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  • 151.
    Wilcox, Scott
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Erdélyi, Máté
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Probing Halogen Bonding via Paramagnetic Ligand Tagging2018Inngår i: EMBO Course: Multidimensional NMR in Structural Biology, Joachimsthal, 12-17 Aug, 2018, 2018Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Halogen Bonding is a spectacle that has recently received widespread attention, despite the fact that it was discovered over 200 years ago. This fundamental interaction is vastly abundant in today’s world, and a better understanding of it would enable us to both design and improve upon existing drugs, materials and catalysts, to name a few. Halogen bonds (XB) are roughly 180°, non-covalent interactions that exploit the anisotropic electron density of a halogen atom. Analogous to hydrogen bonding, a halogen bond acceptor (being an electron donor in the form of a Lewis base (LB)) and a halogen bond donor (being an electron acceptor consisting of a halogen with a σ-hole) must exist. σ-Holes are electrophilic regions that arise on the opposite tip of an R-X bond in the anti-bonding orbital and to maximise these holes, one can make ‘R’ more electron withdrawing and/or ‘X’ larger with a more diffuse outer electron shell (I > Br > Cl > F).

    Halogen bonding, like many other weak bonding interactions, is incredibly difficult to measure accurately in solution. Thus, we hypothesize that paramagnetic NMR techniques are potentially useful for their detection and characterization. This involves the use of a compound containing free electrons, and when these are subjected to the large magnetic field of an NMR spectrometer, they exhibit unique qualities that one can fruitfully exploit. In these studies, we mainly focus on measuring Pseudocontact Shifts (PCS) that arise from vast spectral broadening due to the free electrons. With this technique, we are able to assess very weak bonding interactions by the detection of small chemical shift differences due to a much larger spectral window than commonly detected.

    In this work, building upon previous studies carried out within the group,[1] we synthesise cyclen-based organic ligands which complex a paramagnetic lanthanide (Ln3+) species. Attached to one amine in the cyclen core, via a linker, is a Lewis Base (or halogen bond acceptor) which is utilised in probing halogen bonding between itself and a free halogen bond donor in solution. Expected PCS measurements will give an accurate value of the weak bonding interaction between donor and acceptor in solution- the resolution of which is something that is simply not possible via classical NMR studies.

  • 152.
    Wilcox, Scott
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Erdélyi, Máté
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Probing Halogen Bonding via Paramagnetic NMR2018Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Halogen Bonding is a spectacle that has recently received widespread attention, despite the fact that it was discovered over 200 years ago. This fundamental interaction is vastly abundant in today’s world, and a better understanding of it would enable us to both design and improve upon existing drugs, materials and catalysts, to name a few. Halogen bonds (XB) are roughly 180°, non-covalent interactions that exploit the anisotropic electron density of a halogen atom. Analogous to hydrogen bonding, a halogen bond acceptor (being an electron donor in the form of a Lewis base (LB)) and a halogen bond donor (being an electron acceptor consisting of a halogen with a σ-hole) must exist. σ-Holes are electrophilic regions that arise on the opposite tip of an R-X bond in the anti-bonding orbital and to maximise these holes, one can make ‘R’ more electron withdrawing and/or ‘X’ larger with a more diffuse outer electron shell (I > Br > Cl > F).Halogen bonding, like many other weak bonding interactions, is incredibly difficult to measure accurately in solution. Thus, we hypothesize that paramagnetic NMR techniques are potentially useful for their detection and characterization. This involves the use of a compound containing free electrons, and when these are subjected to the large magnetic field of an NMR spectrometer, they exhibit unique qualities that one can fruitfully exploit. In these studies, we mainly focus on measuring Pseudocontact Shifts (PCS) that arise from vast spectral broadening due to the free electrons. With this technique, we are able to assess very weak bonding interactions by the detection of small chemical shift differences due to a much larger spectral window than commonly detected.In this work, building upon previous studies carried out within the group,1 we synthesise cyclen-based organic ligands which complex a paramagnetic lanthanide (Ln3+) species. Attached to one amine in the cyclen core is a Lewis Base (or halogen bond acceptor) which is utilised in probing halogen bonding between itself and a free halogen bond donor in solution. Expected PCS measurements will give an accurate value of the weak bonding interaction between donor and acceptor in solution- the resolution of which is something that is simply not possible via classical NMR studies.

