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  • 1. Abdissa, Negera
    et al.
    Fangfang, Pan
    Gruhonjic, Amra
    Gräfenstein, Jürgen
    Fitzpatrick, Paul A
    Landberg, Göran
    Rissanen, Kari
    Yenesew, Abiy
    Erdelyi, Mate
    Naphthalene Derivatives from the Roots of Pentas parvifolia and Pentas bussei.2016In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 79, no 9, p. 2181-2187Article in journal (Refereed)
    Abstract [en]

    The phytochemical investigation of the CH2Cl2/MeOH (1:1) extract of the roots of Pentas parvifolia led to the isolation of three new naphthalenes, parvinaphthols A (1), B (2), and C (3), two known anthraquinones, and five known naphthalene derivatives. Similar investigation of the roots of Pentas bussei afforded a new polycyclic naphthalene, busseihydroquinone E (4), a new 2,2'-binaphthralenyl-1,1'-dione, busseihydroquinone F (5), and five known naphthalenes. All purified metabolites were characterized by NMR and MS data analyses, whereas the absolute configurations of 3 and 4 were determined by single-crystal X-ray diffraction studies. The E-geometry of compound 5 was supported by DFT-based chemical shift calculations. Compounds 2-4 showed marginal cytotoxicity against the MDA-MB-231 human triple-negative breast cancer cell line with IC50 values ranging from 62.3 to 129.6 μM.

  • 2. Abdissa, Negera
    et al.
    Induli, Martha
    Fitzpatrick, Paul
    Alao, John Patrick
    Sunnerhagen, Per
    Landberg, Göran
    Yenesew, Abiy
    Erdelyi, Mate
    Cytotoxic quinones from the roots of Aloe dawei.2014In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 19, no 3, p. 3264-3273Article in journal (Refereed)
    Abstract [en]

    Seven naphthoquinones and nine anthraquinones were isolated from the roots of Aloe dawei by chromatographic separation. The purified metabolites were identified by NMR and MS analyses. Out of the sixteen quinones, 6-hydroxy-3,5-dimethoxy-2-methyl-1,4-naphthoquinone is a new compound. Two of the isolates, 5,8-dihydroxy-3-methoxy-2-methylnaphthalene-1,4-dione and 1-hydroxy-8-methoxy-3-methylanthraquinone showed high cytotoxic activity (IC₅₀ 1.15 and 4.85 µM) on MCF-7 breast cancer cells, whereas the others showed moderate to low cytotoxic activity against MDA-MB-231 (ER Negative) and MCF-7 (ER Positive) cancer cells.

  • 3.
    Andersson, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Carlsson, Anna-Carin C.
    University of Gothenburg, Gothenburg, Sweden.
    Nekoueishahraki, Bijan
    University of Gothenburg, Gothenburg, Sweden.
    Brath, Ulrika
    University of Gothenburg, Gothenburg, Sweden.
    Erdélyi, Máté
    University of Gothenburg, Gothenburg, Sweden.
    Chapter Two - Solvent Effects on Nitrogen Chemical Shifts2015In: Annual Reports on NMR Spectroscopy, Academic Press , 2015, Vol. 86, p. 73-210Chapter in book (Other academic)
    Abstract [en]

    Due to significant developments in cryogenic probe technology and the easy access to inverse detection pulse programmes (HSQC, HMBC), the sensitivity of nitrogen NMR has lately vastly improved. As a consequence, nitrogen NMR has turned into a useful and commonly available tool for solution studies of molecular structure and properties for small organic compounds likewise biopolymers. The high sensitivity of the nitrogen lone pair to changes in the molecular environment, alterations in intra- and intermolecular interactions, and in molecular conformation along with its wide, up to 1200ppm chemical shift dispersion make nitrogen NMR to an exceptionally sensitive reporter tool. The nitrogen chemical shift has been applied in various fields of chemistry, including for instance the studies of transition metal complexes, chemical reactions such as N-alkylation and N-oxidation, tautomerization, protonation–deprotonation equilibria, hydrogen and halogen bonding, and elucidation of molecular conformation and configuration. The 15N NMR data observed in the investigation of these molecular properties and processes is influenced by the medium it is acquired in. This influence may be due to direct coordination of solvent molecules to transition metal complexes, alteration of tautomerization equilibria, and solvent polarity induced electron density changes of conjugated systems, for example. Thus, the solvent may significantly alter the observed nitrogen NMR shifts. This review aims to provide an overview of solvent effects of practical importance, and discusses selected experimental reports from various subfields of chemistry.

