalian cells and higher selectivity towards both parasites when compared to the free HL compounds. The complexes interact with DNA and affect the redox metabolism of the parasites. Furthermore, the most active and selective compound of the new series showed no in vivo toxicity in zebrafish embryos.


Assuntos
Compostos Ferrosos/química , Metalocenos/química , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Paládio/química , Platina/química , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Células A549 , Animais , Bovinos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Compostos Organometálicos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Soroalbumina Bovina/metabolismo , Tripanossomicidas/metabolismo , Trypanosoma cruzi/efeitos dos fármacos
7.
Clin Nucl Med ; 44(10): e593-e594, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31058693

RESUMO

Fibrous dysplasia is an uncommon benign bone pathology with only rare potential for malignant transformation. We describe the heterogeneous uptake of fibrous dysplasia of a whole rib on Ga-labeled prostate-specific membrane antigen (PSMA) PET/CT. Ga-PSMA binds to PSMA-expressing prostate cancer cells, but it can also bind to the neovasculature of various solid tumors, as well as to some benign lesions. Ga-PSMA expression in fibrous dysplasia should not automatically be equated with malignant transformation or confused with prostate cancer metastases.


Assuntos
Displasia Fibrosa Óssea/diagnóstico por imagem , Displasia Fibrosa Óssea/metabolismo , Glicoproteínas de Membrana/metabolismo , Compostos Organometálicos/metabolismo , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Idoso , Transporte Biológico , Diagnóstico Diferencial , Humanos , Masculino
8.
Dalton Trans ; 48(24): 8702-8716, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31123737

RESUMO

In the quest for therapeutic iron-based metallodrugs, two new mixed-ligand iron(iii) complexes bearing the tripodal aminobisphenolate ligand N,N-bis(3,5-dimethyl-2-hydroxybenzyl)-N-(2-pyridylmethyl)amine (H2L) and hydroxyquinoline co-ligands, 8-hydroxyquinoline (8HQ) or 5-chloro-8-hydroxyquinoline (Cl8HQ), are synthesized, fully characterized and formulated as [Fe(L)(8HQ)] (1) and [Fe(L)(Cl8HQ)] (2), respectively. These high-spin Fe(iii) complexes are stable in aqueous solution in the presence of equimolar amounts of Bovine Serum Albumin (BSA), which indicates a likely binding interaction with the protein. In fact, binding constant log values at pH 7.4 for HSA of 5.08 and 6.35 were obtained for 1 and 2, respectively. Compounds 1 and 2 are cytotoxic against both human triple-negative breast adenocarcinoma (MDA-MB-231) and human cervical carcinoma (HeLa) cancer cells, and the activity is significantly improved by inclusion of the co-ligands 8HQ and Cl8HQ to the precursor complex Fe(L). Moreover, 1 and 2 are more active than 8HQ and Cl8HQ, particularly at lower incubation times tested, 24 and 48 h. Cells treated with the complexes display typical features of apoptosis as assessed by cellular morphology, DNA condensation and TUNEL analysis. COMET assays show that both drug candidates induce genomic damage in both cell lines. The complexes exhibit DNA cleavage activity and DNA damage that may be related to their ability to generate ROS. Overall, data supports that 1 and 2 are both active anticancer drug candidates within the low micromolar range. This is particularly interesting in the case of the breast MDA-MB-231 line, a model for triple-negative breast cancer that is an aggressive form of breast cancer, highly invasive and with limited treatment options and very poor prognosis. Furthermore, both complexes exhibited good anti-Mycobacterium tuberculosis activity, suggesting that 1 and 2 might have a wide spectrum of biological activity and justify further research.


