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1.
J Steroid Biochem Mol Biol ; 200: 105662, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32209387

RESUMO

Urinary steroid profiling is commonly used in clinical routine for the diagnosis of steroid-related diseases through the analysis of absolute steroid excretion values as well as apparent enzyme activities based on catalysed product-to-precursor ratios. To compensate for diurnal fluctuations in steroid concentrations, 24 hour collections are preferred yet impractical and sometimes not feasible. We therefore measured 40 steroid metabolites by GC-MS in 24 hour and spot urine samples of healthy volunteers and systematically evaluated to which extent 24 hour urine collections can be replaced by spot urine collections for diagnostic purposes. Whereas most steroid concentrations show poor correlation between 24 hour and spot urine collection, apparent enzyme activities show better correlation and defects in steroidogenic enzymes such as SRD5A2, CYP17A1, CYP21A2 and CYP11B1. We confirmed our findings in patient samples from our clinic.

2.
Diabetes Technol Ther ; 22(4): 326-329, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32031881

RESUMO

Adequacy of insulin concentration in commercially available insulin formulations has recently been challenged. We therefore repeatedly evaluated insulin content and stability of 58 insulin vials containing 5 different insulin formulations (human insulin, standard/faster-acting insulin aspart, insulin lispro, and insulin glargine) over a period of 85 days. High-resolution mass spectrometry was used to quantify intact monomeric insulin in glass vials and plastic pump cartridges exposed to three different temperatures (4°C, 22°C, 37°C), simulating real-life conditions. In all cases, measured insulin concentration was in accordance with FDA and European Medicines Agency (EMA) requirements without evidence of chemical instability.

3.
J Chromatogr A ; 1612: 460661, 2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-31708215

RESUMO

Untargeted steroid identification represents a great analytical challenge even when using sophisticated technology such as two-dimensional gas chromatography coupled to high resolution mass spectrometry (GC × GCHRMS) due to the chemical similarity of the analytes. Moreover, when analytical standards, mass spectral and retention index databases are not available, compound annotation is cumbersome. Hence, there is a need for the development of retention time prediction models in order to explore new annotation approaches. In this work, we evaluated the use of several in silico methods for retention time prediction in multidimensional gas chromatography. We use three classical machine learning (CML) algorithms (Partial Least Squares (PLS), Support Vector Regression (SVR) and Random Forest Regression (RFR)) and two deep learning approaches (dense neural network (DNN) and three-dimensional convolutional neural network (CNN)). Whereas molecular descriptors were utilized for the CLM and DNN algorithms, three-dimensional molecular representation based on the electrostatic potential (ESP) was studied as input data as is for the CNN. All the developed models showed similar performances with Q2 values over 0.9. However, among all CNN showed the best performance, resulting in average retention time prediction errors of 2% and 6% for the first and second separation dimension, respectively. Additionally, only the three-dimensional ESP representation coupled with CNN was able to extract the stereochemical information crucial for the separation of diastereomers. The combination of retention time prediction and high-resolution mass spectral data applied to clinical samples enabled the untargeted annotation of 12 steroid metabolites in the urine of new-borns.


Assuntos
Aprendizado Profundo , Cromatografia Gasosa-Espectrometria de Massas/métodos , Esteroides/análise , Análise dos Mínimos Quadrados , Redes Neurais de Computação , Eletricidade Estática , Esteroides/química , Máquina de Vetores de Suporte
4.
Anal Chem ; 91(18): 12085-12093, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31441640

RESUMO

Quantitative bottom-up shotgun lipidomics relies on molecular species-specific "signature" fragments consistently detectable in tandem mass spectra of analytes and standards. Molecular species of glycerophospholipids are typically quantified using carboxylate fragments of their fatty acid moieties produced by higher-energy collisional dissociation of their molecular anions. However, employing standards whose fatty acids moieties are similar, yet not identical, to the target lipids could severely compromise their quantification. We developed a generic and portable fragmentation model implemented in the open-source LipidXte software that harmonizes the abundances of carboxylate anion fragments originating from fatty acid moieties having different sn-1/2 positions at the glycerol backbone, length of the hydrocarbon chain, and number and location of double bonds. The postacquisition adjustment enables unbiased absolute (molar) quantification of glycerophospholipid species independent of instrument settings, collision energy, and employed internal standards.