  • 153.
    Wu, Gaochan
    et al.
    Shandong Univ, Sch Pharmaceut Sci, Key Lab Chem Biol, Dept Med Chem,Minist Educ, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China.
    Zhao, Tong
    Shandong Univ, Sch Pharmaceut Sci, Key Lab Chem Biol, Dept Med Chem,Minist Educ, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China.
    Kang, Dongwei
    Shandong Univ, Sch Pharmaceut Sci, Key Lab Chem Biol, Dept Med Chem,Minist Educ, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China.
    Zhang, Jian
    Shandong Univ, Sch Pharmaceut Sci, Key Lab Chem Biol, Dept Med Chem,Minist Educ, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China.
    Song, Yuning
    Shandong Univ, Qilu Hosp, Dept Clin Pharm, Jinan 250012, Shandong, Peoples R China.
    Namasivayam, Vigneshwaran
    Univ Bonn, Pharmaceut Chem 2, Pharmaceut Inst, D-53121 Bonn, Germany.
    Kongsted, Jacob
    Univ Southern Denmark, Dept Phys Chem & Pharm, DK-5230 Odense M, Denmark.
    Pannecouque, Christophe
    Katholieke Univ Leuven, Lab Virol & Chemotherapy, Rega Inst Med Res, Herestr 49,Postbus 1043 09-A097, B-3000 Leuven, Belgium.
    De Clercq, Erik
    Katholieke Univ Leuven, Lab Virol & Chemotherapy, Rega Inst Med Res, Herestr 49,Postbus 1043 09-A097, B-3000 Leuven, Belgium.
    Poongavanam, Vasanthanathan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi. Univ Southern Denmark, Dept Phys Chem & Pharm, DK-5230 Odense M, Denmark.
    Liu, Xinyong
    Shandong Univ, Sch Pharmaceut Sci, Key Lab Chem Biol, Dept Med Chem,Minist Educ, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China.
    Zhan, Peng
    Shandong Univ, Sch Pharmaceut Sci, Key Lab Chem Biol, Dept Med Chem,Minist Educ, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China.
    Overview of Recent Strategic Advances in Medicinal Chemistry2019Inngår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 62, nr 21, s. 9375-9414Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introducing novel strategies, concepts, and technologies that speed up drug discovery and the drug development cycle is of great importance both in the highly competitive pharmaceutical industry as well as in academia. This Perspective aims to present a "big-picture" overview of recent strategic innovations in medicinal chemistry and drug discovery.

  • 154. Yamamoto, Sayoko
    et al.
    Yamaguchi, Takumi
    Erdélyi, Máté
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Griesinger, Christian
    Kato, Koichi
    Paramagnetic lanthanide tagging for NMR conformational analyses of N-linked oligosaccharides.2011Inngår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 17, nr 34, s. 9280-2Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Sweet measurement: Paramagnetic tags are proposed as new tools for NMR analyses of carbohydrate conformations. A newly designed, lanthanide‐chelating tag can be attached to the common disaccharide core shared among all N‐linked oligosaccharides (see figure) and thereby provide reliable information on the glycosidic‐linkage conformation. This success opens the door to conformational studies of a variety of sugar chains of biological interest.

  • 155.
    Yan, Jiajie
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Regenerable Organochalcogen Antioxidants: An Explorative Study2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Antioxidants are widely used to protect organic materials from damages caused by autoxidation, an oxidation process that occurs under normal aerobic conditions. In this thesis, novel multifunctional organoselenium and organotellurium antioxidants were designed, synthesized, and evaluated in search for compounds with better radical-trapping capacity, regenerability, and hydroperoxide-decomposing ability.

