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  • 1.
    Aftab, Obaid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Engskog, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Haglöf, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Elmsjö, Albert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Arvidsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Hammerling, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Gustafsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    NMR spectroscopy based metabolic profiling of drug induced changes in vitro can discriminate between pharmacological classes2014In: Journal of chemical information and modeling, ISSN 1549-9596, Vol. 54, no 11, p. 3251-3258Article in journal (Refereed)
    Abstract [en]

    Drug induced changes in mammalian cell line models have already been extensively profiled at the systemic mRNA level and subsequently used to suggest mechanisms of action for new substances as well as to support drug repurposing, i.e. identifying new potential indications for drugs already licensed for other pharmacotherapy settings. The seminal work in this field, which includes a large database and computational algorithms for pattern matching, is known as the “Connectivity Map” (CMap). The potential of similar exercises at the metabolite level is, however, still largely unexplored. Only recently the first high throughput metabolomic assay pilot study was published, involving screening of metabolic response to a set of 56 kinase inhibitors in a 96-well format. Here we report results from a separately developed metabolic profiling assay, which leverages 1H NMR spectroscopy to the quantification of metabolic changes in the HCT116 colorectal cancer cell line, in response to each of 26 compounds. These agents are distributed across 12 different pharmacological classes covering a broad spectrum of bioactivity. Differential metabolic profiles, inferred from multivariate spectral analysis of 18 spectral bins, allowed clustering of most tested drugs according to their respective pharmacological class. A more advanced supervised analysis, involving one multivariate scattering matrix per pharmacological class and using only 3 spectral bins (three metabolites), showed even more distinct pharmacology-related cluster formations. In conclusion, this kind of relatively fast and inexpensive profiling seems to provide a promising alternative to that afforded by mRNA expression analysis, which is relatively slow and costly. As also indicated by the present pilot study, the resulting metabolic profiles do not seem to provide as information rich signatures as those obtained using systemic mRNA profiling, but the methodology holds strong promise for significant refinement.

  • 2.
    Colombo, Stefano
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Brisander, Magnus
    Haglöf, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Sjövall, Peter
    Andersson, Per
    Østergaard, Jesper
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Matrix effects in nilotinib formulations with pH-responsive polymer produced by carbon dioxide-mediated precipitation2015In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 494, no 1, p. 205-217Article in journal (Refereed)
    Abstract [en]

    Factors determining the pH-controlled dissolution kinetics of nilotinib formulations with the pH-titrable polymer hydroxypropyl methylcellulose phthalate, obtained by carbon dioxide-mediated precipitation, were mechanistically examined in acid and neutral environment. The matrix effect, modulating the drug dissolution, was characterized with a battery of physicochemical methodologies, including ToF-SIMS for surface composition, SAXS/WAXS and modulated DSC for crystallization characterization, and simultaneous UV-imaging and Raman spectroscopy for monitoring the dissolution process in detail. The hybrid particle formulations investigated consisted of amorphous nilotinib embedded in a polymer matrix in single continuous phase, displaying extended retained amorphicity also under wet conditions. It was demonstrated by Raman and FTIR spectroscopy that the efficient drug dispersion and amorphization in the polymer matrix were mediated by hydrogen bonding between the drug and the phthalate groups on the polymer. Simultaneous Raman and UV-imaging studies of the effect of drug load on the swelling and dissolution of the polymer matrix revealed that high nilotinib load prevented matrix swelling on passage from acid to neutral pH, thereby preventing re-precipitation and re-crystallization of incorporated nilotinib. These findings provide a mechanistic foundation of formulation development of nilotinib and other protein kinase inhibitors, which are now witnessing an intense therapeutic and industrial attention due to the difficulty in formulating these compounds so that efficient oral bioavailability is reached.