  • 4. Andersson, Hanna
    et al.
    Carlsson, anna-Carin
    Nekoueishahraki, Bijan
    Brath, Ulrika
    Erdelyi, Mate
    Solvent effects of nitrogen chemical shifts2015In: Annual Reports on NMR Spectroscopy, ISSN 0066-4103, E-ISSN 2163-6052, Vol. 86, p. 73-210Article, review/survey (Refereed)
  • 5. Andersson, Hanna
    et al.
    Danelius, Emma
    University of Gothenburg, Kemivägen 10, SE-412 96 Gothenburg, Sweden.
    Jarvoll, Patrik
    University of Gothenburg, Kemivägen 10, SE-412 96 Gothenburg, Sweden.
    Niebling, Stephan
    University of Gothenburg, Kemivägen 10, SE-412 96 Gothenburg, Sweden.
    Hughes, Ashley J
    University of Gothenburg, Kemivägen 10, SE-412 96 Gothenburg, Sweden.
    Westenhoff, Sebastian
    University of Gothenburg, Kemivägen 10, SE-412 96 Gothenburg, Sweden.
    Brath, Ulrika
    University of Gothenburg, Kemivägen 10, SE-412 96 Gothenburg, Sweden.
    Erdélyi, Máté
    The Swedish NMR Centre, Medicinaregatan 5c, SE-413 96 Gothenburg, Sweden.
    Assessing the Ability of Spectroscopic Methods to Determine the Difference in the Folding Propensities of Highly Similar β-Hairpins2017In: ACS omega, ISSN 2470-1343, Vol. 2, no 2, p. 508-516Article in journal (Refereed)
    Abstract [en]

    We have evaluated the ability of nuclear magnetic resonance (NMR) and circular dichroism (CD) spectroscopies to describe the difference in the folding propensities of two structurally highly similar cyclic β-hairpins, comparing the outcome to that of molecular dynamics simulations. NAMFIS-type NMR ensemble analysis and CD spectroscopy were observed to accurately describe the consequence of altering a single interaction site, whereas a single-site 13C NMR chemical shift melting curve-based technique was not.

  • 6.
    Andersson, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. University of Gothenburg, SE-412 96 Gothenburg, Sweden.
    Gräfenstein, Jürgen
    National Sun Yat-Sen University, Kaohsiung, Taiwan.
    Isobe, Minoru
    National Sun Yat-Sen University, Kaohsiung, Taiwan.
    Erdélyi, Máté
    University of Gothenburg, SE-412 96 Gothenburg, Sweden; The Swedish NMR Centre, SE-413 96 Gothenburg, Sweden.
    Sydnes, Magne O
    University of Stavanger, NO-4036 Stavanger, Norway.
    Photochemically Induced Aryl Azide Rearrangement: Solution NMR Spectroscopic Identification of the Rearrangement Product2017In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 82, no 3, p. 1812-1816Article in journal (Refereed)
    Abstract [en]

    Photolysis of ethyl 3-azido-4,6-difluorobenzoate at room temperature in the presence of oxygen results in the regioselective formation of ethyl 5,7-difluoro-4-azaspiro[2.4]hepta-1,4,6-triene-1-carboxylate, presumably via the corresponding ketenimine intermediate which undergoes a photochemical four-electron electrocyclization followed by a rearrangement. The photorearrangement product was identified by multinuclear solution NMR spectroscopic techniques supported by DFT calculations.

  • 7. Aronsson, Per
    et al.
    Munissi, Joan J E
    Gruhonjic, Amra
    Fitzpatrick, Paul A
    Landberg, Göran
    Nyandoro, Stephen S
    Erdelyi, Mate
    Phytoconstituents with Radical Scavenging and Cytotoxic Activities from Diospyros shimbaensis.2016In: Diseases (Basel, Switzerland), ISSN 2079-9721, Vol. 4, no 1, article id E3Article in journal (Refereed)
    Abstract [en]

    As part of our search for natural products having antioxidant and anticancer properties, the phytochemical investigation of Diospyros shimbaensis (Ebenaceae), a plant belonging to a genus widely used in East African traditional medicine, was carried out. From its stem and root barks the new naphthoquinone 8,8'-oxo-biplumbagin (1) was isolated along with the known tetralones trans-isoshinanolone (2) and cis-isoshinanolone (3), and the naphthoquinones plumbagin (4) and 3,3'-biplumbagin (5). Compounds 2, 4, and 5 showed cytotoxicity (IC50 520-82.1 μM) against MDA-MB-231 breast cancer cells. Moderate to low cytotoxicity was observed for the hexane, dichloromethane, and methanol extracts of the root bark (IC50 16.1, 29.7 and > 100 μg/mL, respectively), and for the methanol extract of the stem bark (IC50 59.6 μg/mL). The radical scavenging activity of the isolated constituents (1-5) was evaluated on the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. The applicability of the crude extracts and of the isolated constituents for controlling degenerative diseases is discussed.