    Selenium was incorporated into ebselenols and hydroxy-2,3-dihydrobenzo[b]selenophenes and tellurium into diaryl disulfides and aryltellurophenols. All newly developed antioxidants were evaluated in a chlorobenzene/water two-phase lipid peroxidation system containing suitable co-antioxidants in the aqueous phase. Ebselenol carrying a hydroxyl group (OH) ortho to selenium showed a two-fold longer inhibition time than the reference α-tocopherol in the presence of aqueous-phase ascorbic acid. 2,3-Dihydrobenzo[b]selenophenes carrying a 5- or 7-OH outperformed α-tocopherol both when it comes to radical-trapping capacity and regenerability. Alkyltellurothiophenols, in situ formed from their corresponding disulfides by tris(2-carboxyethyl)phosphine, were also efficient regenerable radical-trapping antioxidants. The consumption of N-acetylcysteine in the water phase was followed and found to be limiting for the duration of the inhibition. The hydroperoxide-decomposing ability of all organoselenium antioxidants was evaluated. Ebselenols were often better glutathione peroxidase mimics than the parent.

    In an effort to find out more about antioxidant mechanisms, aryltellurophenols carrying electron donating and electron withdrawing groups in the phenolic or aryltelluro parts were synthesized and OH bond dissociation enthalpies, BDEO-Hs, were calculated. Compounds carrying electron donating groups in the phenolic or aryltelluro part of the molecule showed the best radical-trapping capacity. Deuterium labelling experiments suggested that hydrogen atom transfer could be the rate-limiting step in the antioxidant mechanism.  

    Delarbeid
    1. Multifunctional Antioxidants: Regenerable Radical-Trapping and Hydroperoxide-Decomposing Ebselenols
    Åpne denne publikasjonen i ny fane eller vindu >>Multifunctional Antioxidants: Regenerable Radical-Trapping and Hydroperoxide-Decomposing Ebselenols
    Vise andre…
    2016 (engelsk)Inngår i: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 55, nr 11, s. 3729-3733Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Regenerable, multifunctional ebselenol antioxidants were prepared that could quench peroxyl radicals more efficiently than -tocopherol. These compounds act as better mimics of the glutathione peroxidase enzymes than ebselen. Production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in human mononuclear cells was considerably decreased upon exposure to the organoselenium compounds. At a concentration of 25m, the ebselenol derivatives showed minimal toxicity in pre-osteoblast MC3T3cells.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-280006 (URN)10.1002/anie.201510947 (DOI)000371521000034 ()26879742 (PubMedID)
    Forskningsfinansiär
    Swedish Research CouncilCarl Tryggers foundation , 13:346, 13:120
    Tilgjengelig fra: 2016-03-07 Laget: 2016-03-07 Sist oppdatert: 2017-11-30bibliografisk kontrollert
    2. Chain-Breaking Phenolic 2,3-Dihydrobenzo[b]selenophene Antioxidants: Proximity Effects and Regeneration Studies
    Åpne denne publikasjonen i ny fane eller vindu >>Chain-Breaking Phenolic 2,3-Dihydrobenzo[b]selenophene Antioxidants: Proximity Effects and Regeneration Studies
    Vise andre…
    2017 (engelsk)Inngår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 23, nr 60, s. 15080-15088Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Phenolic 2,3-dihydrobenzo[b]selenophene anti-oxidants carrying the OH-group ortho (9), meta (10, 11) and para (8) to the Se were prepared by seleno-Claisen rearrangement/intramolecular hydroselenation. Meta-isomer (11) was studied by X-ray crystallography. The radical-trapping activity and regenerability of compounds 8-11 were evaluated using a two-phase system where linoleic acid was undergoing peroxidation in the lipid phase while regeneration of the antioxidant by co-antioxidants (N-acetylcysteine, glutathione, dithiothreitol, ascorbic acid, tris(carboxyethyl)phosphine hydrochloride) was ongoing in the aqueous layer. Compound 9 quenched peroxyl radicals