  • 3.
    Elmsjö, Albert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Haglöf, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Engskog, Mikael K. R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Nestor, Marika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Arvidsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry. Med Prod Agcy, Uppsala, Sweden.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    The co-feature ratio, a novel method for the measurement of chromatographic and signal selectivity in LC-MS-based metabolomics.2017In: Analytica Chimica Acta, ISSN 0003-2670, E-ISSN 1873-4324, Vol. 956, p. 40-47Article in journal (Refereed)
    Abstract [en]

    Evaluation of analytical procedures, especially in regards to measuring chromatographic and signal selectivity, is highly challenging in untargeted metabolomics. The aim of this study was to suggest a new straightforward approach for a systematic examination of chromatographic and signal selectivity in LC-MS-based metabolomics. By calculating the ratio between each feature and its co-eluting features (the co-features), a measurement of the chromatographic selectivity (i.e. extent of co-elution) as well as the signal selectivity (e.g. amount of adduct formation) of each feature could be acquired, the co-feature ratio. This approach was used to examine possible differences in chromatographic and signal selectivity present in samples exposed to three different sample preparation procedures. The capability of the co-feature ratio was evaluated both in a classical targeted setting using isotope labelled standards as well as without standards in an untargeted setting. For the targeted analysis, several metabolites showed a skewed quantitative signal due to poor chromatographic selectivity and/or poor signal selectivity. Moreover, evaluation of the untargeted approach through multivariate analysis of the co-feature ratios demonstrated the possibility to screen for metabolites displaying poor chromatographic and/or signal selectivity characteristics. We conclude that the co-feature ratio can be a useful tool in the development and evaluation of analytical procedures in LC-MS-based metabolomics investigations. Increased selectivity through proper choice of analytical procedures may decrease the false positive and false negative discovery rate and thereby increase the validity of any metabolomic investigation.

  • 4.
    Elmsjö, Albert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Rosqvist, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Engskog, Mikael K R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Haglöf, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Iggman, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Arvidsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    NMR-based metabolic profiling in healthy individuals overfed different types of fat: links to changes in liver fat accumulation and lean tissue mass.2015In: Nutrition & Diabetes, ISSN 2044-4052, E-ISSN 2044-4052, Vol. 5, no 19, p. e182-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Overeating different dietary fatty acids influence the amount of liver fat stored during weight gain, however, the mechanisms responsible are unclear. We aimed to identify non-lipid metabolites that may differentiate between saturated (SFA) and polyunsaturated fatty acid (PUFA) overfeeding using a non-targeted metabolomic approach. We also investigated the possible relationships between plasma metabolites and body fat accumulation.

    METHODS: In a randomized study (LIPOGAIN study), n=39 healthy individuals were overfed with muffins containing SFA or PUFA. Plasma samples were precipitated with cold acetonitrile and analyzed by nuclear magnetic resonance (NMR) spectroscopy. Pattern recognition techniques were used to overview the data, identify variables contributing to group classification and to correlate metabolites with fat accumulation.

    RESULTS: We previously reported that SFA causes a greater accumulation of liver fat, visceral fat and total body fat, whereas lean tissue levels increases less compared with PUFA, despite comparable weight gain. In this study, lactate and acetate were identified as important contributors to group classification between SFA and PUFA (P<0.05). Furthermore, the fat depots (total body fat, visceral adipose tissue and liver fat) and lean tissue correlated (P(corr)>0.5) all with two or more metabolites (for example, branched amino acids, alanine, acetate and lactate). The metabolite composition differed in a manner that may indicate higher insulin sensitivity after a diet with PUFA compared with SFA, but this needs to be confirmed in future studies.

    CONCLUSION: A non-lipid metabolic profiling approach only identified a few metabolites that differentiated between SFA and PUFA overfeeding. Whether these metabolite changes are involved in depot-specific fat storage and increased lean tissue mass during overeating needs further investigation.

  • 5.
    Engskog, Mikael K R
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Björklund, My
    Haglöf, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Arvidsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Shoshan, Maria
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Metabolic profiling of epithelial ovarian cancer cell lines: evaluation of harvesting protocols for profiling using NMR spectroscopy2015In: Bioanalysis, ISSN 1757-6180, E-ISSN 1757-6199, Vol. 7, no 2, p. 157-166Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Metabolic profiling represents a novel technology for analyzing tumor cells. Epithelial ovarian carcinoma has a low survival rate due to the development of aggressive and chemotherapy-resistant cells. A tailored and reliable protocol is presented for profiling of chemoresistant cells using the cell line SKOV3 and a multiresistant subline SKOV3R.