  • 8. Atilaw, Yoseph
    et al.
    Duffy, Sandra
    Heydenreich, Matthias
    Muiva-Mutisya, Lois
    Avery, Vicky M
    Erdelyi, Mate
    Yenesew, Abiy
    Three Chalconoids and a Pterocarpene from the Roots of Tephrosia aequilata.2017In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 22, no 2, article id E318Article in journal (Refereed)
    Abstract [en]

    In our search for new antiplasmodial agents, the CH₂Cl₂/CH₃OH (1:1) extract of the roots of Tephrosia aequilata was investigated, and observed to cause 100% mortality of the chloroquine-sensitive (3D7) strain of Plasmodium falciparum at a 10 mg/mL concentration. From this extract three new chalconoids, E-2',6'-dimethoxy-3',4'-(2'',2''-dimethyl)pyranoretrochalcone (1, aequichalcone A), Z-2',6'-dimethoxy-3',4'-(2'',2''-dimethyl)pyranoretrochalcone (2, aequichalcone B), 4''-ethoxy-3''-hydroxypraecansone B (3, aequichalcone C) and a new pterocarpene, 3,4:8,9-dimethylenedioxy-6a,11a-pterocarpene (4), along with seven known compounds were isolated. The purified compounds were characterized by NMR spectroscopic and mass spectrometric analyses. Compound 1 slowly converts into 2 in solution, and thus the latter may have been enriched, or formed, during the extraction and separation process. The isomeric compounds 1 and 2 were both observed in the crude extract. Some of the isolated constituents showed good to moderate antiplasmodial activity against the chloroquine-sensitive (3D7) strain of Plasmodium falciparum.

  • 9. Atilaw, Yoseph
    et al.
    Muiva-Mutisya, Lois
    Ndakala, Albert
    Akala, Hoseah M
    Yeda, Redemptah
    Wu, Yu J
    Coghi, Paolo
    Wong, Vincent K W
    Erdelyi, Mate
    Yenesew, Abiy
    Four Prenylflavone Derivatives with Antiplasmodial Activities from the Stem of Tephrosia purpurea subsp. leptostachya.2017In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 22, no 9, article id E1514Article in journal (Refereed)
    Abstract [en]

    Four new flavones with modified prenyl groups, namely (E)-5-hydroxytephrostachin (1), purleptone (2), (E)-5-hydroxyanhydrotephrostachin (3), and terpurlepflavone (4), along with seven known compounds (5-11), were isolated from the CH₂Cl₂/MeOH (1:1) extract of the stem of Tephrosia purpurea subsp. leptostachya, a widely used medicinal plant. Their structures were elucidated on the basis of NMR spectroscopic and mass spectrometric evidence. Some of the isolated compounds showed antiplasmodial activity against the chloroquine-sensitive D6 strains of Plasmodium falciparum, with (E)-5-hydroxytephrostachin (1) being the most active, IC50 1.7 ± 0.1 μM, with relatively low cytotoxicity, IC50 > 21 μM, against four cell-lines.

  • 10. Bedin, Michele
    et al.
    Karim, Alavi
    Reitti, Marcus
    Carlsson, Anna-Carin C
    Topić, Filip
    Cetina, Mario
    Pan, Fangfang
    Havel, Vaclav
    Al-Ameri, Fatima
    Sindelar, Vladimir
    Rissanen, Kari
    Gräfenstein, Jürgen
    Erdelyi, Mate
    Counterion influence on the N-I-N halogen bond.2015In: Chemical Science, ISSN 2041-6520, E-ISSN 2041-6539, Vol. 6, no 7, p. 3746-3756Article in journal (Refereed)
    Abstract [en]

    A detailed investigation of the influence of counterions on the [N-I-N]+ halogen bond in solution, in the solid state and in silico is presented. Translational diffusion coefficients indicate close attachment of counterions to the cationic, three-center halogen bond in dichloromethane solution. Isotopic perturbation of equilibrium NMR studies performed on isotopologue mixtures of regioselectively deuterated and nondeuterated analogues of the model system showed that the counterion is incapable of altering the symmetry of the [N-I-N]+ halogen bond. This symmetry remains even in the presence of an unfavorable geometric restraint. A high preference for the symmetric geometry was found also in the solid state by single crystal X-ray crystallography. Molecular systems encompassing weakly coordinating counterions behave similarly to the corresponding silver(i) centered coordination complexes. In contrast, systems possessing moderately or strongly coordinating anions show a distinctly different behavior. Such silver(i) complexes are converted into multi-coordinate geometries with strong Ag-O bonds, whereas the iodine centered systems remain linear and lack direct charge transfer interaction with the counterion, as verified by 15N NMR and DFT computation. This suggests that the [N-I-N]+ halogen bond may not be satisfactorily described in terms of a pure coordination bond typical of transition metal complexes, but as a secondary bond with a substantial charge-transfer character.