5.
PLoS One ; 14(3): e0214549, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30925175

RESUMO

OBJECTIVE: Urinary steroid metabolomics by GC-MS is an established method in both clinical and research settings to describe steroidogenic disorders. However, population-based reference intervals for adults do not exist. METHODS: We measured daytime and night time urinary excretion of 40 steroid metabolites by GC-MS in 1128 adult participants of European ancestry, aged 18 to 90 years, within a large population-based, multicentric, cross-sectional study. Age and sex-related patterns in adjacent daytime and night time urine collections over 24 hours were modelled for each steroid metabolite by multivariable linear mixed regression. We compared our results with those obtained through a systematic literature review on reference intervals of urinary steroid excretion. RESULTS: Flexible models were created for all urinary steroid metabolites thereby estimating sex- and age-related changes of the urinary steroid metabolome. Most urinary steroid metabolites showed an age-dependence with the exception of 6ß-OH-cortisol, 18-OH-cortisol, and ß-cortol. Reference intervals for all metabolites excreted during 24 hours were derived from the 2.5th and 97.5th percentile of modelled reference curves. The excretion rate per period of metabolites predominantly derived from the adrenals was mainly higher during the day than at night and the correlation between day and night time metabolite excretion was highly positive for most androgens and moderately positive for glucocorticoids. CONCLUSIONS: This study gives unprecedented new insights into sex- and age-specificity of the human adult steroid metabolome and provides further information on the day/night variation of urinary steroid hormone excretion. The population-based reference ranges for 40 GC-MS-measured metabolites will facilitate the interpretation of steroid profiles in clinical practice.


Assuntos
Envelhecimento/metabolismo , Envelhecimento/urina , Metabolômica/normas , Caracteres Sexuais , Esteroides/biossíntese , Esteroides/urina , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valores de Referência , Esteroides/metabolismo , Fatores de Tempo , Adulto Jovem
6.
Mass Spectrom Rev ; 38(3): 291-320, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30707468

RESUMO

Here we present a guide to ion mobility mass spectrometry experiments, which covers both linear and nonlinear methods: what is measured, how the measurements are done, and how to report the results, including the uncertainties of mobility and collision cross section values. The guide aims to clarify some possibly confusing concepts, and the reporting recommendations should help researchers, authors and reviewers to contribute comprehensive reports, so that the ion mobility data can be reused more confidently. Starting from the concept of the definition of the measurand, we emphasize that (i) mobility values (K0 ) depend intrinsically on ion structure, the nature of the bath gas, temperature, and E/N; (ii) ion mobility does not measure molecular surfaces directly, but collision cross section (CCS) values are derived from mobility values using a physical model; (iii) methods relying on calibration are empirical (and thus may provide method-dependent results) only if the gas nature, temperature or E/N cannot match those of the primary method. Our analysis highlights the urgency of a community effort toward establishing primary standards and reference materials for ion mobility, and provides recommendations to do so. © 2019 The Authors. Mass Spectrometry Reviews Published by Wiley Periodicals, Inc.

7.
J Clin Endocrinol Metab ; 104(6): 2195-2215, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30690465

RESUMO

CONTEXT: Sex steroid hormones exhibit anabolic effects whereas a deficiency engenders sarcopenia. Moreover, supraphysiological levels of glucocorticoids promote skeletal muscle atrophy, whereas physiologic levels of glucocorticoids may improve muscle performance. OBJECTIVE: To study the relationship between both groups of steroid hormones at a physiological range with skeletal muscle mass and function in the general population. DESIGN: Cross-sectional analysis of the associations between urinary excreted androgens, estrogens, glucocorticoids, and steroid hormone metabolite ratios with lean mass and handgrip strength in a population-based cohort. SETTING: Three centers in Switzerland including 1128 participants. MEASURES: Urinary steroid hormone metabolite excretion by gas chromatography-mass spectrometry, lean mass by bioimpedance analysis, and isometric handgrip strength by dynamometry. RESULTS: For lean mass a strong positive association was found with 11ß-OH-androsterone and with most glucocorticoids. Androsterone showed a positive association in middle-aged and older adults. Estriol showed a positive association only in men. For handgrip strength, strong positive associations with androgens were found in middle-aged and older adults, whereas positive associations were found with cortisol metabolites in young to middle-aged adults. CONCLUSIONS: Sex steroids and glucocorticoids are strongly positively associated with skeletal muscle mass and strength in the upper limbs. The associations with muscle strength appear to be independent of muscle mass. Steroid hormones exert age-specific anabolic effects on lean mass and handgrip strength. Deficits in physical performance of aged muscles may be attenuated by androgens, whereas glucocorticoids in a physiological range increase skeletal muscle mass at all ages, as well as muscle strength in particular in younger adults.


