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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 1431-5157, 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, E-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.
    Andersson, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Jarvoll, Patrik
    Univ Gothenburg, Ctr Antibiot Resistance Res CARe, SE-40530 Gothenburg, Sweden..
    Yang, Shao-Kang
    Northwest Univ, Coll Chem & Mat Sci, Key Lab Synthet & Nat Funct Mol Chem, Minist Educ, Xian 710127, Peoples R China..
    Yang, Ke-Wu
    Northwest Univ, Coll Chem & Mat Sci, Key Lab Synthet & Nat Funct Mol Chem, Minist Educ, Xian 710127, Peoples R China..
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Binding of 2-(Triazolylthio)acetamides to Metallo-beta-lactamase CcrA Determined with NMR2020In: ACS Omega, E-ISSN 2470-1343, Vol. 5, no 34, p. 21570-21578Article in journal (Refereed)
    Abstract [en]

    Metallo-beta-lactamase (MBL)-producing bacteria resistant to beta-lactam antibiotics are a serious threat to human health. Despite great efforts and important progress in the discovery of MBL inhibitors (MBLIs), there is none in clinical use. Herein, inhibitor complexes of the MBL CcrA were investigated by NMR spectroscopy to provide perspectives on the further development of 2-(triazolylthio)acetamide-type MBLIs. By using the NMR-based chemical shift perturbation (CSP) and direction of CSP methodologies together with molecular docking, the spatial orientation of three compounds in the CcrA active site was investigated (4-6). Inhibitor 6 showed the best binding affinity (K-d approximate to 2.3 +/- 0.3 mu M), followed by 4 (K-d approximate to 11 +/- 11 mu M) and 5 (K-d = 34 +/- 43 mu M), as determined from the experimental NMR data. Based on the acquired knowledge, analogues of other MBLIs (1-3) were designed and evaluated in silico with the purpose of examining a strategy for promoting their interactions with the catalytic zinc ions.

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  • 8. 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.

  • 9. 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 1431-5157, 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.

  • 10.
    Atilaw, Yoseph
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. Uppsala Univ, Dept ChemUniv Nairobi, Dept Chem, Nairobi 3019700100, Kenya..
    Muiva-Mutisya, Lois
    Univ Nairobi, Dept Chem, Nairobi 3019700100, Kenya..
    Bogaerts, Jonathan
    Univ Antwerp, Dept Chem, B-2020 Antwerp, Belgium..
    Duffy, Sandra
    Griffith Univ, Griffith Inst Drug Discovery, Discovery Biol, Nathan, Qld 4111, Australia..
    Valkonen, Arto
    Univ Jyvaskyla, Dept Chem, FI-40014 Jyvaskyla, Finland..
    Heydenreich, Matthias
    Univ Potsdam, Inst Chem, D-14476 Potsdam, Germany..
    Avery, Vicky M.
    Griffith Univ, Griffith Inst Drug Discovery, Discovery Biol, Nathan, Qld 4111, Australia..
    Rissanen, Kari
    Univ Jyvaskyla, Dept Chem, FI-40014 Jyvaskyla, Finland..
    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..
    Yenesew, Abiy
    Univ Nairobi, Dept Chem, Nairobi 3019700100, Kenya..
    Prenylated Flavonoids from the Roots of Tephrosia rhodesica2020In: Journal of Natural Products, ISSN 0163-3864, E-ISSN 1520-6025, Vol. 83, no 8, p. 2390-2398Article in journal (Refereed)
    Abstract [en]

    Five new compounds-rhodimer (1), rhodiflavan A (2), rhodiflavan B (3), rhodiflavan C (4), and rhodacarpin (5)-along with 16 known secondary metabolites, were isolated from the CH2Cl2-CH3OH (1:1) extract of the roots of Tephrosia rhodesica. They were identified by NMR spectroscopic, mass spectrometric, X-ray crystallographic, and ECD spectroscopic analyses. The crude extract and the isolated compounds 2-5, 9, 15, and 21 showed activity (100% at 10 mu g and IC50 = 5-15 mu M) against the chloroquine-sensitive (3D7) strain of Plasmodium falciparum.

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  • 11. 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 1431-5157, 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.