  • 11. 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.

  • 12. Brath, Ulrika
    et al.
    Lau, Kelvin
    Van Petegem, Filip
    Erdelyi, Mate
    Mapping the sevoflurane-binding sites of calmodulin.2014In: Pharmacology research & perspectives, ISSN 2052-1707, Vol. 2, article id e0025Article in journal (Refereed)
    Abstract [en]

    General anesthetics, with sevoflurane (SF) being the first choice inhalational anesthetic agent, provide reversible, broad depressor effects on the nervous system yet have a narrow margin of safety. As characterization of low-affinity binding interactions of volatile substances is exceptionally challenging with the existing methods, none of the numerous cellular targets proposed as chief protagonists in anesthesia could yet be confirmed. The recognition that most critical functions modulated by volatile anesthetics are under the control of intracellular Ca(2+) concentration, which in turn is primarily regulated by calmodulin (CaM), motivated us for characterization of the SF-CaM interaction. Solution NMR (Nuclear Magnetic Resonance) spectroscopy was used to identify SF-binding sites using chemical shift displacement, NOESY and heteronuclear Overhauser enhancement spectroscopy (HOESY) experiments. Binding affinities were measured using ITC (isothermal titration calorimetry). SF binds to both lobes of (Ca(2+))4-CaM with low mmol/L affinity whereas no interaction was observed in the absence of Ca(2+). SF does not affect the calcium binding of CaM. The structurally closely related SF and isoflurane are shown to bind to the same clefts. The SF-binding clefts overlap with the binding sites of physiologically relevant ion channels and bioactive small molecules, but the binding affinity suggests it could only interfere with very weak CaM targets.

  • 13. Brath, Ulrika
    et al.
    Swamy, Shashikala I
    Veiga, Alberte X
    Tung, Ching-Chieh
    Van Petegem, Filip
    Erdelyi, Mate
    Paramagnetic Ligand Tagging To Identify Protein Binding Sites.2015In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 137, no 35, p. 11391-11398Article in journal (Refereed)
    Abstract [en]

    Transient biomolecular interactions are the cornerstones of the cellular machinery. The identification of the binding sites for low affinity molecular encounters is essential for the development of high affinity pharmaceuticals from weakly binding leads but is hindered by the lack of robust methodologies for characterization of weakly binding complexes. We introduce a paramagnetic ligand tagging approach that enables localization of low affinity protein-ligand binding clefts by detection and analysis of intermolecular protein NMR pseudocontact shifts, which are invoked by the covalent attachment of a paramagnetic lanthanoid chelating tag to the ligand of interest. The methodology is corroborated by identification of the low millimolar volatile anesthetic interaction site of the calcium sensor protein calmodulin. It presents an efficient route to binding site localization for low affinity complexes and is applicable to rapid screening of protein-ligand systems with varying binding affinity.

  • 14.
    Carlsson, Anna-Carin C.
    et al.
    Department of Chemistry and the Swedish NMR Centre, University of Gothenburg, Sweden.
    Grafenstein, Jurgen
    Department of Chemistry and the Swedish NMR Centre, University of Gothenburg, Sweden.
    Laurila, Jesse L.
    Department of Chemistry and the Swedish NMR Centre, University of Gothenburg, Sweden.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Erdelyi, Mate
    Department of Chemistry and the Swedish NMR Centre, University of Gothenburg, Sweden.
    Symmetry of [N-X-N]+ halogen bonds in solution2012In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 48, no 10, p. 1458-1460Article in journal (Refereed)
    Abstract [en]

    The first investigation of halogen bond symmetry is presented. In contrast to related hydrogen bonds, the iodous halogen bond is symmetric in solution and in the crystal. The bromous analogue is symmetric in solution, but shows asymmetry in the solid state. NMR results are in agreement with DFT predictions.

