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  • 1. Begum, Sartaz
    et al.
    Nyandoro, Stephen
    Buriyo, Amelia
    Makangara, John
    Munissi, Joan
    Duffy, Sandra
    Avery, Vicky
    Erdelyi, Mate
    University of Gothenburg.
    Bioactivities of extracts, debromolaurintrerol and fucosterol from Macroalgae species2018In: Tanzania Journal of Science, ISSN 2507-7961, Vol. 44, no 2, p. 104-116Article in journal (Refereed)
    Abstract [en]

    Parasitic diseases including malaria, and other numerous microbial infections and physiological diseases are threatening the global population. Tanzanian coast shores are endowed with a variety of macroalgae (seaweeds), hitherto unsystematically explored to establish their biomedical potentials. Thus, antiplasmodial activity using malarial imaging assay, antimicrobial activity using microplate dilution technique, antioxidant activity using DPPH radical scavenging method and cytotoxicity using brine shrimp test were carried out on crude extracts from the selected species of algae (Acanthophora spicifera, Cystoseira myrica, Cystoseira trinodis, Laurencia filiformis, Padina boryana, Sargassum oligocystum, Turbinaria crateriformis, Ulva fasciata and Ulva reticulata) occurring along the coast of Tanzania. The extracts showed antimicrobial activities with MIC ranging from 0.3- 5.0 µg/mL against Staphylococcus aureus, Streptococcus pyogenes, Pseudomonas aeruginosa, Escherichia coli, Candida albicans and Cryptococcus neoformans; DPPH radical scavenging activity at EC50 1.0- 100 µg/mL and cytotoxicity on brine shrimp larvae with LC50 value ranging from20 - 1000 µg/mL. The extracts from C. myrica and P. boryana inhibited growth of Plasmodium falciparum (3D7 strain) by 80 and 71%, respectively at 40 µg/mL while a sesquiterpene debromolaurinterol (1) which was chromatographically isolated from C. myrica exhibited antiplasmodial activity with IC50 20 µM whereas a sterol fucosterol (2) from P. boryana showed weak activity at 40 µM. Bioactivities portrayed by the investigated extracts indicate their ingredients as potential sources of bioactive agents that warrant further explorations.

  • 2.
    Danelius, Emma
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Andersson, Hanna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Solution ensemble analysis of macrocycles2018Conference paper (Refereed)
    Abstract [en]

    Macrocycles are key drug leads for protein targets with large, flat and featureless binding sites, including protein-protein interfaces.  Due to their conformational flexibility macrocycles typically exist as a mixture of interconverting geometries in solution, and hence cannot be represented by a single, averaged conformation.  This flexibility is a result of continuously forming and breaking a number of weak intramolecular interactions.  The yielded conformations in solution vastly impact the bioactivity, solubility and membrane permeability of the macrocycles.  Therefore, describing their conformational ensembles, as well as the impact of conformation stabilizing weak interactions, is of fundamental importance, and the knowledge gained is directly applicable to medicinal chemistry.

    In order to describe macrocycle structure and dynamics, time-averaged solution spectroscopic data has to be deconvoluted into the present conformations along with their respective probability.  We have studied the solution ensembles of a series of macrocycles using the NAMFIS (NMR analysis of molecular flexibility in solution) algorithm.  This combined computational and spectroscopic ensembles analysis deconvolutes time averaged NMR data by identifying the real conformations and assigning them with their molar fractions.  Theoretical ensembles were predicted using Monte Carlo conformational searches with molecular mechanics minimization.  The generated ensembles, typically containing 40-150 conformers, were then used together with experimental NOE-based distances and J-coupling-based dihedral angles to identify the molar fractions of the conformations present in solution.

    We applied this technique to gain understanding of weak chemical interactions in a biologically relevant environment, by analyzing macrocyclic β-hairpin peptides.  The stabilizing effect provided by an interstrand weak interaction, as compared to a reference peptide lacking this interaction, was quantified through ensemble analysis.  We have shown that a single interstrand hydrogen [1,2,3] or halogen bond (Figure 1) [4], can significantly influence the folding, and increase the population of the folded conformation by up to 40%.  The NMR results were corroborated by CD-spectroscopy and MD-calculations.

