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Vanderkooy, A., Gupta, A. K., Foldes, T., Lindblad, S., Orthaber, A., Papai, I. & Erdélyi, M. (2019). Halogen Bonding Helicates Encompassing Iodonium Cations. Angewandte Chemie International Edition, 58(27), 9012-9016
Open this publication in new window or tab >>Halogen Bonding Helicates Encompassing Iodonium Cations
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2019 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 58, no 27, p. 9012-9016Article in journal (Refereed) Published
Abstract [en]

The first halonium-ion-based helices were designed and synthesized using oligo-aryl/pyridylene-ethynylene backbones that fold around reactive iodonium ions. Halogen bonding interactions stabilize the iodonium ions within the helices. Remarkably, the distance between two iodonium ions within a helix is shorter than the sum of their van der Waals radii. The helical conformations were characterized by X-ray crystallography in the solid state, by NMR spectroscopy in solution and corroborated by DFT calculations. The helical complexes possess potential synthetic utility, as demonstrated by their ability to induce iodocyclization of 4-penten-1-ol.

Place, publisher, year, edition, pages
WILEY-V C H VERLAG GMBH, 2019
Keywords
3c-4e bonds, halocyclization, halogen bonds, helices, iodonium ions
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-391952 (URN)10.1002/anie.201904817 (DOI)000476691200005 ()31074942 (PubMedID)
Funder
Swedish Research Council Formas, 2017-01173
Available from: 2019-08-28 Created: 2019-08-28 Last updated: 2019-08-28Bibliographically approved
Erdélyi, M. (2019). The three-center halogen bond. In: : . Paper presented at 34. Organisk Kjemisk Vintermøte, 10. - 13. januar 2019, Skeikampen, Norge.
Open this publication in new window or tab >>The three-center halogen bond
2019 (English)Conference paper, Oral presentation with published abstract (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.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-373611 (URN)
Conference
34. Organisk Kjemisk Vintermøte, 10. - 13. januar 2019, Skeikampen, Norge
Available from: 2019-01-15 Created: 2019-01-15 Last updated: 2019-01-15
Lindblad, S., Mehmeti, K. & Erdélyi, M. (2018). Asymmetric [N-X-N]+ Halogen Bonds in Solution. In: : . Paper presented at 1ST NATIONAL MEETING OF THE SWEDISH CHEMICAL SOCIETY in Lund, 17-20 June 2018.
Open this publication in new window or tab >>Asymmetric [N-X-N]+ Halogen Bonds in Solution
2018 (English)Conference paper, Poster (with or without abstract) (Other academic)
National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-357744 (URN)
Conference
1ST NATIONAL MEETING OF THE SWEDISH CHEMICAL SOCIETY in Lund, 17-20 June 2018
Available from: 2018-08-20 Created: 2018-08-20 Last updated: 2018-08-22Bibliographically approved
Begum, S., Nyandoro, S., Buriyo, A., Makangara, J., Munissi, J., Duffy, S., . . . Erdelyi, M. (2018). Bioactivities of extracts, debromolaurintrerol and fucosterol from Macroalgae species. Tanzania Journal of Science, 44(2), 104-116
Open this publication in new window or tab >>Bioactivities of extracts, debromolaurintrerol and fucosterol from Macroalgae species
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2018 (English)In: Tanzania Journal of Science, ISSN 2507-7961, Vol. 44, no 2, p. 104-116Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Dar es Salaam: , 2018
Keywords
Macrolgae, antiplasmodial, antimicrobial, antioxidant, cytotoxicity, DPPH radical scavenging, debromolaurinterol and fucosterol
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-355944 (URN)
Available from: 2018-07-09 Created: 2018-07-09 Last updated: 2019-01-08Bibliographically approved
Szałaj, N., Lu, L., Benediktsdottir, A., Zamaratski, E., Cao, S., Olanders, G., . . . Brandt, P. (2018). Boronic ester-linked macrocyclic lipopeptides as serine protease inhibitors targeting Escherichia coli type I signal peptidase.. European Journal of Medicinal Chemistry, 157, 1346-1360
Open this publication in new window or tab >>Boronic ester-linked macrocyclic lipopeptides as serine protease inhibitors targeting Escherichia coli type I signal peptidase.
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2018 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 157, p. 1346-1360Article in journal (Refereed) Published
Abstract [en]

Type I signal peptidase, with its vital role in bacterial viability, is a promising but underexploited antibacterial drug target. In the light of steadily increasing rates of antimicrobial resistance, we have developed novel macrocyclic lipopeptides, linking P2 and P1' by a boronic ester warhead, capable of inhibiting Escherichia coli type I signal peptidase (EcLepB) and exhibiting good antibacterial activity. Structural modifications of the macrocyclic ring, the peptide sequence and the lipophilic tail led us to 14 novel macrocyclic boronic esters. It could be shown that macrocyclization is well tolerated in terms of EcLepB inhibition and antibacterial activity. Among the synthesized macrocycles, potent enzyme inhibitors in the low nanomolar range (e.g. compound 42f, EcLepB IC50 = 29 nM) were identified also showing good antimicrobial activity (e.g. compound 42b, E. coli WT MIC = 16 μg/mL). The unique macrocyclic boronic esters described here were based on previously published linear lipopeptidic EcLepB inhibitors in an attempt to address cytotoxicity and hemolysis. We show herein that structural changes to the macrocyclic ring influence both the cytotoxicity and hemolytic activity suggesting that the P2 to P1' linker provide means for optimizing off-target effects. However, for the present set of compounds we were not able to separate the antibacterial activity and cytotoxic effect.