  • 12.
    Atilaw, Yoseph
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Poongavanam, Vasanthanathan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Svensson Nilsson, Caroline
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Nguyen, Duy
    Giese, Anja
    Meibom, Daniel
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Solution Conformations Shed Light on PROTAC Cell Permeability2021In: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, Vol. 12, no 1, p. 107-114Article in journal (Refereed)
    Abstract [en]

    Proteolysis targeting chimeras (PROTACs) induce intracellular degradation of target proteins. Their bifunctional structure puts degraders in a chemical space where ADME properties often complicate drug discovery. Herein we provide the first structural insight into PROTAC cell permeability obtained by NMR studies of a VHL-based PROTAC (1), which is cell permeable despite having a high molecular weight and polarity and a large number of rotatable bonds. We found that 1 populates elongated and polar conformations in solutions that mimic extra- and intracellular compartments. Conformations were folded and had a smaller polar surface area in chloroform, mimicking a cell membrane interior. Formation of intramolecular and nonclassical hydrogen bonds, π–π interactions, and shielding of amide groups from solvent all facilitate cell permeability by minimization of size and polarity. We conclude that molecular chameleonicity appears to be of major importance for 1 to enter into target cells.

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  • 13. 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.

  • 14.
    Begnini, Fabio
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Poongavanam, Vasanthanathan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Atilaw, Yoseph
    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.
    Schiesser, Stefan
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Cell Permeability of Isomeric Macrocycles: Predictions and NMR Studies2021In: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, Vol. 12, no 6, p. 983-990Article in journal (Refereed)
    Abstract [en]

    Conformation-dependent 3D descriptors have been shown to provide better predictions of the physicochemical properties of macrocycles than 2D descriptors. However, the computational identification of relevant conformations for macrocycles is nontrivial. Herein, we report that the Caco- 2 cell permeability difference between a pair of diastereomeric macrocycles correlated with their solvent accessible 3D polar surface area and radius of gyration. The descriptors were calculated from the macrocycles’ solution- phase conformational ensembles and independently from ensembles obtained by conformational sampling. Calculation of the two descriptors for three other stereo- and regioisomeric macrocycles also allowed the correct ranking of their cell permeability. Methods for conformational sampling may thus allow ranking of passive permeability for moderatelyflexible macrocycles, thereby contributing to the prioritization of macro- cycles for synthesis in lead optimization.

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  • 15. Begum, Sartaz
    et al.
    Munissi, Joan J.E.
    Buriyo, Amelia S.
    Makangara, John J.
    Lucantoni, Leonardo
    Avery, Vicky M.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Nyandoro, Stephen S.
    Antiplasmodial, Antimicrobial and Cytotoxic Activities of Extracts from Selected Medicinal Plants Growing in Tanzania2020In: Journal of Biologically Active Products from Nature, ISSN 2231-1866, Vol. 10, no 2, p. 165-176Article in journal (Refereed)
    Abstract [en]

    This paper reports on the evaluation of antiplasmodial, antimicrobial and cytotoxic activities of extracts from eleven plant species traditionally used by some Tanzanian coastal communities for treatment of malaria, microbial infections and related ailments. Crude extracts from selected plant species namely Acacia zanzibarica,  Danais  xanthorrhoea, Diospyros  loureiriana  ssp.  rufescens, Erythrina  sacleuxii, Newtonia paucijuga, Pentas lanceolata, Scorodophloeus fischeri, Stuhlmannia moavi, Tarenna pavettoides, Tessmannia burttii  and  Toussaintia  orientalis  growing  in  Tanzania  were  investigated  using  an  imaging-based  assay (antiplasmodial), well diffusion and microplate dilution methods (antimicrobial) and human embryonic kidney cells (HEK 293) and brine shrimp larvae assays (toxicity). The extracts exhibited activities of varying potencies and cytotoxicity with IC 50 values ranging from 0.45±0.09 to 75.70±24.19 μg/mL against Plasmodium falciparum (3D7 strain), MIC ranging from 0.25 to 2.0 mg/mL (against Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Candida albicans and Cryptococcus neoformans), LC 50 ranging from 0.75 to 1000 μg/mL against brine shrimp larvae (Artemia salina) and IC 50 ranging from 4.02±1.05 to more than 289 μg/mL against HEK 293 cells. The observed bioactivities of some of the investigated plant extracts validate their ethnomedicinal use and are indicative of the presence of bioactive ingredients for further phytochemical investigations.