  • 3.
    Danelius, Emma
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Andersson, Hanna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Jarvoll, Patrik
    Lood, Kajsa
    Gräfenstein, Jürgen
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Halogen bond promoted peptide folding2018Conference paper (Refereed)
    Abstract [en]

    We have developed a β-hairpin peptide model system that permits quantitative evaluation of weak interactions in a biologically relevant environment. The influence of a single weak force was measured by detection of the extent to which it modulates peptide folding. Initially we have optimized a β-hairpin model system, using the simpler to synthesize hydrogen bonding analogues of our target system encompassing halogen bond donor and acceptor sites [1,2,3]. Using a combined computational and NMR spectroscopic ensemble analysis, we have quantified the stabilizing effect of a single secondary interaction on the folded β-hairpin conformation. We have demonstrated that a chlorine centered halogen bond, formed between two amino acid side chains in an interstrand manner (Figure 1), provides a conformational stabilization comparable to the analogous hydrogen bond [4]. The negative control, i.e. the peptide containing a noninteracting aliphatic side chain, was ~30% less folded than the hydrogen and halogen bonding analogues, revealing the high impact of the interstrand interaction on folding. The experimental results are corroborated by computation on the DFT level. This is the first report of quantification of a conformation-stabilizing chlorine centered halogen bond in a peptide system.  

  • 4. Endale, Milkyas
    et al.
    Alao, John Patrick
    Akala, Hoseah M
    Rono, Nelson K
    Eyase, Fredrick L
    Derese, Solomon
    Ndakala, Albert
    Mbugua, Martin
    Walsh, Douglas S
    Sunnerhagen, Per
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Yenesew, Abiy
    Antiplasmodial quinones from Pentas longiflora and Pentas lanceolata.2012In: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 78, no 1, p. 31-5Article in journal (Refereed)
    Abstract [en]

    The dichloromethane/methanol (1:1) extracts of the roots of Pentas longiflora and Pentas lanceolata showed low micromolar (IC(50) = 0.9-3 µg/mL) IN VITRO antiplasmodial activity against chloroquine-resistant (W2) and chloroquine-sensitive (D6) strains of PLASMODIUM FALCIPARUM. Chromatographic separation of the extract of PENTAS LONGIFLORA led to the isolation of the pyranonaphthoquinones pentalongin (1) and psychorubrin (2) with IC(50) values below 1 µg/mL and the naphthalene derivative mollugin (3), which showed marginal activity. Similar treatment of Pentas lanceolata led to the isolation of eight anthraquinones ( 4-11, IC(50) = 5-31 µg/mL) of which one is new (5,6-dihydroxydamnacanthol, 11), while three--nordamnacanthal (7), lucidin-ω-methyl ether (9), and damnacanthol (10)--are reported here for the first time from the genus Pentas. The compounds were identified by NMR and mass spectroscopic techniques.

  • 5. Endale, Milkyas
    et al.
    Ekberg, Annabel
    Akala, Hoseah M
    Alao, John Patrick
    Sunnerhagen, Per
    Yenesew, Abiy
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Busseihydroquinones A-D from the roots of Pentas bussei2012In: Journal of Natural Products, ISSN 0163-3864, E-ISSN 1520-6025, Vol. 75, no 7, p. 1299-1304Article in journal (Refereed)
    Abstract [en]

    Four new naphthohydroquinones, named busseihydroquinones A-D (1-4), along with a known homoprenylated dihydronaphthoquinone (5), were isolated from the CH(2)Cl(2)/MeOH (1:1) extract of the roots of Pentas bussei. Although the genus Pentas is frequently used by traditional healers for the treatment of malaria, only marginal activities against the chloroquine-sensitive (D6) and the chloroquine-resistant (W2) strains of Plasmodium falciparum were observed for the crude root extract and the isolated constituents of this plant.

  • 6.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    15N NMR chemical shift in the characterisation of halogen bonding in solution2017Conference paper (Refereed)
    Abstract [en]

    15N NMR chemical shift in the characterisation of halogen bonding in solution  

    Sebastiaan B. Hakkert, Jürgen Gräfenstein and Mate Erdelyi*   

    NMR chemical shift changes induced upon formation of non-covalent interactions have been used as sensitive and specific observables in the evaluation of weak chemical forces in solutions, among others of halogen bonding.1 1H NMR has high sensitivity yet a narrow chemical shift range, ca 10 ppm, resulting in small and thus difficult to measure chemical shift changes upon binding. In contrast, 13C NMR offers a wider shift range, ca 200 ppm, providing larger chemical shift changes upon weak binding to be detected; however, its low sensitivity limits its applicability. 19F NMR provides high sensitivity and a wide chemical shift range, ca 500 ppm, and hence is straightforwardly applicable on substances that possess a fluorine close to the halogen bond donor site,2 but is unfortunately often unavailable for real-life substances applied in medicinal chemistry, for example, typically missing fluorine substitution. 15N NMR despite its low sensitivity, which can be overcome by indirect detection experiments (HMBC), provides several advantages, such as an unusually wide chemical shift range, ca 900 ppm, and most importantly the detectability of halogen and hydrogen bonds directly at the Lewis base involved in the interaction. Accordingly, upon formation of a halogen bond with a nitrogen donor ligand typically 10-20 ppm,3 and for very strong interactions up to 100 ppm,4 15N chemical shift changes have been reported.  