Assuntos
Glucocorticoides/urina , Hormônios Esteroides Gonadais/urina , Força Muscular/fisiologia , Músculo Esquelético/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Força da Mão/fisiologia , Humanos , Pessoa de Meia-Idade , Adulto Jovem
8.
J Steroid Biochem Mol Biol ; 186: 74-78, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30268410

RESUMO

Due to possible matrix interferences and artefact generation during sample preparation, careful method validation is required for quantitative bioanalytical methods, especially for analytes that are only present in low concentrations. Using the identification and quantification of progesterone metabolites in the urine of newborns as an example, we show how modern high-resolution instruments can be used to verify analyte assignment and avoid pitfalls commonly encountered by the use of low-resolution instruments.


Assuntos
Cromatografia Gasosa-Espectrometria de Massas/métodos , Progesterona/metabolismo , Progesterona/urina , Feminino , Humanos , Recém-Nascido , Limite de Detecção , Masculino , Esteroides/metabolismo , Esteroides/urina , Urinálise/métodos
9.
Analyst ; 143(18): 4484-4494, 2018 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-30156584

RESUMO

Steroids are key players in a high variety of physiological processes and are typically analyzed for the diagnosis of hormonal disorders. Due to their chemical and structural similarity many of these metabolites cannot be separated by conventional techniques such as liquid chromatography. Herein, we present an analysis strategy based on two dimensional gas chromatography (GC×GC) coupled to time-of-flight mass spectrometry (TOF MS) which demonstrates superior separation power and enables comprehensive screening of steroids. We show absolute quantitation of 40 steroids in human urine over three orders of magnitude with limits of detection ≤50 nM and the tentative identification of additional 30 steroids based on accurate mass, isotopic pattern analysis and spectral similarity matching to known steroids. The method displays excellent inter- and intra-day stability, repeatability and recovery and was validated for clinical routine analysis. Additionally, we demonstrate the potential of the approach for untargeted analysis of urinary steroids in mouse and rat.


Assuntos
Cromatografia Gasosa-Espectrometria de Massas , Esteroides/urina , Urinálise/métodos , Animais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley
10.
Rapid Commun Mass Spectrom ; 32(19): 1703-1710, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-29989245

RESUMO

RATIONALE: Polyoxometalates (POMs) are remarkable oxo-clusters forming compact highly charged anions. We measured their collision cross sections (CCS) in N2 with drift tube ion mobility spectrometry (DTIMS). These values were then used to calibrate a traveling wave ion mobility spectrometry (TWIMS) device and the accuracy of the calibration was tested. METHODS: Six POM standards were analyzed by DTIM-MS (Tofwerk, Thun, Switzerland) at different voltages to determine absolute DT CCS (N2 ) values. Five POM compounds (Lindqvist TBA2 Mo6 O19; decatungstate TBA4 W10 O32; Keggin TBA3 PMo12 O40 ; TBA3 PW12 O40 and Dawson TBA6 P2 W18 O62 ) were used for the calibration of the TWIM-MS instrument (Synapt G2 HDMS, Waters, Manchester, UK) and a sixth Dawson POM, TBA9 P2 Nb3 W15 O62 , was used to compare the accuracy of the calibrations with POM or with polyalanine and dextran reference ions. RESULTS: We determined 45 DT CCS (N2 ) values at 30°C or 60°C. Fourteen DT CCS (N2 ) values at 30°C were used to perform calibration of the TWIMS instrument. Better correlations were observed than when DT CCS values in helium from the literature were used. The accuracy tests on six ions of Dawson POM TBA9 P2 Nb3 W15 O62 led to relative errors below 3.1% while relative errors of 3.6% to 10.1% were observed when calibration was performed with polyalanine and dextran reference ions. CONCLUSIONS: Our novel calibration strategy for determination of CCS values of multiply negatively charged ions on TWIM-MS devices based on DT CCS (N2 ) of standard POM structures covered a wider range of CCS and improved the accuracy to 2.1% relative error on average compared with 6.9% using polyalanine and dextran calibration.