Assuntos
Hidroxiquinolinas/química , Ferro/química , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Animais , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Bovinos , Linhagem Celular Tumoral , Humanos , Mycobacterium tuberculosis/efeitos dos fármacos , Compostos Organometálicos/metabolismo , Soroalbumina Bovina/metabolismo
9.
Chem Biol Interact ; 306: 78-88, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30954465

RESUMO

SALEN- and SALAN-based complexes with catalytically active metal centers are very promising small molecules to be utilized as part of antioxidant therapies. Here we discuss a modified SALAN-type molecule armed with two phosphonate groups that significantly increase its water solubility and aid to furnish mono- or dinuclear complexes with Cu2+ ions. The regulation of the SOD-mimicking (i.e., catalytic) disproportionation reaction of the superoxide radical anion (O2•-) at pH ~7.5 could be achieved by adjusting the metal-to-ligand stoichiometry as confirmed by McCord-Fridovich and pulse radiolysis tests. The higher antioxidant activity of the dicopper complex can be explained by the better access of O2•- to the copper centers and their more positive Cu(II)/Cu(I) redox potential. Simultaneously the analysis of in vitro effect on cells morphology indicates that cytotoxicity is also affected by the metal-to-ligand ratio, however, the active complex molecules do not show notable cytotoxicity that, together with the observed SOD-like activities, makes them potential candidates for antioxidant therapies.


Assuntos
Antioxidantes/metabolismo , Cobre/farmacologia , Compostos Organometálicos/metabolismo , Superóxido Dismutase/metabolismo , Células 3T3-L1 , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cobre/química , Ligantes , Camundongos , Conformação Molecular , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Oxirredução
10.
Clin Nucl Med ; 44(6): e396-e397, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30932978

RESUMO

Prostate cancer is one of the most common malignancies. Imaging tools play an important role throughout the entire process of the disease. The scenario, however, is going to change. Thanks to a higher sensitivity and specificity, the use of the prostate-specific membrane antigen (PSMA) PET is of increasing importance, particularly at the time of diagnosis and in case of biochemical recurrence. Nevertheless, previous reports have described false-positive findings, as tracer-avid physiological findings or benign processes, potential pitfalls for interpretation of Ga-PSMA PET/CT. Here we report a case of PSMA uptake in a histologically proven fibrous dysplasia.


Assuntos
Displasia Fibrosa Óssea/diagnóstico por imagem , Glicoproteínas de Membrana , Compostos Organometálicos , Idoso , Transporte Biológico , Reações Falso-Positivas , Displasia Fibrosa Óssea/metabolismo , Humanos , Masculino , Glicoproteínas de Membrana/metabolismo , Compostos Organometálicos/metabolismo , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Neoplasias da Próstata/patologia , Sensibilidade e Especificidade
11.
Clin Nucl Med ; 44(6): e420-e422, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31021914

RESUMO

We present a case of biopsy-proven prostatic adenocarcinoma with a tracer-avid left paravertebral location at D4 to D5 vertebrae, suggestive of metastasis. However, in view of uncommon location of single-site metastasis at paravertebral region with no tracer-avid regional lymphadenopathy, image-guided biopsy was done, which was suggestive of paraganglioma. Ga-PSMA is known to have variable tracer avidity in multiple nonprostatic benign as well as malignant lesions, and our case adds to the list of nonspecific uptake by this once considered "specific" to prostate PET radiotracer.


Assuntos
Adenocarcinoma/patologia , Neoplasias Primárias Múltiplas/diagnóstico por imagem , Paraganglioma/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Neoplasias da Próstata/patologia , Adenocarcinoma/diagnóstico por imagem , Idoso , Biópsia , Diagnóstico Diferencial , Humanos , Imagem por Ressonância Magnética , Masculino , Glicoproteínas de Membrana/metabolismo , Compostos Organometálicos/metabolismo , Paraganglioma/secundário , Neoplasias da Próstata/diagnóstico por imagem , Compostos Radiofarmacêuticos/metabolismo
12.
Clin Nucl Med ; 44(10): 799-800, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30985420

RESUMO

A 54-year-old man with mesenteric carcinoid tumor metastatic to the liver completed staging Ga-DOTATATE PET/CT demonstrating uptake in multiple hepatic lesions consistent with liver metastases with additional asymmetric increased uptake in the right greater than the left breast. Subsequent bilateral diagnostic mammogram revealed benign right greater than left gynecomastia without suspicious underlying mass. With Food and Drug Administration approval of Ga-DOTATATE and the increased use of this analog in neuroendocrine tumor imaging, this case illustrates a relevant example of uptake that can potentially mimic malignancy.