    In this project we have evaluated the capability of 15N NMR to describe halogen bonding interactions with respect to solvent and electronic effects, and the alteration of N-X bond lengths. The observations made for halogen bonds were compared to those obtained for analogous hydrogen bonding systems using the same nitrogen donor halogen/hydrogen bond acceptor. The experimental data obtained on an 800 MHz spectrometer was compared to and interpreted with the help of computational data (DFT).The observed chemical shift changes upon formation of halogen bonds were correlated to various descriptors to understand their origin. Based on the above data the scope and limitations of 15N NMR for detection and understanding of halogen bonding in solution will be discussed.

    References

    1. Bertrán, J. F.; Rodríguez, M. Org. Magn. Reson. 1979, 12, 92, 1980, 14, 244; 1981, 16, 79.

    2. Metrangolo, P.; Panzeri, W.; Recupero F; Resnati, G. J. Fluorine Chem. 2002, 114, 27.

    3. Castro-Fernandez, S.; Lahoz, I. R.; Llamas-Saiz, A. L.; Alonso-Gomez, J. L.; Cid, M. M.; Navarro-Vazquez, A. Org. Lett. 2014, 16, 1136; Puttreddy, R.; Jurcek, O.; Bhowmik, S.; Makela, T.; Rissanen, K. Chem. Commun. 2016, 52, 2338.

    4. Carlsson, A.-C. C.; Grafenstein, J.; Budnjo, A.; Laurila, J. L.; Bergquist, J.; Karim, A.; Kleinmaier, R.; Brath, U.; Erdelyi, M. J. Am. Chem. Soc. 2012, 134, 5706

  • 7.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Halogen and hydrogen bonding - computationally supported NMR spectroscopy2017Conference paper (Refereed)
  • 8.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Halogen Bonding: An Alternative Tool to Modulate Peptide Conformation2017Conference paper (Refereed)
    Abstract [en]

    Halogen bonding: an alternative tool to modulate peptide conformation

    Emma Danelius(1), Hanna Andersson(1), Patrik Jarvoll(1), Kajsa Lood(1), Jürgen Gräfenstein(1) and  Mate Erdelyi(1,2)

    1) Department of Chemistry and Molecular Biology, University of Gothenburg, Sweden

    2) Department of Chemistry – BMC, Uppsala University, Sweden   

    Halogen bonding is a weak chemical force that resembles hydrogen bonding in many aspects. Despite its potential for use in drug discovery, as a new molecular tool in the direction of molecular recognition events, it has so far rarely been assessed in biopolymers. Motivated by this fact, we have developed a peptide model system that permits the quantitative evaluation of weak forces in a biologically relevant proteinlike environment and have applied it for the assessment of a halogen bond formed between two amino acid side chains. 

    The influence of a single weak force is measured by detection of the extent to which it modulates the conformation of a cooperatively folding system. We have optimized the amino acid sequence of the model peptide on analogues with a hydrogen bond-forming site as a model for the intramolecular halogen bond to be studied, demonstrating the ability of the technique to provide information about any type of weak secondary interaction. 

    A combined solution nuclear magnetic resonance spectroscopic and computational investigation demonstrates that an interstrand halogen bond is capable of conformational stabilization of a β-hairpin foldamer comparable to an analogous hydrogen bond. This is the first report of incorporation of a conformation-stabilizing halogen bond into a peptide/protein system, and the first quantification of a chlorine-centered halogen bond in a biologically relevant system in solution.  