    RESULTS: Harvesting protocols with cold methanol or MilliQ freeze/thaw cycles were compared. Increased reproducibility using MilliQ was evidenced. Importantly, both approaches resulted in similar profiles. Compared with parental SKOV3, the SKOV3R cells showed a significantly different profile.

    CONCLUSION: The MilliQ protocol is preferred owing to higher reproducibility and increased sample preparation options. The resulting metabolic profiles summarize metabolic alterations in chemoresistant cells consistent with a progressed and aggressive phenotype.

  • 6.
    Engskog, Mikael K. R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Ersson, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Haglöf, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Arvidsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry. Medical Product Agency, Box 26, Dag Hammarskjölds väg 42, 751 03 Uppsala, Sweden.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Brittebo, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    β-N-Methylamino-L-alanine (BMAA) perturbs alanine, aspartate and glutamate metabolism pathways in human neuroblastoma cells as determined by metabolic profiling2017In: Amino Acids, ISSN 0939-4451, E-ISSN 1438-2199, Vol. 49, no 5, p. 905-919Article in journal (Refereed)
    Abstract [en]

    β-Methylamino-L-alanine (BMAA) is a non-proteinogenic amino acid that induces long-term cognitive deficits, as well as an increased neurodegeneration and intracellular fibril formation in the hippocampus of adult rodents following short-time neonatal exposure and in vervet monkey brain following long-term exposure. It has also been proposed to be involved in the etiology of neurodegenerative disease in humans. The aim of this study was to identify metabolic effects not related to excitotoxicity or oxidative stress in human neuroblastoma SH-SY5Y cells. The effects of BMAA (50, 250, 1000 µM) for 24 h on cells differentiated with retinoic acid were studied. Samples were analyzed using LC-MS and NMR spectroscopy to detect altered intracellular polar metabolites. The analysis performed, followed by multivariate pattern recognition techniques, revealed significant perturbations in protein biosynthesis, amino acid metabolism pathways and citrate cycle. Of specific interest were the BMAA-induced alterations in alanine, aspartate and glutamate metabolism and as well as alterations in various neurotransmitters/neuromodulators such as GABA and taurine. The results indicate that BMAA can interfere with metabolic pathways involved in neurotransmission in human neuroblastoma cells.

  • 7.
    Engskog, Mikael K R
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Haglöf, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Arvidsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Evaluation of harvesting protocols for metabolic profiling of epithelial ovarian cancer cells2014Conference paper (Other academic)
  • 8.
    Engskog, Mikael K. R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Haglöf, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Arvidsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry. Med Prod Agcy, Dag Hammarskjolds Vag 42,Box 26, SE-75103 Uppsala, Sweden..
    Pettersson, Curt
    LC-MS based global metabolite profiling: the necessity of high data quality2016In: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 12, no 7, article id 114Article, review/survey (Refereed)
    Abstract [en]

    LC-MS based global metabolite profiling currently lacks detailed guidelines to demonstrate that the obtained data is of high enough analytical quality. Insufficient data quality may result in the failure to generate a hypothesis, or in the worst case, a false or skewed hypothesis. After assessing the literature, it is apparent that an analytically focused summary and critical discussion related to this subject would be beneficial for both beginners and experts engaged in this field. A particular focus will be placed on data quality, which we here define as the degree to which a set of parameters fulfills predetermined criteria, similar to the established guidelines for targeted analysis. However, several of these parameters are difficult to assess since holistic approaches measure thousands of metabolites in parallel and seldom include predefined knowledge of which metabolites will differ between sample groups. In this review, the following parameters will be discussed in detail: reproducibility, selectivity, certainty of metabolite identification and metabolite coverage. The review systematically describes the generic workflow for LC-MS based global metabolite profiling and highlights how each separate part may affect data quality. The last part of the review describes how data quality can be evaluated as well as identifies areas where additional improvement is needed. In this review, we provide our own analytical opinions in regards to evaluation and, to some extent, improvement of data quality.