11.
Anal Chem ; 90(15): 8764-8768, 2018 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-29943977

RESUMO

We report initial results from an ion mobility spectrometry (IMS)-based analysis of natural cannabis samples and explore the possibility of using this technique to distinguish medical marijuana from illegal forms of the drug, as defined by Swiss legislation. We analyzed cannabis extracts by electrospray ionization IMS-MS and found that high-resolution drift-tube IMS ( R > 150) can effectively isolate and quantify the controlled substance, Δ9-tetrahydrocannabinol (THC), even in the presence of other noncontrolled cannabinoid isomers including cannabidiol (CBD). We used this information to determine whether the THC content of a given sample surpassed the legal limit, which is 1% by weight in Switzerland. Our IMS-MS methodology produced equivalent quantification results to standard HPLC-based methods and offers the additional advantage of significantly shorter time requirements for the analysis. In addition, IMS-based analysis offers flexibility over HPLC in that it can be performed on portable devices. As such, these findings may have implications for cannabis testing in police laboratories.


Assuntos
Cannabis/química , Dronabinol/análise , Espectrometria de Mobilidade Iônica/métodos , Canabidiol/análise , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Isomerismo , Fumar Maconha/legislação & jurisprudência , Suíça
12.
Angew Chem Int Ed Engl ; 56(36): 10942-10946, 2017 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-28665506

RESUMO

The formation of complexes between hexafluorophosphate (PF6- ) and tetraisobutyloctahydroxypyridine[4]arene has been thoroughly studied in the gas phase (ESI-QTOF-MS, IM-MS, DFT calculations), in the solid state (X-ray crystallography), and in chloroform solution (1 H, 19 F, and DOSY NMR spectroscopy). In all states of matter, simultaneous endo complexation of solvent molecules and exo complexation of a PF6- anion within a pyridine[4]arene dimer was observed. While similar ternary complexes are often observed in the solid state, this is a unique example of such behavior in the gas phase.

13.
Environ Sci Technol ; 51(11): 5932-5940, 2017 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-28445044

RESUMO

Highly oxygenated multifunctional organic compounds (HOMs) originating from biogenic emissions constitute a widespread source of organic aerosols in the pristine atmosphere. However, the molecular forms in which HOMs are present in the condensed phase upon gas-particle partitioning remain unclear. In this study, we show that highly oxygenated molecules that contain multiple peroxide functionalities are readily cationized by the attachment of Na+ during electrospray ionization operated in the positive ion mode. With this method, we present the first identification of HOMs characterized as C8-10H12-18O4-9 monomers and C16-20H24-36O8-14 dimers in α-pinene derived secondary organic aerosol (SOA). Simultaneous detection of these molecules in the gas phase provides direct evidence for their gas-to-particle conversion. Molecular properties of particulate HOMs generated from ozonolysis and OH oxidation of unsubstituted (C10H16) and deuterated (C10H13D3) α-pinene are investigated using coupled ion mobility spectrometry with mass spectrometry. The systematic shift in the mass of monomers in the deuterated system is consistent with the decomposition of isomeric vinylhydroperoxides to release vinoxy radical isotopologues, the precursors to a sequence of autoxidation reactions that ultimately yield HOMs in the gas phase. The remarkable difference observed in the dimer abundance under O3- versus OH-dominant environments underlines the competition between intramolecular hydrogen migration of peroxy radicals and their bimolecular termination reactions. Our results provide new and direct molecular-level information for a key component needed for achieving carbon mass closure of α-pinene SOA.


Assuntos
Aerossóis , Poluentes Atmosféricos , Monoterpenos , Monoterpenos Bicíclicos , Ozônio
14.
Chem Commun (Camb) ; 53(30): 4246-4249, 2017 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-28361137

RESUMO

Metalation of hen egg white lysozyme (HEWL) with organometallics was studied with physicochemical methods in solid state, solution and the gas phase. While metalation did not affect the crystal structure of HEWL significantly, protein destabilisation was detected in gas phase and solution.