  • 9.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    ParLig: Paramagnetic Ligand Tagging to Identify Protein Binding Sites2017Conference paper (Refereed)
    Abstract [en]

    ParLig: Paramagnetic Ligand Tagging to  Identify Protein Binding Sites

    Ulrika Brath,1 Shashikala I. Swamy,1 Alberte X. Veiga,1 Ching-Chieh Tung,2 Filip Van Petegem,2 Mate Erdelyi1*

    Department of Chemistry & Molecular Biology and the Swedish NMR Centre, University of Gothenburg,Sweden

    Department of Biochemistry & Molecular Biology, University of British Columbia, Vancouver, Canada  

    Abstract: Identification of the binding site and binding mode of low affinity ligands, such as screening hits, is essential for the development of pharmaceutical leads using rational drug design strategies. We introduce ParLig, a paramagnetic ligand tagging approach that enables localization of protein – ligand binding clefts by detection and analysis of intermolecular protein NMR pseudocontact shifts, invoked by the covalent attachment of a paramagnetic lanthanoid chelating tag to the ligand of interest. Its scope is demonstrated by identification of the low mM volatile anesthetic interaction site of calmodulin. The technique provides an efficient route to rapid screening of protein – ligand systems, and to the identification of the binding site and mode of low affinity complexes.

    References: 

    1. Brath, U., Swami, S.I., Veiga, A.X., Tung, C.-C., Van Petegem, F., Erdelyi, M., J. Am. Chem Soc. 137, 11391-11398 (2015) .

  • 10.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Pentacoordinate carbonium ions in solution2018Conference paper (Refereed)
  • 11.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Solid-phase methods for the synthesis of heterocycles2006In: Microwave-Assisted  Synthesis of Heterocycles, Topics in Heterocyclic Chemistry, Berlin/Heidelberg, Germany: Springer GmbH & Co KB, Berlin/Heidelberg, Germany , 2006, p. 79-128Chapter in book (Refereed)
  • 12.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    The three-center halogen bond2019Conference paper (Refereed)
    Abstract [en]

    Halonium ions, X+, play important roles in chemistry. In halogenation reactions, they are transferred from a halogen donor, D, to an acceptor, A, in the formally stepwise process D+- X + A →[D-X∙∙∙A]+ → [D∙∙∙X∙∙∙A]+→ [D∙∙∙X-A]  → D + X-A+. The same process takes place when a halogen moves from a halogen bond [1] acceptor to another one within a complex, that has so far mostly been studied in model systems with the two donor sites possessing comparable Lewis basicities (A ~ D) [2-5]. Throughout these processes the halonium ion simultaneously forms bonds to two Lewis bases, with the bonds having varying degrees of covalency and secondary character [2].  Halonium ions are strong halogen bond donors that prefer to form a three-center geometry, [D∙∙∙X∙∙∙D]+, in which both D-X halogen bonds have partial covalent and partial secondary characters [2-6].

    In this talk, the influence of electronic and steric factors, solvent polarity and counterions, and of the type of the halogen on the geometry and reactivity of [D∙∙∙X∙∙∙D]+ halogen bond complexes will be discussed. The symmetric state, [D∙∙∙X∙∙∙D]+, is demonstrated to be strongly preferred over the alternative asymmetric arrangements [D∙∙∙X-D]+. Understanding the three-center halogen bonds provides insights into the fundamentals of the halogen bonding phenomenon and of halonium transfer reactions. The studied complexes are isoelectronic to the transition state of SN2 reactions, and thus may provide model systems for the exploration of fundamental reaction mechanisms.

    The synthesis, and the NMR spectroscopic and computational (DFT) studies of a variety of three-center halogen bond systems [2-6] will be presented focusing on the influence of steric and electronic factors on the geometry and electronic character of the three-center-fourelectron halogen bond.

    References 1. Halogen bonding is the noncovalent interaction of halogen in which they act as electron acceptors. 2. Karim, A.; Reitti, M.; Carlsson, A.-C.C.; Gräfenstein, J.; Erdelyi, M. Chem. Sci. 2014, 5, 3226. 3. Carlsson, A.-C.C.; Mehmeti, K.; Uhrbom, M.; Karim, A.; Bedin, M.; Puttreddy, R.; Kleinmaier, R.; Neverov, A.; Nekoueishahraki, B.; Gräfenstein, J.; Rissanen, K.; Erdelyi, M., J. Am. Chem. Soc. 2016, 138, 9853. 4. Carlsson, A.-C.C.; Gräfenstein,J.; Budnjo, A.; Bergquist, J.; Karim, A.; Kleinmaier, R.; Brath, U.; Erdelyi, M. J. Am. Chem. Soc. 2012, 134, 5706.  5. Hakkert, S.B.; Erdelyi, M. J. Phys. Org. Chem. 2015, 28, 226. 6.Lindblad, S.; Mehmeti, K.; Veiga, A.; Nekoueishahraki, B.; Gräfenstein, J.; Erdelyi, M. J. Am. Chem. Soc.2018, 140, 13503.