Assuntos
Ginecomastia/diagnóstico por imagem , Ginecomastia/metabolismo , Achados Incidentais , Compostos Organometálicos/metabolismo , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Diagnóstico Diferencial , Humanos , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/patologia
13.
Dalton Trans ; 48(24): 8578-8593, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-30946409

RESUMO

Immunocompromised cancer patients are often at high risk of developing infections. Standard infection control measures are required to prevent the onset of infection but, under some circumstances, antimicrobial prophylaxis is necessary. We have developed a family of innovative metallo-antibiotics of general formula [Cu(N,N)(CipA)Cl] where N,N represents a phenanthrene ligand and CipA stands for a derivative of the clinically used fluoroquinolone antibiotic ciprofloxacin. The X-ray crystal structure of one member from this family, [Cu(phen)(CipA)Cl] (where phen is 1,10-phenanthroline), is also reported. These complexes combine into one drug entity a Cu-N,N-framework with DNA binding and DNA oxidant properties and an antibiotic derivative with known anti-proliferative and anti-microbial activities. The complexes were all found to exhibit excellent DNA recognition with binding affinity of lead agents in the order of ∼107 M(bp)-1. Biophysical studies involving calf thymus DNA indicate the complexes intercalate or semi-intercalate DNA via the minor groove. All complexes exhibited excellent nuclease activity with DNA strand scission being mediated predominantly via superoxide and hydroxyl radicals. The complexes were found to have promising anti-proliferative effects against a human breast adenocarcinoma cell line (MCF-7) and a human prostate carcinoma cell line (DU145) with low micromolar and, in some cases, nanomolar cytotoxicities observed. Selective targeting of Gram positive bacteria was also identified by this complex class with one lead compound having an order of magnitude greater potency against Methicillin-resistant S. aureus (MRSA) as compared to the CipA ligand. Importantly, from a clinical stand point, these complexes were also found to be well tolerated in an in vivo Galleria mellonella larvae model, which has both functional and structural similarities to that of the innate immune system of mammals.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Ciprofloxacino/química , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Antibacterianos/metabolismo , Antineoplásicos/metabolismo , Cobre/química , DNA/metabolismo , DNA Topoisomerases Tipo I/metabolismo , DNA Topoisomerases Tipo II/metabolismo , Humanos , Modelos Moleculares , Conformação Molecular , Compostos Organometálicos/metabolismo , Fenantrolinas/química
14.
Alkaloids Chem Biol ; 82: 29-145, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30850032

RESUMO

Major Cinchona alkaloids quinine, quinidine, cinchonine, and cinchonidine are available chiral natural compounds (chiral pool). Unlike many other natural products, these alkaloids are available in multiple diastereomeric forms which are separated on an industrial scale. The introduction discusses in short conformational equilibria, traditional separation scheme, biosynthesis, and de novo chemical syntheses. The second section concerns useful chemical applications of the alkaloids as chiral recognition agents and effective chiral catalysts. Besides the Sharpless ethers and quaternary ammonium salts (chiral PTC), the most successful bifunctional organocatalysts are based on 9-amino derivatives: thioureas and squaramides. The third section reports the main transformations of Cinchona alkaloids. This covers reactions of the 9-hydroxyl group with the retention or inversion of configuration. Specific Cinchona rearrangements enlarging [2.2.2]bicycle of quinuclidine to [3.2.2] products are connected to the 9-OH substitution. The syntheses of numerous esterification and etherification products are described, including many examples of bi-Cinchona alkaloid ethers. Further derivatives comprise 9-N-substituted compounds. The amino group is introduced via an azido function with the inversion of configuration at the stereogenic center C9. The 9-epi-amino-alkaloids provide imines, amides, imides, thioureas, and squaramides. The syntheses of 9-carbon-, 9-sulfur-, and 9-selenium-substituted derivatives are discussed. Oxidation of the hydroxyl group of any alkaloid gives ketones, which can be selectively reduced, reacted with Grignard reagents, or subjected to the Corey-Chaykovsky reaction. The alkaloids were also partially degraded by splitting C4'-C9 or N1-C8 bonds. In order to immobilize Cinchona alkaloids the transformations of the 3-vinyl group were often exploited. Finally, miscellaneous functionalizations of quinuclidine, quinoline, and examples of various metal complexes of the alkaloids are considered.