  • 15.
    Carlsson, Anna-Carin C.
    et al.
    Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden.;Colorado State Univ, Dept Biochem & Mol Biol, Ft Collins, CO 80523 USA..
    Mehmeti, Krenare
    Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden..
    Uhrbom, Martin
    Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden.;AstraZeneca, CVMD iMED, Pepparedsleden 1, S-43183 Molndal, Sweden..
    Karim, Alavi
    Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden..
    Bedin, Michele
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Molecular Biomimetics. Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden..
    Puttreddy, Rakesh
    Univ Jyvaskyla, Dept Chem, Nanosci Ctr, POB 35, FI-40014 Jyvaskyla, Finland..
    Kleinmaier, Roland
    Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden.;Chemtura Organometall GmbH, D-59192 Bergkamen, Germany..
    Neverov, Alexei A.
    Queens Univ, Dept Chem, Kingston, ON K7L 3N6, Canada.;Afton Chem, Richmond, VA 23219 USA..
    Nekoueishahraki, Bijan
    Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden..
    Grafenstein, Jurgen
    Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden..
    Rissanen, Kari
    Univ Jyvaskyla, Dept Chem, Nanosci Ctr, POB 35, FI-40014 Jyvaskyla, Finland..
    Erdelyi, Mate
    Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden.;Swedish NMR Ctr, Medicinaregatan 5, SE-41390 Gothenburg, Sweden..
    Substituent Effects on the [N-I-N](+) Halogen Bond2016In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 138, no 31, p. 9853-9863Article in journal (Refereed)
    Abstract [en]

    We have investigated the influence of electron density on the three-center [N-I-N](+) halogen bond. A series of [bis(pyri din e) io dine](+) and [1,2-bis ( (pyridin e-2-71 ethynyl)b e nze n e)io dine](+) BF4- complexes substituted with electron withdrawing and donating functionalities in the para-position of their pyridine nitrogen were synthesized and studied by spectroscopic and computational methods. The systematic change of electron density of the pyridine nitrogens upon alteration of the para-substituent (NO2, CF3, H, F, Me, OMe, NMe2) was confirmed by N-15 NMR and by computation of the natural atomic population and the pi electron population of the nitrogen atoms. Formation of the [N-I-N](+) halogen bond resulted in >100 ppm N-15 NMR coordination shifts. Substituent effects on the N-15 NMR chemical shift are governed by the pi population rather than the total electron population at the nitrogens. Isotopic perturbation of equilibrium NMR studies along with computation on the DFT level indicate that all studied systems possess static, symmetric [N-I-N](+) halogen bonds, independent of their electron density. This was further confirmed by single crystal X-ray diffraction data of 4-substituted [bis(pyridine)iodine](+) complexes. An increased electron density of the halogen bond acceptor stabilizes the [N center dot center dot center dot I center dot center dot center dot N](+) bond, whereas electron deficiency reduces the stability of the complexes, as demonstrated by UV-kinetics and computation. In contrast, the N-I bond length is virtually unaffected by changes of the electron density. The understanding of electronic effects on the [N-X-N](+) halogen bond is expected to provide a useful handle for the modulation of the reactivity of [bis(pyridine)halogen](+)-type synthetic reagents.

  • 16. Carlsson, Anna-Carin C
    et al.
    Veiga, Alberte X
    Erdelyi, Mate
    Halogen bonding in solution.2015In: Topics in current chemistry, ISSN 0340-1022, E-ISSN 1436-5049, Vol. 359, p. 49-76Article, review/survey (Refereed)
    Abstract [en]

    Because of its expected applicability for modulation of molecular recognition phenomena in chemistry and biology, halogen bonding has lately attracted rapidly increasing interest. As most of these processes proceed in solution, the understanding of the influence of solvents on the interaction is of utmost importance. In addition, solution studies provide fundamental insights into the nature of halogen bonding, including, for example, the relative importance of charge transfer, dispersion, and electrostatics forces. Herein, a selection of halogen bonding literature is reviewed with the discussion focusing on the solvent effect and the electronic characteristics of halogen bonded complexes. Hence, charged and neutral systems together with two- and three-center bonds are presented in separate sub-sections. Solvent polarity is shown to have a slight stabilizing effect on neutral, two-center halogen bonds while strongly destabilizes charged, two-center complexes. It does not greatly influence the geometry of three-center halogen bonds, even though polar solvents facilitate dissociation of the counter-ion of charged three-center bonds. The charged three-center bonds are strengthened by increased environment polarity. Solvents possessing hydrogen bond donor functionalities efficiently destabilize all types of halogen bonds, primarily because of halogen vs hydrogen bond competition. A purely electrostatic model is insufficient for the description of halogen bonds in polar systems whereas it may give reasonable correlation to experimental data obtained in noninteracting, apolar solvents. Whereas dispersion plays a significant role for neutral, two-center halogen bonds, charged halogen bond complexes possess a significant charge transfer characteristic.

  • 17. Carlsson, Anna-Carin
    et al.
    Uhrbom, Martin
    Karim, Alavi
    Brath, Ulrika
    Gräfenstein, Jurgen
    Erdelyi, Mate
    Solvent effects on halogen bond symmetry2013In: CrystEngComm, ISSN 1466-8033, E-ISSN 1466-8033, Vol. 15, p. 3087-3092Article in journal (Refereed)
    Abstract [en]

    The symmetric arrangement of the iodine and bromine centred 3-center–4-electron halogen bond is revealed to remain preferred in a polar, aprotic solvent environment. Acetonitrile is unable to compete with pyridine for halogen bonding; however, its polarity weakly modulates the energy of the interaction and influences IPE-NMR experiments.