15.
Chemistry ; 23(8): 1881-1890, 2017 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-28071820

RESUMO

Response profiling using shotgun proteomics for establishing global metallodrug mechanisms of action in two colon carcinoma cell lines, HCT116 and SW480, has been applied and evaluated with the clinically approved arsenic trioxide. Surprisingly, the complete established mechanism of action of arsenic trioxide was observed by protein regulations in SW480, but not HCT116 cells. Comparing the basal protein expression in the two cell lines revealed an 80 % convergence of protein identification, but with significant expression differences, which in turn seem to affect the extent of protein regulation. A clear-cut redox response was observed in SW480 cells upon treatment with arsenic, but hardly in HCT116 cells. Response profiling was then used to investigate four anti-cancer metallodrugs (KP46, KP772, KP1339 and KP1537). Proteome alterations were mapped to selected functional groups, including DNA repair, endocytosis, protection from oxidative stress, protection from endoplasmatic reticulum (ER) stress, cell adhesion and mitochondrial function. The present data suggest that knowledge of the mechanism of action of anti-cancer metallodrugs and improved patient stratification strategies are imperative for the design of clinical studies.

16.
Angew Chem Int Ed Engl ; 54(51): 15462-7, 2015 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-26530790

RESUMO

Large, non-symmetrical, inherently chiral bispyridyl ligand L derived from natural ursodeoxycholic bile acid was used for square-planar coordination of tetravalent Pd(II) , yielding the cationic single enantiomer of superchiral coordination complex 1 Pd3 L6 containing 60 well-defined chiral centers in its flower-like structure. Complex 1 can readily be transformed by addition of chloride into a smaller enantiomerically pure cyclic trimer 2 Pd3 L3 Cl6 containing 30 chiral centers. This transformation is reversible and can be restored by the addition of silver cations. Furthermore, a mixture of two constitutional isomers of trimer, 2 and 2', and dimer, 3 and 3', can be obtained directly from L by its coordination to trans- or cis-N-pyridyl-coordinating Pd(II) . These intriguing, water-resistant, stable supramolecular assemblies have been thoroughly described by (1) H DOSY NMR, mass spectrometry, circular dichroism, molecular modelling, and drift tube ion-mobility mass spectrometry.

17.
Inorg Chem ; 54(12): 6055-61, 2015 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-26039343

RESUMO

A novel modular approach to electron-deficient and electron-rich M6L4 cages is presented. From the same starting compound, via a minor modulation of the synthesis route, two C3-symmetric ligands L1 and L2 with different electronic properties are obtained in good yield. The trifluoro-triethynylbenzene-based ligand L1 is more electron-deficient than the well-known 2,4,6-tri(4-pyridyl)-1,3,5-triazine, while the trimethoxy-triethynylbenzene-based ligand L2 is more electron-rich than the corresponding benzene analogue. Complexation of the ligands with cis-protected square-planar [(dppp)Pt(OTf)2] or [(dppp)Pd(OTf)2] corner-complexes yields two electron-deficient (1a and 1b) and two electron-rich (2a and 2b) M6L4 cages. The single crystal X-ray diffraction study of 1a and 2a confirms the expected octahedral shape with a ca. 2000 Å(3) cavity and ca. 11 Å wide apertures. The crystallographically determined diameters of 1a and 2a are 3.7 and 3.6 nm, respectively. The hydrodynamic diameters obtained from the DOSY NMR in CDCl3:CD3OD (4:1), and diameters calculated from collision cross sections (CCS) acquired by ion-mobility mass spectrometry (IM-MS) were for all four cages similar. In solution, the cage structures have diameters between 3.3 to 3.6 nm, while in the gas phase the corresponding diameters varied between 3.4 to 3.6 nm. In addition to the structural information the relative stabilities of the Pt6L4 and Pd6L4 cages were studied in the gas phase by collision-induced dissociation (CID) experiments, and the photophysical properties of the ligands L1 and L2 and cages 1a, 1b, 2a, and 2b were studied by UV-vis and fluorescence spectroscopy.