  • 9.
    Engskog, Mikael K R
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Haglöf, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Elmsjö, Albert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Brittebo, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Arvidsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    The cyanobacterial amino acid beta-N-methylamino-L-alanine perturbs the intermediary metabolism in neonatal rats2017In: Amino Acids, ISSN 0939-4451, E-ISSN 1438-2199, Vol. 49, no 5, p. 905-919, article id 10.1007/s00726-017-2391-8Article in journal (Refereed)
    Abstract [en]

    The neurotoxic amino acid β-N-methylamino-l-alanine (BMAA) is produced by most cyanobacteria. BMAA is considered as a potential health threat because of its putative role in neurodegenerative diseases. We have previously observed cognitive disturbances and morphological brain changes in adult rodents exposed to BMAA during the development. The aim of this study was to characterize changes of major intermediary metabolites in serum following neonatal exposure to BMAA using a non-targeted metabolomic approach. NMR spectroscopy was used to obtain serum metabolic profiles from neonatal rats exposed to BMAA (40, 150, 460mg/kg) or vehicle on postnatal days 9-10. Multivariate data analysis of binned NMR data indicated metabolic pattern differences between the different treatment groups. In particular five metabolites, d-glucose, lactate, 3-hydroxybutyrate, creatine and acetate, were changed in serum of BMAA-treated neonatal rats. These metabolites are associated with changes in energy metabolism and amino acid metabolism. Further statistical analysis disclosed that all the identified serum metabolites in the lowest dose group were significantly (p<0.05) decreased. The neonatal rat model used in this study is so far the only animal model that displays significant biochemical and behavioral effects after a low short-term dose of BMAA. The demonstrated perturbation of intermediary metabolism may contribute to BMAA-induced developmental changes that result in long-term effects on adult brain function.

  • 10.
    Haglöf, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Enantiomeric Separations using Chiral Counter-Ions2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis describes the use of chiral counter-ions for the enantiomeric separation of amines in non-aqueous capillary electrophoresis. The investigations have been concentrated on studies of the influence, of the chiral counter-ion, the solvent, the electrolyte and the analyte, on the enantioselective separation.

    Modified divalent dipeptides have been introduced in capillary electrophoresis for the separation of amino alcohols and chiral resolution of amines. Association constants for the ion-pair between dipeptide and amino alcohol could be utilized for development of separation systems with higher amino alcohol selectivity. Chiral discrimination (ion-pair formation) between the dipeptides and amines are preferably generated in non-aqueous background electrolytes (BGEs). The amount of triethylamine in the BGE determined the dipeptide charge and a divalent dipeptide promoted higher enantioselectivity than a monovalent dipeptide. An N-terminal-end blocking group and glutamic acid at the C-terminal-end of the dipeptide was important for chiral separation of the amines.

    Chemometric and univariate methods have been employed for evaluation of suitable solvent compositions in the BGE. An experimental design including a single solvent as well as binary, ternary and quaternary mixtures of polar organic solvents, showed that optimal enantioresolution was obtained with an ethanol:methanol 80:20 mixture in the BGE.  Furthermore, water was found to have an adverse influence on enantioselectivity and no enantioresolution was obtained with BGEs containing more than 30 % water.

    An alkali metal hydroxide added to the BGE affected the chiral separation by competing ion-pair formation with the selector. The electroosmosis was reduced in order of decreasing alkali metal ion solvated radius and became anodic using K, Rb or Cs in ethanolic BGEs.

    The correlation between the amino alcohol structure and the enantioselectivity was investigated using chemometrics. The obtained models showed that enantioselectivity for the amino alcohols was promoted by e.g. degree of substitution and substituent size on the nitrogen.