  • 18.
    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.

  • 19.
    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.  

  • 20.
    Danelius, Emma
    et al.
    University of Gothenburg, SE-41296 Gothenburg, Sweden.
    Andersson, Hanna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. University of Gothenburg, SE-41296 Gothenburg, Sweden.
    Jarvoll, Patrik
    University of Gothenburg, SE-41296 Gothenburg, Sweden.
    Lood, Kajsa
    University of Gothenburg, SE-41296 Gothenburg, Sweden.
    Gräfenstein, Jürgen
    University of Gothenburg, SE-41296 Gothenburg, Sweden.
    Erdélyi, Máté
    University of Gothenburg, SE-41296 Gothenburg, Sweden.
    Halogen Bonding: A Powerful Tool for Modulation of Peptide Conformation2017In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Biochemistry, ISSN 0006-2960, Vol. 56, no 25, p. 3265-3272Article in journal (Refereed)
    Abstract [en]

    Halogen bonding is a weak chemical force that has so far mostly found applications in crystal engineering. Despite its potential for use in drug discovery, as a new molecular tool in the direction of molecular recognition events, it has 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.

  • 21. Danelius, Emma
    et al.
    Brath, Ulrika
    Erdelyi, Mate
    Insight into β-Hairpin Stability: Interstrand Hydrogen Bonding2013In: Synlett: Accounts and Rapid Communications in Synthetic Organic Chemistry, ISSN 0936-5214, E-ISSN 1437-2096, Vol. 24, p. 2407-2410Article in journal (Refereed)
    Abstract [en]

    For evaluation of the role of interstrand hydrogen bonding for -hairpin stability, two cyclic peptides differing only in side chain hydroxy-to-methyl substitution were designed and synthesized on solid phase following the Fmoc-t-Bu-Trt protection strategy. Subsequent to cyclization in solution, combined computational and experimental ensemble analysis revealed higher conformational stability of the peptide capable of interstrand hydrogen bonding. Insight into β-Hairpin Stability: Interstrand Hydrogen Bonding | Request PDF. Available from: https://www.researchgate.net/publication/275142981_Insight_into_b-Hairpin_Stability_Interstrand_Hydrogen_Bonding [accessed Jul 11 2018].

  • 22. Danelius, Emma
    et al.
    Pettersson, Mariell
    Bred, Matilda
    Min, Jaeki
    Waddell, M Brett
    Guy, R Kiplin
    Grøtli, Morten
    Erdelyi, Mate
    Flexibility is important for inhibition of the MDM2/p53 protein-protein interaction by cyclic β-hairpins.2016In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 14, no 44, p. 10386-10393Article in journal (Refereed)
    Abstract [en]

    Protein-protein interactions that have large, flat and featureless binding sites are difficult drug targets. In the development of their modulators conventional drug discovery strategies are often unsuccessful. Gaining a detailed understanding of the binding mode of protein-protein interaction inhibitors is therefore of vast importance for their future pharmaceutical use. The MDM2/p53 protein pair is a highly promising target for cancer treatment. Disruption of the protein complex using p53 α-helix mimetics has been shown to be a successful strategy to control p53 activity. To gain further insight into the binding of inhibitors to MDM2, the flexibility of four cyclic β-hairpins that act as α-helical mimetics and potential MDM2/p53 interaction inhibitors was investigated in relation to their inhibitory activity. MDM2-binding of the mimetics was determined using fluorescence polarization and surface plasmon resonance assays, whereas their conformation and dynamics in solution was described by the combined experimental and computational NAMFIS analysis. Molecular flexibility was shown to be important for the activity of the cyclic β-hairpin based MDM2 inhibitors.