Keywords
Antibacterial lipopeptides, Bacterial type I signal peptidase, Escherichia coli type I signal peptidase (EcLepB), P2–P1′ boronic ester-linked macrocycles
National Category
Medicinal Chemistry
Research subject
Infectious Diseases
Identifiers
urn:nbn:se:uu:diva-362335 (URN)10.1016/j.ejmech.2018.08.086 (DOI)000447480000096 ()30196059 (PubMedID)
Funder
Swedish Research Council, 2014-6711Swedish Research Council, 2015-05406Swedish Research Council, 2017-03953
Available from: 2018-10-03 Created: 2018-10-03 Last updated: 2018-12-11Bibliographically approved
Karim, A., Schulz, N., Andersson, H., Nekoueishahraki, B., Carlsson, A.-C. C., Sarabi, D., . . . Erdélyi, M. (2018). Carbon's Three-Center, Four-Electron Tetrel Bond, Treated Experimentally. Journal of the American Chemical Society, 140(50), 17571-17579
Open this publication in new window or tab >>Carbon's Three-Center, Four-Electron Tetrel Bond, Treated Experimentally
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2018 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 140, no 50, p. 17571-17579Article in journal (Refereed) Published
Abstract [en]

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

National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-373369 (URN)10.1021/jacs.8b09367 (DOI)000454383400038 ()30484646 (PubMedID)
Funder
Swedish Research Council, ME 2016:03602
Available from: 2019-01-15 Created: 2019-01-15 Last updated: 2019-01-15Bibliographically approved
Wieske, H., Danelius, E., Peintner, S., Kihlberg, J. & Erdélyi, M. (2018). Conformational Analysis of Rifampicin in Solution. In: : . Paper presented at 1st National Meeting of the Swedish Chemical Society, Lund, 17-20 June, 2018.
Open this publication in new window or tab >>Conformational Analysis of Rifampicin in Solution
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2018 (English)Conference paper, Poster (with or without abstract) (Other academic)
Abstract [en]

Rifampicin is a macrocyclic drug used to treat bacterial infections.1 With a mass of 823 Da, rifampicin violates the Lipinki’s rule of five (Ro5),2 and therefore would be expected to have poor membrane permeability, and hence to not be applicable as an oral therapeutic agent. Despite this fact, rifampicin has proven to reach its target in a biological system and thus is able to pass multiple cell membranes without major problems. We hypothesize that the permeability of rifampicin may be explained by its molecular flexibility. We have therefore determined the conformational ensembles of rifampicin in aqueous and in chloroform solutions using the NMR Analysis of Molecular Flexibility in Solution (NAMFIS) approach.3 Comparing the ensembles present in environments possessing different polarities, we hypothesized that simultaneous aqueous solubility and membrane permeability of rifampicin may be explained by its ability to adjust its conformation to the molecular environment. In this presentation the ensemble analysis of rifampicin in polar and non-polar media will be disclosed, and the results will be discussed in relation to the above hypothesis on its permeability. We propose that this macrocycle folds into a conformation with its hydrophilic groups being better shielded from the hydrophobic membrane when it crosses a membrane, whereas it makes its polar functions solvent accessible in a polar environment (Fig. 1).

National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-355761 (URN)
Conference
1st National Meeting of the Swedish Chemical Society, Lund, 17-20 June, 2018
Available from: 2018-07-04 Created: 2018-07-04 Last updated: 2018-08-01Bibliographically approved
Wieske, H., Danelius, E., Peintner, S., Kihlberg, J. & Erdélyi, M. (2018). Conformational Analysis of Rifampicin in Solution.. In: : . Paper presented at NMR Practical Course 2018 - Multidimensional NMR in Structural Biology.
Open this publication in new window or tab >>Conformational Analysis of Rifampicin in Solution.
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2018 (English)Conference paper, Poster (with or without abstract) (Other academic)
Abstract [en]