Assuntos
Alcaloides de Cinchona/química , Compostos Organometálicos/química , Alcaloides de Cinchona/isolamento & purificação , Alcaloides de Cinchona/metabolismo , Estrutura Molecular , Compostos Organometálicos/isolamento & purificação , Compostos Organometálicos/metabolismo , Quinolinas/química , Quinuclidinas/química
15.
Mol Med Rep ; 19(5): 3449-3458, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896839

RESUMO

The present study aimed to investigate the effect of carbon monoxide (CO)­releasing molecule­2 (CORM­2) on pancreatic function in sepsis­model mice. To perform the present investigation, mice were rendered septic by cecal ligation and puncture (CLP). Then, mice were either treated with or without CORM­2 (8 mg/kg, intravenous) for different durations (6, 12 and 24 h) immediately following CLP. The levels of serum amylase and lipase, tumor necrosis factor α, interleukin­1ß and interleukin­6 in addition to myeloperoxidase (MPO) activity in pancreatic tissues were determined at 6, 12 and 24 h post­CLP. Histological scores and the expression of intercellular adhesion molecule 1 (ICAM­1), vascular cell adhesion molecule 1 (VCAM­1), nuclear factor­κB (NF­κB) and phosphorylated inhibitor of κB (p­IκB­α) in the pancreas were also evaluated at 24 h post­CLP. The results of the present study revealed that compared with CLP­alone group, CORM­2 treatment significantly (P<0.05) reduced the levels of serum amylase, lipase and pro­inflammatory cytokines. In parallel, the severity of pancreatic histology, MPO activity and the expression levels of ICAM­1 and VCAM­1 in the pancreas of CORM­2 treated CLP mice were substantially decreased compared with the untreated group. Furthermore, CORM­2 treatment inhibited the expression levels of NF­κB and P­IκB­α in the pancreas of mice following CLP compared with the untreated group. CORM­2­liberated CO exerted protective effects on the pancreatic function of septic mice, and the beneficial effects may be due to the suppression of NF­κB activation and subsequent regulation of NF­κB­dependent expression of cytokines.


Assuntos
Compostos Organometálicos/metabolismo , Pâncreas/metabolismo , Sepse/metabolismo , Animais , Biomarcadores , Monóxido de Carbono/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Camundongos , NF-kappa B/metabolismo , Pancreatopatias/etiologia , Sepse/complicações , Sepse/etiologia
17.
Ultrason Sonochem ; 55: 207-216, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30745233