  • 13.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    The three-centered halogen bond2018Conference paper (Refereed)
  • 14.
    Erdélyi, Máté
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    d’Auvergne, E.
    Navarro-Vazquez, A.
    Griesinger, C.
    Dynamics of the glycosidic linkage: conformational space of lactose2011In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 17, no 34, p. 9368-9376Article in journal (Refereed)
    Abstract [en]

    The dynamics of the glycosidic bond of lactose was studied by a paramagnetic tagging‐based NMR technique, which allowed the collection of an unusually large series of NMR data for a single compound. By the use of distance‐ and orientation‐dependent residual dipolar couplings and pseudocontact shifts, the simultaneous fitting of the probabilities of computed conformations and the orientation of the magnetic susceptibility tensor of a series of lanthanide complexes of lactose show that its glycosidic bond samples syn/syn, anti/syn and syn/anti ϕ/ψ regions of the conformational space in water. The analysis indicates a higher reliability of pseudocontact shift data as compared to residual dipolar couplings with the presently available weakly orienting paramagnetic tagging technique. The method presented herein allows for an improved understanding of the dynamic behaviour of oligosaccharides.

  • 15.
    Erdélyi, Máté
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Gogoll, Adolf
    Rapid Microwave-assisted solid-phase peptide synthesis2003Conference paper (Refereed)
  • 16.
    Erdélyi, Máté
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Gogoll, Aldof
    Development of a stilbene-type photoswitchable β-hairpin mimetic2005Conference paper (Refereed)
  • 17.
    Erdélyi, Máté
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Karlén, A.
    Gogoll, Aldolf
    Studies of Photoswitchable β-Hairpin Mimetics2003Conference paper (Refereed)
  • 18.
    Erdélyi, Máté
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Langer, V.
    Karlén, A.
    Gogoll, Adolf
    Structural Studies of Diastereomeric β-Hairpin Mimetics2002Conference paper (Refereed)
  • 19.
    Erdélyi, Máté
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Lindblad, Sofia
    Mehmeti, Krenare
    Veiga, Alberte X
    Nekoueishahraki, Bijan
    Gräfenstein, Jurgen
    The Halogen Bond of Halonium Ions2018Conference paper (Refereed)
    Abstract [en]

    Halonium ions, X+ , play important roles in chemistry. In halogenation reactions, they are transferred from a donor, D, to an acceptor, A, in the formally stepwise process D-X + A

    → [D-X∙∙∙A]+ → [D∙∙∙X∙∙∙A][D∙∙∙X - A]+ → D + X - A+. The same process takes place when a halogen moves from a halogen bond donor to an acceptor within a complex, which has been studied so far mostly in model systems in which the donor and the acceptor possess comparable Lewis basicities (A ~ D) [1-4].  Throughout these processes the halonium ion simultaneously forms bonds to two Lewis bases that may possess varying degrees of covalency and secondary character [1]. Halonium ions are strong halogen bond donors that prefer to form a symmetric geometry, [D∙∙∙X∙∙∙D]+, with two D-X bonds of partial covalent and partial secondary character. This symmetric state is much preferred over the asymmetric alternative arrangement, [D∙∙∙X - D]+[1-4].

    We have explored how electronic and steric factors influence the electron density distribution and the geometry of [D∙∙∙X∙∙∙D]+-type complexes. Understanding this provides insights into the fundamental details of halonium transfer reactions, halogen transfer processes within halogen bonded systems as well as into important reaction mechanisms, such as SN2.

    In this talk the synthesis, NMR spectroscopic and computational (DFT) studies of so far undiscussed systems [5] will be presented, and the influence of steric and electronic factors on the geometry and electronic character of the three-center-four-electron halogen bond will be discussed.

  • 20.
    Erdélyi, Máté
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Navarro-Vázquez, Armando
    Pfeiffer, Bernhard
    Kuzniewski, Christian N
    Felser, Andrea
    Widmer, Toni
    Gertsch, Jürg
    Pera, Benet
    Díaz, José Fernando
    Altmann, Karl-Heinz
    Carlomagno, Teresa
    The binding mode of side chain- and C3-modified epothilones to tubulin2010In: ChemMedChem, ISSN 1860-7179, E-ISSN 1860-7187, Vol. 5, no 6, p. 911-920Article in journal (Refereed)
    Abstract [en]