    List of papers
    1.
    The record could not be found. The reason may be that the record is no longer available or you may have typed in a wrong id in the address field.
    2. Separation of amino alcohols using divalent dipeptides as counter ions in aqueous CE
    Open this publication in new window or tab >>Separation of amino alcohols using divalent dipeptides as counter ions in aqueous CE
    2010 (English)In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 31, no 10, p. 1706-1712Article in journal (Refereed) Published
    Abstract [en]

    Divalent dipeptides have been introduced as counter ions in aqueous CZE. The dipeptides form ion pairs with amino alcohols in the BGE and facilitate the separation of amino alcohols. High concentrations of dipeptide caused reversed effective mobility for the analytes. The net charge of the dipeptide can be controlled using a buffer or a strong base, and regulates the interaction between the dipeptide and the amino alcohol. A stronger interaction and higher selectivity of amino alcohols was observed when the dipeptides were used as divalent counter ions, than in monovalent or uncharged form. Association constants for ion pairs between divalent dipeptides and amino alcohols can be used to enhance selectivity for amino alcohols in CZE. No chiral separation of amino alcohols was observed when using the dipeptides as ion-pairing chiral selectors in aqueous BGE, but addition of methanol to the BGE promoted enantioselectivity.

    Keyword
    Association constants, CE, divalent counter ion, Ion-pair formation, reversed mobility
    National Category
    Medicinal Chemistry
    Research subject
    Analytical Pharmaceutical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-125470 (URN)10.1002/elps.200900702 (DOI)000278650500015 ()20414882 (PubMedID)
    Available from: 2010-05-19 Created: 2010-05-19 Last updated: 2018-01-12Bibliographically approved
    3. Enantiomeric separation of amines using divalent dipeptides as chiral counter-ions in non-aqueous CE
    Open this publication in new window or tab >>Enantiomeric separation of amines using divalent dipeptides as chiral counter-ions in non-aqueous CE
    (English)Manuscript (preprint) (Other academic)
    Keyword
    Capillary electrophoresis, nonaqueous solvents, divalent chiral counter ion, ion-pairing
    National Category
    Medicinal Chemistry
    Research subject
    Analytical Pharmaceutical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-130047 (URN)
    Available from: 2010-08-30 Created: 2010-08-30 Last updated: 2018-01-12
    4. Multivariate data analysis of a chiral separation system using N-derivatized dipeptides as chiral counter-ions on porous graphitic carbon stationary phase
    Open this publication in new window or tab >>Multivariate data analysis of a chiral separation system using N-derivatized dipeptides as chiral counter-ions on porous graphitic carbon stationary phase
    (English)Manuscript (preprint) (Other academic)
    Keyword
    Chiral counter ion, selectivity, molecular descriptor, topological index, PCA, PLS, OPLS
    National Category
    Medicinal Chemistry
    Research subject
    Analytical Pharmaceutical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-130048 (URN)
    Available from: 2010-08-30 Created: 2010-08-30 Last updated: 2018-01-12
  • 11.
    Haglöf, Jakob
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Karlsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Multivariate analysis of enantiomeric separation of amino alcohols using N-derivatized dipeptides as chiral selectors in HPLC2010Conference paper (Other academic)
  • 12.
    Haglöf, Jakob
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Karlsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Multivariate data analysis of a chiral separation system using N-derivatized dipeptides as chiral counter-ions on porous graphitic carbon stationary phaseManuscript (preprint) (Other academic)
  • 13.
    Haglöf, Jakob
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Capillary electrophoretic studies of ion pairing in aqueous solution using N-derivatized dipeptides2008Conference paper (Other academic)
  • 14.
    Haglöf, Jakob
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Enantiomeric separation of amines using divalent dipeptides as chiral counter-ions in non-aqueous CEManuscript (preprint) (Other academic)
  • 15.
    Haglöf, Jakob
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Enantiomeric separation of amines using divalent N-derivatized dipeptides as chiral selectors in non-aqueous capillary electrophoresis2008Conference paper (Other academic)
  • 16.
    Haglöf, Jakob
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Separation of amino alcohols using divalent dipeptides as counter ions in aqueous CE2010In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 31, no 10, p. 1706-1712Article in journal (Refereed)
    Abstract [en]

    Divalent dipeptides have been introduced as counter ions in aqueous CZE. The dipeptides form ion pairs with amino alcohols in the BGE and facilitate the separation of amino alcohols. High concentrations of dipeptide caused reversed effective mobility for the analytes. The net charge of the dipeptide can be controlled using a buffer or a strong base, and regulates the interaction between the dipeptide and the amino alcohol. A stronger interaction and higher selectivity of amino alcohols was observed when the dipeptides were used as divalent counter ions, than in monovalent or uncharged form. Association constants for ion pairs between divalent dipeptides and amino alcohols can be used to enhance selectivity for amino alcohols in CZE. No chiral separation of amino alcohols was observed when using the dipeptides as ion-pairing chiral selectors in aqueous BGE, but addition of methanol to the BGE promoted enantioselectivity.