RESUMO

The dandelion-shaped nanostructure of an organotin complex with formula Sn(CH3)2Cl2}NC5H4C(O)NHP(O)[NHC6H11]2}2 (C1) was synthesized by means of a sonochemical method. Nano-structures were characterized by elemental analysis, NMR, SEM-EDS, XRD, UV-Vis, and FT-IR spectroscopy. The thermal stability of the complex C1 has been studied by thermal gravimetric analysis (TGA), and compared to the bulk form (C2). Both the morphology and the size of the ultrasound-assisted synthesized organotin complex have been investigated using scanning electron microscopy (SEM) by changing such parameters as the concentration of initial reactants and the sonication frequency. Two different forms of the organotin complex (C1, C2) and the corresponding ligand (L) were evaluated by a modified Ellman's method on acetyl- and butyrylcholinesterase enzymes. Nanodendalion C1 and ligand L showed the best activity against AChE and BChE, respectively, with the IC50 values being 326.59 µg/ml and 426.68 µg/ml. Further, Lineweaver Burk plots indicated that these compounds are mixed inhibitors. The synthesized compounds and cholinesterase enzymes were simulated by molecular docking for more details concerning the conformation and the orientations of these compounds in the active site of the receptor.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Simulação de Acoplamento Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/farmacologia , Fosfatos/química , Estanho/química , Ondas Ultrassônicas , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Domínio Catalítico , Técnicas de Química Sintética , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Ligantes , Modelos Moleculares , Compostos Organometálicos/química , Compostos Organometálicos/metabolismo
18.
Inorg Chem ; 58(14): 8969-8982, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30788970

RESUMO

Nickel-containing enzymes such as methyl coenzyme M reductase (MCR) and carbon monoxide dehydrogenase/acetyl coenzyme A synthase (CODH/ACS) play a critical role in global energy conversion reactions, with significant contributions to carbon-centered processes. These enzymes are implied to cycle through a series of nickel-based organometallic intermediates during catalysis, though identification of these intermediates remains challenging. In this work, we have developed and characterized a nickel-containing metalloprotein that models the methyl-bound organometallic intermediates proposed in the native enzymes. Using a nickel(I)-substituted azurin mutant, we demonstrate that alkyl binding occurs via nucleophilic addition of methyl iodide as a methyl donor. The paramagnetic NiIII-CH3 species initially generated can be rapidly reduced to a high-spin NiII-CH3 species in the presence of exogenous reducing agent, following a reaction sequence analogous to that proposed for ACS. These two distinct bioorganometallic species have been characterized by optical, EPR, XAS, and MCD spectroscopy, and the overall mechanism describing methyl reactivity with nickel azurin has been quantitatively modeled using global kinetic simulations. A comparison between the nickel azurin protein system and existing ACS model compounds is presented. NiIII-CH3 Az is only the second example of two-electron addition of methyl iodide to a NiI center to give an isolable species and the first to be formed in a biologically relevant system. These results highlight the divergent reactivity of nickel across the two intermediates, with implications for likely reaction mechanisms and catalytically relevant states in the native ACS enzyme.


Assuntos
Acetilcoenzima A/química , Acetilcoenzima A/metabolismo , Níquel/química , Compostos Organometálicos/química , Azurina/genética , Azurina/metabolismo , Catálise , Cromatografia Gasosa , Regulação Bacteriana da Expressão Gênica , Cinética , Fenômenos Magnéticos , Mutação , Compostos Organometálicos/metabolismo , Pseudomonas aeruginosa/enzimologia , Análise Espectral
19.
Ann Nucl Med ; 33(5): 317-325, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30726551