Rifampicin is a macrocyclic drug used to treat bacterial infections.1 With a mass of 823 Da, rifampicin violates the Lipinki’s rule of five (Ro5),2 and therefore would be expected to have poor membrane permeability, and hence to not be applicable as an oral therapeutic agent. Despite this fact, rifampicin has proven to reach its target in a biological system and thus is able to pass multiple cell membranes without major problems. We hypothesize that the permeability of rifampicin may be explained by its molecular flexibility. We have therefore determined the conformational ensembles of rifampicin in aqueous and in chloroform solutions using the NMR Analysis of Molecular Flexibility in Solution (NAMFIS) approach.3 Comparing the ensembles present in environments possessing different polarities, we hypothesized that simultaneous aqueous solubility and membrane permeability of rifampicin may be explained by its ability to adjust its conformation to the molecular environment. In this presentation the ensemble analysis of rifampicin in polar and non-polar media will be disclosed, and the results will be discussed in relation to the above hypothesis on its permeability. We propose that this macrocycle folds into a conformation with its hydrophilic groups being better shielded from the hydrophobic membrane when it crosses a membrane, whereas it makes its polar functions solvent accessible in a polar environment (Fig. 1).

National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-357668 (URN)
Conference
NMR Practical Course 2018 - Multidimensional NMR in Structural Biology
Available from: 2018-08-20 Created: 2018-08-20 Last updated: 2018-08-20
Wieske, H., Danelius, E., Peintner, S., Kihlberg, J. & Erdélyi, M. (2018). Conformational Analysis of Rifampicin in Solution. In: : . Paper presented at International School of Biological Magnetic Resonance.
Open this publication in new window or tab >>Conformational Analysis of Rifampicin in Solution
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2018 (English)Conference paper, Oral presentation only (Other academic)
Abstract [en]

Rifampicin is a macrocyclic drug used to treat bacterial infections.1 With a mass of 823 Da, rifampicin violates the Lipinki’s rule of five (Ro5),2 and therefore would be expected to have poor membrane permeability, and hence to not be applicable as an oral therapeutic agent. Despite this fact, rifampicin has proven to reach its target in a biological system and thus is able to pass multiple cell membranes without major problems. We hypothesize that the permeability of rifampicin may be explained by its molecular flexibility. We have therefore determined the conformational ensembles of rifampicin in aqueous and in chloroform solutions using the NMR Analysis of Molecular Flexibility in Solution (NAMFIS) approach.3 Comparing the ensembles present in environments possessing different polarities, we hypothesized that simultaneous aqueous solubility and membrane permeability of rifampicin may be explained by its ability to adjust its conformation to the molecular environment. In this presentation the ensemble analysis of rifampicin in polar and non-polar media will be disclosed, and the results will be discussed in relation to the above hypothesis on its permeability. We propose that this macrocycle folds into a conformation with its hydrophilic groups being better shielded from the hydrophobic membrane when it crosses a membrane, whereas it makes its polar functions solvent accessible in a polar environment (Fig. 1).

National Category
Natural Sciences
Research subject
Chemistry with specialization in Organic Chemistry; Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-357667 (URN)
Conference
International School of Biological Magnetic Resonance
Available from: 2018-08-20 Created: 2018-08-20 Last updated: 2018-08-22Bibliographically approved
Poongavanam, V., Danelius, E., Peintner, S., Alcaraz, L., Caron, G., Cummings, M. D., . . . Kihlberg, J. (2018). Conformational Sampling of Macrocyclic Drugs in Different Environments: Can We Find the Relevant Conformations?. ACS OMEGA, 3(9), 11742-11757
Open this publication in new window or tab >>Conformational Sampling of Macrocyclic Drugs in Different Environments: Can We Find the Relevant Conformations?
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2018 (English)In: ACS OMEGA, ISSN 2470-1343, Vol. 3, no 9, p. 11742-11757Article in journal (Refereed) Published
Abstract [en]

Conformational flexibility is a major determinant of the properties of macrocycles and other drugs in beyond rule of 5 (bRo5) space. Prediction of conforrriations is essential for design of drugs in this space, and we have evaluated three tools for conformational sampling of la set of 10 bRo5 drugs and clinical candidates in polar and apolar environments. The distance-geometry based OMEGA was found to yield ensembles spanning larger structure and property spaces than the ensembles obtained by MOE LowModeMD (MOE) and MacroModel (MC). Both MC and OMEGA but not MOE generated different ensembles for polar and apolar environments. All three conforinational search methods generated conformers similar to the crystal structure conformers for 9 of the 10 compounds, with OMEGA performing somewhat better than MOE and MC. MOE and OMEGA found all six conformers of roxithromycin that were identified by NMR in aqueous solutions, whereas only OMEGA sampled the three conformers observed in chloroform. We suggest that characterization of conformers using molecular descriptors, e.g., the radius of gyration and polar surface area, is preferred to energy- or root-mean-square deviation-based methods for selection of biologically relevant conformers in drug discovery in bRo5 space.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2018
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-368119 (URN)10.1021/acsomega.8b01379 (DOI)000446186000140 ()30320271 (PubMedID)
Funder
Swedish Research Council, 2016-05160Swedish Research Council, 2016-03602
Available from: 2018-12-03 Created: 2018-12-03 Last updated: 2018-12-03Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-0359-5970

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