  • 16. 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.

  • 17.
    Bogaerts, Jonathan
    et al.
    Department of Chemistry, University of Antwerp, 2020 Antwerp, Belgium.
    Atilaw, Yoseph
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Peintner, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Aerts, Roy
    Department of Chemistry, University of Antwerp, 2020 Antwerp, Belgium.
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Johannessen, Christian
    Department of Chemistry, University of Antwerp, 2020 Antwerp, Belgium.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Employing complementary spectroscopies to study the conformations of an epimeric pair of side-chain stapled peptides in aqueous solution2021In: RSC Advances, E-ISSN 2046-2069, Vol. 11, no 7, p. 4200-4208Article in journal (Refereed)
    Abstract [en]

    Understanding the conformational preferences of free ligands in solution is often necessary to rationalize structure–activity relationships in drug discovery. Herein, we examine the conformational behavior of an epimeric pair of side-chain stapled peptides that inhibit the FAD dependent amine oxidase lysine specific demethylase 1 (LSD1). The peptides differ only at a single stereocenter, but display a major difference in binding affinity. Their Raman optical activity (ROA) spectra are most likely dominated by the C-terminus, obscuring the analysis of the epimeric macrocycle. By employing NMR spectroscopy, we show a difference in conformational behavior between the two compounds and that the LSD1 bound conformation of the most potent compound is present to a measurable extent in aqueous solution. In addition, we illustrate that Molecular Dynamics (MD) simulations produce ensembles that include the most important solution conformations, but that it remains problematic to identify relevant conformations with no a priori knowledge from the large conformational pool. Furthermore, this work highlights the importance of understanding the scope and limitations of the available techniques for conducting conformational analyses. It also emphasizes the importance of conformational selection of a flexible ligand in molecular recognition.

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  • 18. Brath, Ulrika
    et al.
    Lau, Kelvin
    Van Petegem, Filip
    Erdelyi, Mate
    Mapping the sevoflurane-binding sites of calmodulin.2014In: Pharmacology Research & Perspectives, E-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.

  • 19. 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.

  • 20.
    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.

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  • 21. 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.

  • 22. 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.

  • 23.
    Chepkirui, Carolyne
    et al.
    Department of Chemistry, University of Nairobi, P.O. Box 30197, 00100 Nairobi, Kenya;Department of Physical and Biological Sciences, Kabarak University, Private Bag-20157, Nakuru, Kenya.
    Ali Adem, Fozia
    Department of Chemistry, University of Nairobi, P.O. Box 30197, 00100 Nairobi, Kenya.
    Rudenko, Anastasia
    Department of Chemistry and Molecular Biology, University of Gothenburg, and Centre for Antibiotic Resistance Research (CARe) at the University of Gothenburg, SE-405 30 Gothenburg, Sweden.
    Gütlin, Yukino
    Department of Chemistry and Molecular Biology, University of Gothenburg, and Centre for Antibiotic Resistance Research (CARe) at the University of Gothenburg, SE-405 30 Gothenburg, Sweden.
    Ndakala, Albert
    Department of Chemistry, University of Nairobi, P.O. Box 30197, 00100 Nairobi, Kenya.
    Derese, Solomon
    Department of Chemistry, University of Nairobi, P.O. Box 30197, 00100 Nairobi, Kenya.
    Orthaber, Andreas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Synthetic Molecular Chemistry.
    Bourgard, Catarina
    Department of Chemistry and Molecular Biology, University of Gothenburg, and Centre for Antibiotic Resistance Research (CARe) at the University of Gothenburg, SE-405 30 Gothenburg, Sweden.
    Yenesew, Abiy
    Department of Chemistry, University of Nairobi, P.O. Box 30197, 00100 Nairobi, Kenya.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Benzo[b]naphtho[2,1-d]furans and 2-Phenylnaphthalenes from Streblus usambarensis2023In: Journal of Natural Products, ISSN 0163-3864, E-ISSN 1520-6025, Vol. 86, no 4, p. 1010-1018Article in journal (Refereed)
    Abstract [en]