    more efficiently than α-tocopherol. It also provided the most long-lasting antioxidant protection. With thiol co-antioxidants it could inhibit peroxidation for more than five-fold longer than the natural product. Regeneration was more efficient when the aqueous phase pH was slightly acidic. Since calculated O-H bond dissociation energies for 8-11 were substantially larger than for α-tocopherol, an antioxidant mechanism involving O-atom transfer from peroxyl to selenium was proposed. The resulting phenolic selenoxide/alkoxyl radical would then exchange a hydrogen atom in a solvent cage before antioxidant regeneration at the aqueous lipid interphase.

    Emneord
    chain-breaking antioxidants, phenols, dihydrobenzoselenophenes, lipid peroxidation, co-antioxidants
    HSV kategori
    Forskningsprogram
    Kemi med inriktning mot organisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-329201 (URN)10.1002/chem.201702350 (DOI)000413768900018 ()28857289 (PubMedID)
    Tilgjengelig fra: 2017-09-10 Laget: 2017-09-10 Sist oppdatert: 2018-02-23bibliografisk kontrollert
    3. Regenerable thiophenolic radical-trapping antioxidants
    Åpne denne publikasjonen i ny fane eller vindu >>Regenerable thiophenolic radical-trapping antioxidants
    Vise andre…
    2015 (engelsk)Inngår i: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 17, nr 24, s. 6162-6165Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Diphenyl disulfides carrying alkyltelluro groups in the o-, m-, and p-positions were prepared using ortho-lithiation and lithium halogen exchange reactions. The novel antioxidants showed only minimal inhibitory effect on the azo-initiated peroxidation of linoleic acid in chlorobenzene until reduced to the corresponding thiophenols by tris(2-carboxyethyl)phosphine (TCEP). The best in situ generated thiophenol (from 7c) under these conditions quenched peroxyl radicals more efficiently than α-tocopherol with an almost 3-fold increase in inhibition time.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-269896 (URN)10.1021/acs.orglett.5b03169 (DOI)000366878300057 ()
    Forskningsfinansiär
    Swedish Research Council, 621-2011-4006Carl Tryggers foundation , CTS:120
    Tilgjengelig fra: 2015-12-18 Laget: 2015-12-18 Sist oppdatert: 2017-12-01bibliografisk kontrollert
    4. Substituent Effects in Chain-Breaking Aryltellurophenol Antioxidants
    Åpne denne publikasjonen i ny fane eller vindu >>Substituent Effects in Chain-Breaking Aryltellurophenol Antioxidants
    Vise andre…
    2018 (engelsk)Inngår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 24, nr 14, s. 3520-3527Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    2-Aryltellurophenols substituted in the aryltelluro or phenolic part of the molecule were prepared by lithiation of the corresponding O-THP-protected 2-bromophenol, followed by reaction with a suitable diaryl ditelluride and deprotection. In a two-phase system containing N-acetylcysteine as a co-antioxidant in the aqueous phase, all compounds quenched lipid peroxyl radicals more efficiently than α-tocopherol with 3 to 5-fold longer inhibition times. Compounds carrying electron donating para-substituents in the phenolic or aryltelluro part of the molecule showed the best results. The mechanism for quenching of peroxyl radicals was discussed in the light of calculated OH bond dissociation energies, deuterium labeling experiments and studies of thiol-consumption in the aqueous phase. 

    HSV kategori
    Forskningsprogram
    Kemi med inriktning mot organisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-329202 (URN)10.1002/chem.201704811 (DOI)000426764400024 ()29266496 (PubMedID)
    Forskningsfinansiär
    Stiftelsen Olle Engkvist Byggmästare, 1016/159ÅForsk (Ångpanneföreningen's Foundation for Research and Development), 16-364
    Merknad

    Poon, J. and Yan, J. are equally contributing.