    The tubulin-binding mode of C3- and C15-modified analogues of epothilone A (Epo A) was determined by NMR spectroscopy and computational methods and compared with the existing structural models of tubulin-bound natural Epo A. Only minor differences were observed in the conformation of the macrocycle between Epo A and the C3-modified analogues investigated. In particular, 3-deoxy- (compound 2) and 3-deoxy-2,3-didehydro-Epo A (3) were found to adopt similar conformations in the tubulin-binding cleft as Epo A, thus indicating that the 3-OH group is not essential for epothilones to assume their bioactive conformation. None of the available models of the tubulin-epothilone complex is able to fully recapitulate the differences in tubulin-polymerizing activity and microtubule-binding affinity between C20-modified epothilones 6 (C20-propyl), 7 (C20-butyl), and 8 (C20-hydroxypropyl). Based on the results of transferred NOE experiments in the presence of tubulin, the isomeric C15 quinoline-based Epo B analogues 4 and 5 show very similar orientations of the side chain, irrespective of the position of the nitrogen atom in the quinoline ring. The quinoline side chain stacks on the imidazole moiety of beta-His227 with equal efficiency in both cases, thus suggesting that the aromatic side chain moiety in epothilones contributes to tubulin binding through strong van der Waals interactions with the protein rather than hydrogen bonding involving the heteroaromatic nitrogen atom. These conclusions are in line with existing tubulin polymerization and microtubule-binding data for 4, 5, and Epo B.

  • 21.
    Erdélyi, Máté
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Pfeiffer, Bernhard
    Hauenstein, Kurt
    Fohrer, Jörg
    Gertsch, Jürg
    Altmann, Karl-Heinz
    Carlomagno, Teresa
    Conformational preferences of natural and C3-modified epothilones in aqueous solution.2008In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 51, no 5, p. 1469-73Article in journal (Refereed)
    Abstract [en]

    The conformational properties of the microtubule-stabilizing agent epothilone A ( 1a) and its 3-deoxy and 3-deoxy-2,3-didehydro derivatives 2 and 3 have been investigated in aqueous solution by a combination of NMR spectroscopic methods, Monte Carlo conformational searches, and NAMFIS calculations. The tubulin-bound conformation of epothilone A ( 1a), as previously proposed on the basis of solution NMR data, was found to represent a significant fraction of the ensemble of conformations present for the free ligands in aqueous solution.

  • 22. Karim, A.
    et al.
    Schulz, N.
    Andersson, Hanna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Nekoueishahraki, B.
    Carlsson, A-C
    Sarabi, D.
    Valkonen, A.
    Rissanen, K.
    Gräfenstein, Jürgen
    Keller, S.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    The three-center-four-electron tetrel bond2018Conference paper (Refereed)
    Abstract [en]

    We present a thermodynamically stable complex that possesses a three-center-four-electron (3c4e) tetrel bond [1,2], formed by capturing a reactive carbenium ion with a bidentate Lewis base. We report NMR spectroscopic, titration calorimetric and reaction kinetic evidences for the structure of this pentacoordinate species and discuss the properties of its tetrel bond, [N˜˜˜∙∙∙C∙∙∙˜˜˜N]+, in comparison with the analogous halogen, [N˜˜˜∙∙∙X∙∙∙˜˜˜N]+ and hydrogen, [N∙∙∙˜˜˜H∙∙∙˜˜˜N]+, bonds [3]. The necessity of the involvement of a bidentate Lewis base for the formation of a stable 3c4e tetrel bond is demonstrated by providing spectroscopic and crystallographic evidence, that a monodentate Lewis base induces a reaction rather than stabilizing the reactive species. A vastly decreased Lewis basicity of the bidentate ligand or reduced Lewis acidity of the carbenium ion weakens — or even prohibits — the formation of the pentacoordinate species, whereas synthetic modifications facilitating attractive orbital overlaps promote it. As the geometry of the pentacoordinate complex resembles the SN2 transition state, it may provide a model system for the investigation of fundamental reaction mechanisms and chemical bonding theories [4].