RESUMO

PURPOSE: Although it has been traditionally surmised that phosphatidylserine (PS) externalization is a hallmark of apoptosis, most other non-apoptotic modes of cell death, such as necrosis, are also associated with PS externalization. Bis(zinc-dipicolylamine) (ZnDPA) complexes have been reported to exhibit affinity for PS. The present study aimed to develop novel radiolabeled ZnDPA derivatives for cell death imaging in tumor after treatment with anticancer drugs. METHODS: [125I]IB-EG2-ZnDPA and [99mTc]Tc-MAG3-EG2-ZnDPA were designed and prepared. The stabilities of these radiotracers were determined in 0.1 M phosphate buffer (pH 7.4) or murine plasma at 37 °C, and their 1-octanol/water partition coefficients (logP) were measured. The uptake of radioactivity in cancer cells, which were preincubated in a normal medium or in a medium containing 5-FU, was measured after incubation with radiotracers. Accumulation of [99mTc]Tc-MAG3-EG2-ZnDPA in the tumor was evaluated in tumor-bearing mice treated with or without 5-FU, and then TUNEL staining was performed to detect dead cells in the tumor tissue sections. RESULTS: The radiochemical purities of [125I]IB-EG2-ZnDPA and [99mTc]Tc-MAG3-EG2-ZnDPA exceeded 95%. Although [125I]IB-EG2-ZnDPA gradually decomposing with time, more than 90% of [99mTc]Tc-MAG3-EG2-ZnDPA remained in its intact form in phosphate buffer through 6 h of incubation. Neither [125I]IB-EG2-ZnDPA nor [99mTc]Tc-MAG3-EG2-ZnDPA decomposed so much after 6-h incubation in murine plasma. [125I]IB-EG2-ZnDPA could not specifically recognize PS on the cell surface because of its high lipophilicity. Conversely, [99mTc]Tc-MAG3-EG2-ZnDPA accumulated in cancer cells after treatment with an anticancer drug both in vitro and in vivo, and its accumulation was correlated with the number of TUNEL-positive cells. However, the biodistribution of [99mTc]Tc-MAG3-EG2-ZnDPA was not suitable for imaging because of its low accumulation in tumor and high uptake in abdomen organs. CONCLUSION: [99mTc]Tc-MAG3-EG2-ZnDPA could be useful for the early detection of treatment effects after chemotherapy. Since the signal-to-noise ratio is not enough for single photon emission computed tomography imaging, further modification is needed to improve its biodistribution and affinity for PS.


Assuntos
Imagem Molecular/métodos , Compostos Organometálicos/química , Picolinas/química , Animais , Transporte Biológico , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Fluoruracila/química , Fluoruracila/farmacologia , Humanos , Radioisótopos do Iodo/química , Marcação por Isótopo , Camundongos , Compostos Organometálicos/metabolismo , Compostos Organometálicos/farmacocinética , Picolinas/metabolismo , Picolinas/farmacocinética , Radioquímica , Distribuição Tecidual
20.
Eur J Med Chem ; 164: 654-664, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30641446

RESUMO

Although many N-heterocyclic thiosemicarbazone copper complexes have been proposed as potential anticancer agents, little is known about their intracellular localization in cells. In the present study, we synthesized two fluorescent N-heterocyclic thiosemicarbazone copper complexes, ([CuII(L)(Br)] 1 and [CuII2CuI(L)2(Br)3] 2, where HL is (E)-N,N-dimethyl-2-(quinolin-8-ylmethylene)hydrazinecarbothioamide), to assess their intracellular distribution. Our fluorescence studies demonstrated that complex 1 showed an intense emission band at ca. 510 nm (λex = 405 nm) similar to that of complex 2, albeit with about four times lower emission intensity. Both copper complexes showed significantly greater cytotoxicity toward several tumor cell-types with better IC50 (0.27-0.91 µM) than the HL ligand and cisplatin. Scratching wound healing assay and invasion assay were performed, revealing that the copper complexes have good antimetastatic activity. Confocal fluorescence imaging allowed ascertaining that complex 2 was primarily localized to mitochondria. Further studies revealed that the anticancer mechanisms of complex 2 might involve the mitochondrial-mediated apoptotic pathway, probably caused by the reducing mitochondrial membrane potential and induction of ROS (reactive oxygen species) production. Furthermore, complex 2 exhibited promising cytostatic effects in a three-dimensional HeLa spheroid model.


Assuntos
Antineoplásicos/química , Mitocôndrias/metabolismo , Metástase Neoplásica/tratamento farmacológico , Compostos Organometálicos/uso terapêutico , Tiossemicarbazonas/uso terapêutico , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Fluorescência , Células HeLa , Humanos , Metástase Neoplásica/diagnóstico por imagem , Compostos Organometálicos/metabolismo , Compostos Organometálicos/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Tiossemicarbazonas/metabolismo , Tiossemicarbazonas/toxicidade
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