  • 23. Deyou, Tsegaye
    et al.
    Gumula, Ivan
    Pang, Fangfang
    Gruhonic, Amra
    Mumo, Michael
    Holleran, John
    Duffy, Sandra
    Fitzpatrick, Paul
    Heydenreich, Matthias
    Landberg, Göran
    Derese, Solomon
    Avery, Vicky
    Rissanen, Kari
    Erdelyi, Mate
    Yenesew, Abiy
    Rotenoids, Flavonoids, and Chalcones from the Root Bark of Millettia usaramensis2015In: Journal of Natural Products, ISSN 0974-5211, Vol. 78, no 12, p. 2932-2939Article in journal (Refereed)
    Abstract [en]

    Five new compounds, 4-O-geranylisoliquiritigenin (1), 12-dihydrousararotenoid B (2), 12-dihydrousararotenoid C (3), 4′-O-geranyl-7-hydroxyflavanone (4), and 4′-O-geranyl-7-hydroxydihydroflavanol (5), along with 12 known natural products (617) were isolated from the CH2Cl2/MeOH (1:1) extract of the root bark of Millettia usaramensis ssp. usaramensis by chromatographic separation. The purified metabolites were identified by NMR spectroscopic and mass spectrometric analyses, whereas their absolute configurations were established on the basis of chiroptical data and in some cases also by X-ray crystallography. The crude extract was moderately active (IC50 = 11.63 μg/mL) against the ER-negative MDB-MB-231 human breast cancer cell line, and accordingly compounds 6891012, and 16 also showed moderate to low cytotoxic activities (IC50 25.7–207.2 μM). The new natural product 1 exhibited antiplasmodial activity with IC50 values of 3.7 and 5.3 μM against the chloroquine-sensitive 3D7 and the chloroquine-resistant Dd2 Plasmodium falciparum strains, respectively, and was also cytotoxic to the HEK293 cell line.

  • 24. Deyou, Tsegaye
    et al.
    Marco, Makungu
    Heydenreich, Matthias
    Pan, Fangfang
    Gruhonjic, Amra
    Fitzpatrick, Paul A
    Koch, Andreas
    Derese, Solomon
    Pelletier, Jerry
    Rissanen, Kari
    Yenesew, Abiy
    Erdelyi, Mate
    Isoflavones and Rotenoids from the Leaves of Millettia oblata ssp. teitensis.2017In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 80, no 7, p. 2060-2066Article in journal (Refereed)
    Abstract [en]

    A new isoflavone, 8-prenylmilldrone (1), and four new rotenoids, oblarotenoids A-D (2-5), along with nine known compounds (6-14), were isolated from the CH2Cl2/CH3OH (1:1) extract of the leaves of Millettia oblata ssp. teitensis by chromatographic separation. The purified compounds were identified by NMR spectroscopic and mass spectrometric analyses, whereas the absolute configurations of the rotenoids were established on the basis of chiroptical data and in some cases by single-crystal X-ray crystallography. Maximaisoflavone J (11) and oblarotenoid C (4) showed weak activity against the human breast cancer cell line MDA-MB-231 with IC50 values of 33.3 and 93.8 μM, respectively.

  • 25. 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.

  • 26. 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.

  • 27. Endale, Milkyas
    et al.
    Ekberg, Annabel
    Alao, John Patrick
    Akala, Hoseah M
    Ndakala, Albert
    Sunnerhagen, Per
    Erdelyi, Mate
    Yenesew, Abiy
    Anthraquinones of the roots of Pentas micrantha.2013In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 18, p. 311-321Article in journal (Refereed)
    Abstract [en]

    Pentas micrantha is used in the East African indigenous medicine to treat malaria. In the first investigation of this plant, the crude methanol root extract showed moderate antiplasmodial activity against the W2- (3.37 μg/mL) and D6-strains (4.00 μg/mL) of Plasmodium falciparum and low cytotoxicity (>450 μg/mL, MCF-7 cell line). Chromatographic separation of the extract yielded nine anthraquinones, of which 5,6-dihydroxylucidin-11-O-methyl ether is new. Isolation of a munjistin derivative from the genus Pentas is reported here for the first time. The isolated constituents were identified by NMR and mass spectrometric techniques and showed low antiplasmodial activities.

  • 28. Erdelyi, Mate
    A big hello to halogen bonding.2014In: Nature Chemistry, ISSN 1755-4330, E-ISSN 1755-4349, Vol. 6, no 9, p. 762-764Article in journal (Refereed)
  • 29. Erdelyi, Mate
    Application of the Halogen Bond in Protein Systems.2017In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 56, no 22, p. 2759-2761Article, review/survey (Refereed)
  • 30. Erdelyi, Mate
    Deyou, Tsegaye
    Gruhonic, Amra
    Hollerand, John
    Duffy, Sandra
    Heydenreich, Matthias
    Fitzpatrick, Paul
    Landberg, Göran
    Koch, Andreas
    Derese, Solomon
    Pelletier, Jerry
    Avery, Vicky
    Yenesew, Abiy
    Pterocarpans and isoflavones from the root bark of Millettia micans and of Millettia dura2016In: Phytochemistry Letters, ISSN 1874-3900, E-ISSN 1876-7486, Vol. 21, p. 216-220-Article in journal (Refereed)
    Abstract [en]