  • 17.
    Hedeland, Ylva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Haglöf, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Beronius, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Effect of alkali metal hydroxides on the enantioseparation of amines using di-O-isopropylidene-keto-L-gulonic acid as the selector in NACE2006In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 27, no 22, p. 4469-4479Article in journal (Refereed)
    Abstract [en]

    The present work demonstrates the importance of the ionic composition in the BGE for enantioseparation. (-)-2,3:4,6-di-O-Isopropylidene-2-keto-L-gulonic acid ((-)-DIKGA) has been used as the chiral selector in methanolic and ethanolic BGEs. The influence of added alkali metal hydroxides on the EOF and the chiral separation of amines; (atenolol, isoprenaline, pindolol and propranolol) have been studied. The ion-pair formation constants in ethanol were determined by precision conductometry for the enantiomers of pindolol with (-)-DIKGA, for Li+, Na+ and Cs+ with (-)-DIKGA, and also for the corresponding alkali metal hydroxides. The effective mobilities and the enantiomeric mobility differences were affected by the type of alkali metal hydroxide (LiOH, NaOH, KOH, RbOH or CsOH) added to the BGE. The effective mobility and mobility difference were increased with decrease in solvated radius of the alkali metal cation. These differences could partly be correlated to the ion-pair formation constants of the alkali metal cations with the chiral selector, affecting the equilibrium concentration of the free selector. The electroosmosis was also affected by the alkali metal hydroxide added to the BGE. The cathodic electroosmosis decreased with decreasing solvated radius of the alkali metal cation added to the BGE. Interestingly, the cathodic EOF was even reversed, i.e. became anodic in the ethanolic BGEs containing KOH, RbOH or CsOH and the methanolic ones with RbOH and CsOH.

  • 18.
    Häggblad Sahlberg, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Mortensen, Anja C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Haglöf, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Engskog, Mikael K. R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Arvidsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Nestor, Marika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Different functions of AKT1 and AKT2 in molecular pathways, cell migration and metabolism in colon cancer cells2017In: International Journal of Oncology, ISSN 1019-6439, Vol. 50, no 1, p. 5-14Article in journal (Refereed)
    Abstract [en]

    AKT is a central protein in many cellular pathways such as cell survival, proliferation, glucose uptake, metabolism, angiogenesis, as well as radiation and drug response. The three isoforms of AKT (AKT1, AKT2 and AKT3) are proposed to have different physiological functions, properties and expression patterns in a cell type-dependent manner. As of yet, not much is known about the influence of the different AKT isoforms in the genome and their effects in the metabolism of colorectal cancer cells. In the present study, DLD-1 isogenic AKT1, AKT2 and AKT'/2 knockout colon cancer cell lines were used as a model system in conjunction with the parental cell line in order to further elucidate the differences between the AKT isoforms and how they are involved in various cellular pathways. This was done using genome wide expression analyses, metabolic profiling and cell migration assays. In conclusion, downregulation of genes in the cell adhesion, extracellular matrix and Notch-pathways and upregulation of apoptosis and metastasis inhibitory genes in the p53-pathway, confirm that the knockout of both AKT1 and AKT2 will attenuate metastasis and tumor cell growth. This was verified with a reduction in migration rate in the AKT1 KO and AKT2 KO and most explicitly in the AKT1/2 KO. Furthermore, the knockout of AKT1, AKT2 or both, resulted in a reduction in lactate and alanine, suggesting that the metabolism of carbohydrates and glutathione was impaired. This was further verified in gene expression analyses, showing downregulation of genes involved in glucose metabolism. Additionally, both AKT1 KO and AKT2 KO demonstrated an impaired fatty acid metabolism. However, genes were upregulated in the Wnt and cell proliferation pathways, which could oppose this effect. AKT inhibition should therefore be combined with other effectors to attain the best effect.