    References

    1. G.C. Pimentel J. Chem. Phys. 1951, 19, 446-448

    2. R.H. Crabtree Chem. Soc. Rev. 2017, 46, 1720-1729.

    3. S.B. Hakkert, M. Erdelyi J. Phys. Org. Chem. 2015, 95, 2572-2578

    4. Karim, N. Schultz, H. Andersson, B. Nekoueishahraki et al, 2018, submitted.

  • 23.
    Karim, Alavi
    et al.
    Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden.
    Schulz, Nils
    Ruhr Univ Bochum, Fac Chem & Biochem, Organ Chem 1, Univ Str 150, D-44801 Bochum, Germany.
    Andersson, Hanna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden.
    Nekoueishahraki, Bijan
    Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden.
    Carlsson, Anna-Carin C.
    Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden;AstraZeneca R&D, Pepparedsleden 1, Molndal, Sweden.
    Sarabi, Daniel
    Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden.
    Valkonen, Arto
    Univ Jyvaskyla, Dept Chem, POB 35, FI-40014 Jyvaskyla, Finland.
    Rissanen, Kari
    Univ Jyvaskyla, Dept Chem, POB 35, FI-40014 Jyvaskyla, Finland.
    Grafenstein, Juergen
    Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden.
    Keller, Sandro
    TUK, Mol Biophys, D-67663 Kaiserslautern, Germany.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden;Swedish NMR Ctr, Med Gatan, SE-41390 Gothenburg, Sweden.
    Carbon's Three-Center, Four-Electron Tetrel Bond, Treated Experimentally2018In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 140, no 50, p. 17571-17579Article in journal (Refereed)
    Abstract [en]

    Tetrel bonding is the noncovalent interaction of group IV elements with electron donors. It is a weak, directional interaction that resembles hydrogen and halogen bonding yet remains barely explored. Herein, we present an experimental investigation of the carbon-centered, three-center, four-electron tetrel bond, [N-C-N](+), formed by capturing a carbenium ion with a bidentate Lewis base. NMR-spectroscopic, titration-calorimetric, and reaction-kinetic evidence for the existence and structure of this species is reported. The studied interaction is by far the strongest tetrel bond reported so far and is discussed in comparison with the analogous halogen bond. The necessity of the involvement of a bidentate Lewis base in its formation is demonstrated by providing spectroscopic and crystallographic evidence that a monodentate Lewis base induces a reaction rather than stabilizing the tetrel bond complex. A vastly decreased Lewis basicity of the bidentate ligand or reduced Lewis acidity of the carbenium ion weakens or even prohibits the formation of the tetrel bond complex, whereas synthetic modifications facilitating attractive orbital overlaps promote it. As the geometry of the complex resembles the S(N)2 transition state, it provides a model system for the investigation of fundamental reaction mechanisms and chemical bonding theories.

  • 24.
    Lindblad, Sofia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Mehmeti, Krenare
    University of Gothenburg.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Asymmetric [N-X-N]+ Halogen Bonds in Solution2018Conference paper (Other academic)
  • 25.
    Lindblad, Sofia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden.
    Mehmeti, Krenare
    Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden.
    Veiga, Alberte X.
    Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden;Concept Life Sci, Discovery Pk,Ramsgate Rd, Sandwich CT13 9ND, Kent, England.
    Nekoueishahraki, Bijan
    Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden.
    Grafenstein, Jurgen
    Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden; Swedish NMR Ctr, Medicinaregatan 5C, SE-41390 Gothenburg, Sweden.
    Halogen Bond Asymmetry in Solution2018In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 140, no 41, p. 13503-13513Article in journal (Refereed)
    Abstract [en]

    Halogen bonding is the noncovalent interaction of halogen atoms in which they act as electron acceptors. Whereas three-center hydrogen bond complexes, [D center dot center dot center dot H center dot center dot center dot D](+) where D is an electron donor, exist in solution as rapidly equilibrating asymmetric species, the analogous halogen bonds, [D center dot center dot center dot X center dot center dot center dot D](+), have been observed so far only to adopt static and symmetric geometries. Herein, we investigate whether halogen bond asymmetry, i.e., a [D-X center dot center dot center dot D](+) bond geometry, in which one of the D-X bonds is shorter and stronger, could be induced by modulation of electronic or steric factors. We have also attempted to convert a static three-center halogen bond complex into a mixture of rapidly exchanging asymmetric isomers, [D center dot center dot center dot X-D](+) (sic) [D-X center dot center dot center dot D](+), corresponding to the preferred form of the analogous hydrogen bonded complexes. Using N-15 NMR, IPE NMR, and DFT, we prove that a static, asymmetric geometry, [D-X center dot center dot center dot D](+), is obtained upon desymmetrization of the electron density of a complex. We demonstrate computationally that conversion into a dynamic mixture of asymmetric geometries, [D center dot center dot center dot X-D](+) (sic) [D-X center dot center dot center dot D](+), is achievable upon increasing the donor-donor distance. However, due to the high energetic gain upon formation of the three-center-four electron halogen bond, the assessed complex strongly prefers to form a dimer with two static and symmetric three-center halogen bonds over a dynamic and asymmetric halogen bonded form. Our observations indicate a vastly different preference in the secondary bonding of H+ and X+. Understanding the consequences of electronic and steric influences on the strength and geometry of the three-center halogen bond provides useful knowledge on chemical bonding and for the development of improved halonium transfer agents.