    From the CH2Cl2/CH3OH (1:1) extract of the root bark of Millettia micans, a new pterocarpan, (6aR,11aR)-3-hydroxy-7,8,9-trimethoxypterocarpan (1), named micanspterocarpan, was isolated. Similar investigation of the CH2Cl2/CH3OH (1:1) extract of the root bark of Millettia dura gave a further new pterocarpan, (6aR,11aR)-8,9-methylenedioxy-3-prenyloxypterocarpan (2), named 3-O-prenylmaackiain, along with six known isoflavones (3-8) and a chalcone (9). All purified compounds were identified by NMR and MS, whereas the absolute configurations of the new pterocarpans were established by chriptical data analyses including quantum chemical ECD calculation. Among the isolated constituents, calopogonium isoflavone B (3) and isoerythrin A-4′-(3-methylbut-2-enyl) ether (4) showed marginal activities against the 3D7 and the Dd2 strains of Plasmodium falciparum (70–90% inhibition at 40 μM). Maximaisoflavone B (5) and 7,2′-dimethoxy-4′,5′-methylenedioxyisoflavone (7) were weakly cytotoxic (IC50 153.5 and 174.1 μM, respectively) against the MDA-MB-231 human breast cancer cell line. None of the tested compounds showed in-vitro translation inhibitory activity or toxicity against the HEK-293 human embryonic kidney cell line at 40 μM.

  • 31. Erdelyi, Mate
    et al.
    Brath, U
    Lau, K
    Van Petegem, F
    The general anaesthetic binding site of Calmodulin disrupts Ryanodine peptide binding2013Conference paper (Refereed)
  • 32. Erdelyi, Mate
    et al.
    Karim, Alavi
    Reitti, Marcus
    Carlsson, Anna-Carin
    The nature of [N–Cl–N]+ and [N–F–N]+ halogen bonds in solution2014In: Chemical Science, Vol. 5, p. 3226-3233Article in journal (Refereed)
    Abstract [en]

    Halonium ions are synthetically useful, transient species that may be stabilized by attachment to two electron donors. Whereas studies of [C–X–C]+-type ions have greatly contributed to the fundamental understanding of chemical bonding and reaction mechanisms, investigations of the corresponding [N–X–N]+ halogen bond complexes are only at an early stage. Herein we present solution NMR spectroscopic and theoretical evidence for the nature of [N–Cl–N]+ and [N–F–N]+ complexes, and we discuss their geometries and stabilities in comparison to their iodine and bromine-centered analogues as well as the corresponding three-center [N–H–N]+ hydrogen bond. We show the chlorine-centered halogen bond to be weaker but yet to resemble the symmetric geometry of the three-center bond of heavier halogens. In contrast, the [N–F–N]+ bond is demonstrated to prefer asymmetric geometry analogous to the [N–H–N]+ hydrogen bond. However, the [N–F–N]+ system has a high energy barrier for interconversion, and due to entropy loss, its formation is slightly endothermic.

  • 33. Erdelyi, Mate
    et al.
    Metrangolo, Pierangelo
    Introduction to the special issue on halogen bonding.2017In: Acta Crystallographica. Section B: Structural Science, Crystal Engineering and Materials, ISSN 2052-5192, E-ISSN 2052-5206, Vol. 73, no Pt 2, article id 135Article, review/survey (Refereed)
  • 34. Erdelyi, Mate
    et al.
    Pupier, Marion
    Nuzillard, Jean-Marc
    Wist, Julien
    Schlörer, Nils
    Kuhn, Stefan
    Steinbeck, Christoph
    Williams, Antony
    Butts, Craig
    Claridge, Tim
    Mikhova, Bozhana
    Robien, Wolfgang
    Dashti, Hesam
    Eghbalnia, Hamid
    Fares, Christophe
    Adam, Christian
    Pavel, Kessler
    Moriaud, Fabrice
    Elyashberg, Mikhail
    Argyropoulos, Dimitris
    Perez, Manuel
    Giraudeau, Patrick
    Gil, Roberto
    Trevorrow, Paul
    Jeannerat, Damien
    A cross-platform format to associate NMR-extracted data (NMReDATA) to chemical structures2018Conference paper (Refereed)
  • 35.
    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

  • 36.
    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)
  • 37.
    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.  

  • 38.
    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) .

  • 39.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Pentacoordinate carbonium ions in solution2018Conference paper (Refereed)
  • 40.
    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)
  • 41.
    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.

  • 42.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    The three-centered halogen bond2018Conference paper (Refereed)
  • 43.
    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.

  • 44.
    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)
  • 45.
    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)
  • 46.
    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)
  • 47.
    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)
  • 48.
    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.

  • 49.
    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.

  • 50.
    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.

12 1 - 50 of 88
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