18.
J Proteome Res ; 13(11): 4773-82, 2014 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-25238572

RESUMO

Breast cancer is still the most common type of cancer in women; an important role in carcinogenesis is actually attributed to cancer-associated fibroblasts. In this study, we investigated whether it is possible to assess the functional state of cancer-associated fibroblasts through tumor tissue proteome profiling. Tissue proteomics was performed on tumor-central, tumor-near, and tumor-distant biopsy sections from breast adenocarcinoma patients, which allowed us to identify 2074 proteins. Data were interpreted referring to reference proteome profiles generated from primary human mammary fibroblasts comprising 4095 proteins. These cells were analyzed in quiescent cell state as well as after in vitro treatment with TGFß or IL-1ß, stimulating wound healing or inflammatory processes, respectively. Representative for cancer cells, we investigated the mammary carcinoma cell line ZR-75-1, identifying 5212 proteins. All mass analysis data have been made fully accessible via ProteomeXchange, DOI PXD001311 and PXD001323-8. Comparison of tissue proteomics data with all of those reference profiles revealed predominance of cancer cell-derived proteins within the tumor and fibroblast-derived proteins in the tumor-distant tissue sections. Remarkably, proteins characteristic for acute inflammation were hardly identified in the tissue samples. In contrast, several proteins found by us to be induced by TGFß in mammary fibroblasts, including fibulin-5, SLC2A1, and MUC18, were positively identified in all tissue samples, with relatively higher abundance in tumor neighboring tissue sections. These findings indicate a predominance of cancer-associated fibroblasts with wound healing activities localized around tumors.


Assuntos
Adenocarcinoma/metabolismo , Neoplasias da Mama/metabolismo , Fibroblastos/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Proteoma/metabolismo , Proteômica/métodos , Cicatrização/genética , Adenocarcinoma/genética , Neoplasias da Mama/genética , Cromatografia Líquida , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Espectrometria de Massas em Tandem
19.
Chimia (Aarau) ; 68(3): 135-9, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24801843

RESUMO

Hadamard transform atmospheric pressure ion mobility-MS and rapid UHPLC-MS methods were investigated for analysis of closely related isomeric flavonoids and their glycosides using a test set of seven standards. On a time scale of a few minutes, the flavonoid aglycones were all separated by ion mobility, but not by UHPLC. The glycosides were better resolved by IMS but not completely separated by both methods. The results suggest that IMS provides sufficient resolution for separation of isomeric polyphenols such as flavonoids in high-throughput metabolomics studies.


Assuntos
Cromatografia Líquida/métodos , Flavonoides/química , Metabolômica/métodos , Espectrometria de Massas por Ionização por Electrospray/métodos , Cromatografia Líquida/instrumentação , Isomerismo , Metabolômica/instrumentação , Conformação Molecular , Espectrometria de Massas por Ionização por Electrospray/instrumentação
20.
Nat Commun ; 5: 3462, 2014 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-24637564

RESUMO

Ruthenium compounds have become promising alternatives to platinum drugs by displaying specific activities against different cancers and favourable toxicity and clearance properties. Nonetheless, their molecular targeting and mechanism of action are poorly understood. Here we study two prototypical ruthenium-arene agents-the cytotoxic antiprimary tumour compound [(η(6)-p-cymene)Ru(ethylene-diamine)Cl]PF6 and the relatively non-cytotoxic antimetastasis compound [(η(6)-p-cymene)Ru(1,3,5-triaza-7-phosphaadamantane)Cl2]-and discover that the former targets the DNA of chromatin, while the latter preferentially forms adducts on the histone proteins. Using a novel 'atom-to-cell' approach, we establish the basis for the surprisingly site-selective adduct formation behaviour and distinct cellular impact of these two chemically similar anticancer agents, which suggests that the cytotoxic effects arise largely from DNA lesions, whereas the protein adducts may be linked to the other therapeutic activities. Our study shows promise for developing new ruthenium drugs, via ligand-based modulation of DNA versus protein binding and thus cytotoxic potential, to target distinguishing epigenetic features of cancer cells.


Assuntos
Antineoplásicos/química , DNA/metabolismo , Monoterpenos/química , Proteínas/metabolismo , Rutênio/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cimenos , DNA/química , Humanos , Cinética , Ligantes , Estrutura Molecular , Monoterpenos/farmacologia , Ligação Proteica , Proteínas/química , Rutênio/farmacologia
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