  • 19.
    Niklison-Chirou, Maria Victoria
    et al.
    Queen Mary Univ London, Barts & London Sch Med & Dent, Blizard Inst, London E1 2AT, England..
    Erngren, Ida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Engskog, Mikael K R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Haglöf, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Picard, Daniel
    Heinrich Heine Univ Dusseldorf, Dept Pediat Oncol Hematol & Clin Immunol, D-40225 Dusseldorf, Germany.;Heinrich Heine Univ Dusseldorf, Dept Neuropathol, Med Fac, D-40225 Dusseldorf, Germany.;German Canc Consortium DKTK, German Canc Res Ctr DKFZ, Dept Pediat Neurooncogen, D-69120 Heidelberg, Germany..
    Remke, Marc
    Heinrich Heine Univ Dusseldorf, Dept Pediat Oncol Hematol & Clin Immunol, D-40225 Dusseldorf, Germany.;Heinrich Heine Univ Dusseldorf, Dept Neuropathol, Med Fac, D-40225 Dusseldorf, Germany.;German Canc Consortium DKTK, German Canc Res Ctr DKFZ, Dept Pediat Neurooncogen, D-69120 Heidelberg, Germany..
    McPolin, Phelim Hugh Redmond
    Queen Mary Univ London, Barts & London Sch Med & Dent, Blizard Inst, London E1 2AT, England..
    Selby, Matthew
    Newcastle Univ, Wolfson Childhood Canc Res Ctr, Northern Inst Canc Res, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England..
    Williamson, Daniel
    Newcastle Univ, Wolfson Childhood Canc Res Ctr, Northern Inst Canc Res, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England..
    Clifford, Steven C.
    Newcastle Univ, Wolfson Childhood Canc Res Ctr, Northern Inst Canc Res, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England..
    Michod, David
    UCL, Inst Child Hlth, London WC1N 1EH, England..
    Hadjiandreou, Michalis
    Queen Mary Univ London, Barts & London Sch Med & Dent, Blizard Inst, London E1 2AT, England..
    Arvidsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry. Med Prod Agcy, SE-75103 Uppsala, Sweden..
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Melino, Gerry
    Univ Leicester, MRC, Toxicol Unit, Leicester LE1 9HN, Leics, England..
    Marino, Silvia
    Queen Mary Univ London, Barts & London Sch Med & Dent, Blizard Inst, London E1 2AT, England..
    TAp73 is a marker of glutamine addiction in medulloblastoma2017In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 31, no 17, p. 1738-1753Article in journal (Refereed)
    Abstract [en]

    Medulloblastoma is the most common solid primary brain tumor in children. Remarkable advancements in the understanding of the genetic and epigenetic basis of these tumors have informed their recent molecular classification. However, the genotype/phenotype correlation of the subgroups remains largely uncharacterized. In particular, the metabolic phenotype is of great interest because of its druggability, which could lead to the development of novel and more tailored therapies for a subset of medulloblastoma. p73 plays a critical role in a range of cellular metabolic processes. We show overexpression of p73 in a proportion of non-WNT medulloblastoma. In these tumors, p73 sustains cell growth and proliferation via regulation of glutamine metabolism. We validated our results in a xenograft model in which we observed an increase in survival time in mice on a glutamine restriction diet. Notably, glutamine starvation has a synergistic effect with cisplatin, a component of the current medulloblastoma chemotherapy. These findings raise the possibility that glutamine depletion can be used as an adjuvant treatment for p73-expressing medulloblastoma.

  • 20. Videhult Pierre, Pernilla
    et al.
    Haglöf, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Linder, Birgitta
    Engskog, Mikael K R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Arvidsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Laurell, Göran
    Ototoxicity of Cisplatin Correlates with Changes in Blood Antioxidant Status2014Conference paper (Other academic)
1 - 20 of 20
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