  • 26.
    Palica, Katarzyna
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. Katarzyna Palica.
    Andersson, Hanna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Development of Metallo-β-lactamase Inhibitors to Control Antibiotic Resistance2018In: EMBO Course: Multidimensional NMR in Structural Biology Joachimsthal 2018, 2018Conference paper (Refereed)
    Abstract [en]

    The aim of this project is focused on existing antibiotics, their transition states – EI and creation of new bioisosteres, which can have both inhibition and antibiotics properties.This strategy allows for the avoidance of combinatorial therapy and use medicine with widespectrum of action. 

    In this project, subclasses of MβLs (between them: NMD-12) will be tested with series of β-lactam antibiotics transition state, which first will be synthesise. NMR studies are essentialfor success of this project. Evaluation of the complexes of MβLs and the transition stateanalogues will be studied by solution NMR to provide information of their activity. Other partof the project involve NMR technics to provide assignment and determination of proteinstructure.

  • 27.
    Palica, Katarzyna
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Andersson, Hanna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Development of metallo-β-lactamase inhibitors to control antibioticresistance2018Conference paper (Refereed)
    Abstract [en]

    According to the recent reports of WHO,1 one of the major challenges of the XXI century isthe rapidly growing bacterial resistance against antibiotics. As a result, bacterial infectionsmay become untreatable within a considerable time giving simple infections, such aspneumonia or Septicemia, a highly probable mortal prognosis. Without access to efficientantibiotics simple surgeries, giving birth and dental interventions, for example, may becomerisky.The mostly widely spread mechanism of bacterial resistance is mediated by β-lactamases, aspecific group of enzymes responsible for the degradation or modification of antibiotics priorto reaching their bacterial target sites. Metallo-β-lactamases are the clinically mostimportant, as these cleave also carbapenems, which are the last resort antibiotics to date.Recent reports indicate that bacteria need barely three months to develop resistance againstnew antibiotics, making their development into an unattractive, high risk approach.The key point of the mechanism of antibiotics degradation by metallo-β-lactamases is thecreation of a tetrahedral intermediate (EI) upon a C–N bond cleavage (Fig. 1). This stepinvolves irreversible chemical changes, which lead to the inactivation of the β-lactamantibiotics.

    This project is focused on the development of bioisosters of existing antibiotics, i.e.compounds resembling the transition state of their cleavage (Fig 1). These are expected tohave both metallo-β-lactamase inhibitory and antibiotic properties. This strategy allows forthe reactivation of existing antibiotics, and possibly the avoidance of the need forcombinatorial therapy.Further studies of interaction between NDM-1 (New Delhi Metallo-β-Lactamases-1) andsynthesized ligands will bring insights immensely valuable for the prevention of bacterialresistance against antibiotic treatment.

  • 28.
    Palica, Katarzyna
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Andersson, Hanna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Development of metallo-β-lactamase inhibitors to controlantibiotic resistance2018Conference paper (Refereed)
    Abstract [en]

    According to WHO recent reports indicates one of the biggest problem of XXI century is rapidly growing resistance of bacteria.[1] The most powerful human counter weapon –antibiotics, starts to be an ineffective way in the treatment of bacterial infections. Soonwithout any action we can approach a point when simple infections like pneumonia orSepticemia, will carry a highly probable mortal prognosis.The mostly widely spread mechanism of bacteria resistance is the production of a specificgroup of enzymes β-lactamases, responsible for the degradation or modification of antibiotics,prior to it reaching its target side. At the moment, bacteria need around three months to develop resistance for new type of antibiotics. That is why modern treatment begin toabandon the development of new antibiotics and focuses on inhibitions of β-lactamases andquiet often on metallo-β-lactamases which spectrum is the broadest.The key point of the mechanism of antibiotics hydrolysis by metallo- β -lactamases is creationof tetrahedral intermediate (EI) as a C–N bond-cleaved species. This step indicatesirreversible chemical changes which lead to inactive product.

    The aim of this project is focused on existing antibiotics, their transition states - EI andcreation of new bioisosteres, which can have both inhibition and antibiotics properties. Thisstrategy allows for the avoidance of combinatorial therapy and use medicine with widespectrum of action.Further studies of interaction between NDM-1 (New Delhi Metallo-β-Lactamases-1) and synthesized ligands will bring a highly needed and effective way to prevent resistance of bacteria.