    Three new benzo[b]naphtho[2,1-d]furans, usambarins A–C (13), five new 2-phenylnaphthalenes, usambarins D–H (48), a new flavan (9), and a new phenyl-1-benzoxepin (10) as well as two known compounds (11 and 12) were isolated from the extract of the stem and roots of Streblus usambarensis (Moraceae). The structures were deduced using NMR spectroscopic and mass spectrometric analyses, and those of compounds 1 and 4 were confirmed by X-ray crystallography. Usambarin D (4) demonstrated moderate antibacterial activity (MIC 9.0 μM) against Bacillus subtilis, while none of the tested compounds were effective against Escherichia coli.

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  • 24.
    Chepkirui, Carolyne
    et al.
    Department of Chemistry, University of Nairobi, P.O. Box 30197-00100, Nairobi, Kenya; Department of Physical and Biological Sciences, Kabarak University, Private Bag 20157 Nakuru, Kenya.
    Bourgard, Catarina
    Department of Chemistry and Molecular Biology, Center for Antibiotic Resistance Research (CARe), University of Gothenburg, SE-412 96 Gothenburg, Sweden.
    Gilissen, Pieter J.
    Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands.
    Ndakala, Albert
    Department of Chemistry, University of Nairobi, P.O. Box 30197-00100, Nairobi, Kenya.
    Derese, Solomon
    Department of Chemistry, University of Nairobi, P.O. Box 30197-00100, Nairobi, Kenya.
    Gütlin, Yukino
    Department of Chemistry and Molecular Biology, Center for Antibiotic Resistance Research (CARe), University of Gothenburg, SE-412 96 Gothenburg, Sweden.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Yenesew, Abiy
    Department of Chemistry, University of Nairobi, P.O. Box 30197-00100, Nairobi, Kenya.
    A new β-hydroxydihydrochalcone from Tephrosia uniflora, and the revision of three β-hydroxydihydrochalcones to flavanones2022In: Fitoterapia, ISSN 0367-326X, E-ISSN 1873-6971, Vol. 158, article id 105166Article in journal (Refereed)
    Abstract [en]

    The CH2Cl2/MeOH (1:1) extract of the stems of Tephrosia uniflora yielded the new β-hydroxydihydrochalcone (S)-elatadihydrochalcone-2'-methyl ether (1) along with the three known compounds elongatin (2), (S)-elatadihydrochalcone (3), and tephrosin (4). The structures were elucidated by NMR spectroscopic and mass spectrometric data analyses. Elongatin (2) showed moderate antibacterial activity (EC50 of 25.3 μM and EC90 of 32.8 μM) against the Gram-positive bacterium Bacilus subtilis, and comparable toxicity against the MCF-7 human breast cancer cell line (EC50 of 41.3 μM). Based on the comparison of literature and predicted NMR data with that obtained experimentally, we propose the revision of the structures of three β-hydroxydihydrochalcones to flavanones.

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  • 25.
    Chepkirui, Carolyne
    et al.
    University of Nairobi.
    Ochieng, Purity J
    University of Nairobi.
    Sarkar, Biswajyoti
    West Bengal State University.
    Hussain, Aabid
    West Bengal State University.
    Pal, Chiranjib
    West Bengal State University.
    Yang, Li Jun
    Macau University of Science and Technology.
    Coghi, Paolo
    Macau University of Science and Technology.
    Akala, Hoseah M
    Kenya Medical Research Institute.
    Derese, Solomon
    University of Nairobi.
    Ndakala, Albert
    University of Nairobi.
    Heydenreich, Matthias
    Universität Potsdam.
    Wong, Vincent K W
    Macau University of Science and Technology.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Yenesew, Abiy
    University of Nairobi.
    Antiplasmodial and antileishmanial flavonoids from Mundulea sericea2021In: Fitoterapia (Milano), ISSN 0367-326X, E-ISSN 1873-6971, Vol. 149, article id 104796Article in journal (Refereed)
    Abstract [en]

    Five known compounds (1–5) were isolated from the extract of Mundulea sericea leaves. Similar investigation of the roots of this plant afforded an additional three known compounds (6–8). The structures were elucidated using NMR spectroscopic and mass spectrometric analyses. The absolute configuration of 1 was established using ECD spectroscopy. In an antiplasmodial activity assay, compound 1 showed good activity with an IC50 of 2.0 μM against chloroquine-resistant W2, and 6.6 μM against the chloroquine-sensitive 3D7 strains of Plasmodium falciparum. Some of the compounds were also tested for antileishmanial activity. Dehydrolupinifolinol (2) and sericetin (5) were active against drug-sensitive Leishmania donovani (MHOM/IN/83/AG83) with IC50 values of 9.0 and 5.0 μM, respectively. In a cytotoxicity assay, lupinifolin (3) showed significant activity on BEAS-2B (IC50 4.9 μM) and HePG2 (IC50 10.8 μM) human cell lines. All the other compounds showed low cytotoxicity (IC50 > 30 μM) against human lung adenocarcinoma cells (A549), human liver cancer cells (HepG2), lung/bronchus cells (epithelial virus transformed) (BEAS-2B) and immortal human hepatocytes (LO2)

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  • 26.
    Dalenius, Emma
    et al.
    CHU St Justine, Res Ctr, Dept Pediat, Montreal, PQ H3T 1C5, Canada; Univ Calif Los Angeles, Howard Hughes Med Inst, Los Angeles, CA 90024 USA.
    Ohm, Ragnhild G.
    Univ Montreal, Dept Chim, Stn Ctr Ville, CP 6128, Montreal, PQ H3C 3J7, Canada.
    Ahsanullah, Ahsanullah
    Univ Montreal, Dept Chim, Stn Ctr Ville, CP 6128, Montreal, PQ H3C 3J7, Canada; Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan.
    Ong, Huy
    Univ Montreal, Fac Pharm, Stn Ctr Ville, CP 6128, Montreal, PQ H3C 3J7, Canada.
    Chemtob, Sylvain
    Univ Montreal, Dept Pediat, Stn Ctr Ville, CP 6128, Montreal, PQ H3C 3J7, Canada; CHU St Justine, Res Ctr, Dept Pediat, Montreal, PQ H3T 1C5, Canada.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC. The Swedish NMR Centre, Gothenburg.
    D. Lubell, William
    Univ Montreal, Dept Chim, Stn Ctr Ville, CP 6128, Montreal, PQ H3C 3J7, Canada.
    Dynamic Chirality in the Mechanism of Action of Allosteric CD36 Modulators of Macrophage-Driven Inflammation2019In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 62, no 24, p. 111071-11079Article in journal (Refereed)
    Abstract [en]

    Dynamic chirality influences numerous processes in nature from protein folding to catalysis. Azapeptides are peptidomimetics possessing semicarbazide residues that can interconvert between sp2 and sp3 hybridization, resulting in stereodynamic interconversions of pseudo-R and -S-configurations by means of a planar intermediate. Cyclic azapeptides have shown unprecedented binding affinity to the cluster of differentiation 36 receptor (CD36) and ability to mitigate macrophage-driven inflammation by modulation of the toll-like receptor 2/6 pathway. A novel approach to synthesize cyclic peptides via A3-macrocyclization has been used to make R- and S-configuration controls to study the relevance of semicarbazide hybridization for modulator activity. Nuclear magnetic resonance spectroscopy analysis of potent cyclic azapeptide CD36 modulators (e.g., 1 and 2) and related cyclic peptides demonstrated that binding affinity correlated with conformational rigidity, and a hybridization preference for sp2 > S- > R-sp3 semicarbazide nitrogen configuration was evaluated. Evidence of the active conformation and the relevance for dynamic chirality serve as insights for creating cyclic (aza)peptide CD36 modulators to curb inflammation.

  • 27.
    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.

  • 28.
    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.  

  • 29.
    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.

  • 30. 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].

  • 31. 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.

  • 32.
    Danelius, Emma
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Poongavanam, Vasanthanathan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Peintner, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Wieske, Lianne H. E.
    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.
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Solution Conformations Explain the Chameleonic Behaviour of Macrocyclic Drugs2020In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 26, no 23, p. 5231-5244Article in journal (Refereed)
    Abstract [en]

    It has been hypothesised that drugs in the chemical space "beyond the rule of 5" (bRo5) must behave as molecular chameleons to combine otherwise conflicting properties, including aqueous solubility, cell permeability and target binding. Evidence for this has, however, been limited to the cyclic peptide cyclosporine A. Herein, we show that the non-peptidic and macrocyclic drugs roxithromycin, telithromycin and spiramycin behave as molecular chameleons, with rifampicin showing a less pronounced behaviour. In particular roxithromycin, telithromycin and spiramycin display a marked, yet limited flexibility and populate significantly less polar and more compact conformational ensembles in an apolar than in a polar environment. In addition to balancing of membrane permeability and aqueous solubility, this flexibility also allows binding to targets that vary in structure between species. The drugs' passive cell permeability correlates to their 3D polar surface area and corroborate two theoretical models for permeability, developed for cyclic peptides. We conclude that molecular chameleonicity should be incorporated in the design of orally administered drugs in the bRo5 space.

  • 33.
    Daniel, Umereweneza
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Yoseph, Atilaw
    Stefan, Peintner
    Anastasia, Rudenko
    Catarina, Bourgard
    Ruisheng, Xiong
    Théoneste, Muhizi
    Per, Sunnerhagen
    Gogoll, A
    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.
    Macrocyclic pyrrolizidine alkaloids and silphiperfolanol angelate esters from Senecio mannii.Manuscript (preprint) (Other academic)
  • 34. 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.

  • 35. 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.

  • 36.
    Dickman, Rachael
    et al.
    UCL, Dept Chem, 20 Gordon St, London WC1H 0AJ, England.
    Danelius, Emma
    Swedish NMR Ctr, Medicinaregatan 5, S-40530 Gothenburg, Sweden.
    Mitchell, Serena A.
    UCL, Dept Chem, 20 Gordon St, London WC1H 0AJ, England.
    Hansen, D. Flemming
    UCL, Div Biosci, Inst Struct & Mol Biol, Gower St, London WC1E 6BT, England.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. Swedish NMR Ctr, Medicinaregatan 5, S-40530 Gothenburg, Sweden.
    Tabor, Alethea B.
    UCL, Dept Chem, 20 Gordon St, London WC1H 0AJ, England.
    A Chemical Biology Approach to Understanding Molecular Recognition of Lipid II by Nisin(1-12): Synthesis and NMR Ensemble Analysis of Nisin(1-12) and Analogues2019In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 25, no 64, p. 14572-14582Article in journal (Refereed)
    Abstract [en]

    Natural products that target lipid II, such as the lantibiotic nisin, are strategically important in the development of new antibacterial agents to combat the rise of antimicrobial resistance. Understanding the structural factors that govern the highly selective molecular recognition of lipid II by the N-terminal region of nisin, nisin(1-12), is a crucial step in exploiting the potential of such compounds. In order to elucidate the relationships between amino acid sequence and conformation of this bicyclic peptide fragment, we have used solid-phase peptide synthesis to prepare two novel analogues of nisin(1-12) in which the dehydro residues have been replaced. We have carried out an NMR ensemble analysis of one of these analogues and of the wild-type nisin(1-12) peptide in order to compare the conformations of these two bicyclic peptides. Our analysis has shown the effects of residue mutation on ring conformation. We have also demonstrated that the individual rings of nisin(1-12) are pre-organised to an extent for binding to the pyrophosphate group of lipid II, with a high degree of flexibility exhibited in the central amide bond joining the two rings.

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  • 37. 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.

  • 38. 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.

  • 39. 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 1431-5157, 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.

  • 40. 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)
  • 41. 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)
  • 42. 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.

  • 43. Erdelyi, Mate
    et al.
    Brath, U
    Lau, K
    Van Petegem, F
    The general anaesthetic binding site of Calmodulin disrupts Ryanodine peptide binding2013Conference paper (Refereed)
  • 44. 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.

  • 45. 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)
  • 46. 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)
  • 47.
    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

  • 48.
    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)
  • 49.
    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.  

  • 50.
    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) .

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