    Tilgjengelig fra: 2017-09-10 Laget: 2017-09-10 Sist oppdatert: 2018-05-22bibliografisk kontrollert
  • 156.
    Yang, Dong
    et al.
    Northwest Univ, Coll Chem & Mat Sci, Key Lab Synthet & Nat Funct Mol Chem, Minist Educ, Xian 710069, Peoples R China..
    Zhao, Jie
    Northwest Univ, Coll Chem & Mat Sci, Key Lab Synthet & Nat Funct Mol Chem, Minist Educ, Xian 710069, Peoples R China..
    Yu, Le
    Northwest Univ, Coll Chem & Mat Sci, Key Lab Synthet & Nat Funct Mol Chem, Minist Educ, Xian 710069, Peoples R China..
    Lin, Xiangsong
    Jiaxing Univ, Sch Mat & Text Engn, Jiaxing 314001, Peoples R China..
    Zhang, Wenyao
    Northwest Univ, Coll Chem & Mat Sci, Key Lab Synthet & Nat Funct Mol Chem, Minist Educ, Xian 710069, Peoples R China..
    Ma, Hongwei
    Beijing Inst Technol, Anal & Testing Ctr, Beijing 102488, Peoples R China..
    Gogoll, Adolf
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Zhang, Zhibin
    Northwest Univ, Coll Chem & Mat Sci, Key Lab Synthet & Nat Funct Mol Chem, Minist Educ, Xian 710069, Peoples R China..
    Wang, Yaoyu
    Northwest Univ, Coll Chem & Mat Sci, Key Lab Synthet & Nat Funct Mol Chem, Minist Educ, Xian 710069, Peoples R China..
    Yang, Xiao-Juan
    Northwest Univ, Coll Chem & Mat Sci, Key Lab Synthet & Nat Funct Mol Chem, Minist Educ, Xian 710069, Peoples R China..
    Wu, Biao
    Northwest Univ, Coll Chem & Mat Sci, Key Lab Synthet & Nat Funct Mol Chem, Minist Educ, Xian 710069, Peoples R China..
    Air- and Light-Stable P-4 and As-4 within an Anion-Coordination-Based Tetrahedral Cage2017Inngår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 139, nr 16, s. 5946-5951Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In contrast to the stable dinitrogen molecule, white phosphorus (P-4) and yellow arsenic (As-4) are very reactive allotropic modifications of these two heavier pnictogen elements, which has greatly hampered the study of their properties and applications. Thus, the safe storage and transport of them is imperative. Supramolecular caged structures are one of the most efficient approaches for the encapsulation and stabilization of reactive species; however, their use in the P-4 and As-4 chemistry is very rare. In the current work, we demonstrate a new design strategy for constructing finite cages and including guests based on anion coordination chemistry. The phosphate-coordination-based tetrahedral cages can readily accommodate the tetrahedral guests P-4 and As-4, which is facilitated by the shape and size complementarity as well as favorable sigma-pi and lone-pair-pi interactions. Moreover, the latter case represents the first example of As-4 inclusion in a well-defined tetrahedral cage.

  • 157.
    Yang, Jie
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Gustavsson, Anna-Lena
    Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, CBCS, Stockholm, Sweden..
    Haraldsson, Martin
    Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, CBCS, Stockholm, Sweden..
    Karlsson, Göran
    Gothenburg Univ, Swedish NMR Ctr, Gothenburg, Sweden..
    Norberg, Thomas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Baltzer, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    High-affinity recognition of the human C-reactive protein independent of phosphocholine2017Inngår i: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 15, nr 21, s. 4644-4654Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A high-affinity polypeptide conjugate 4-C25L22-DQ, has been developed for the molecular recognition of the human C-reactive protein, CRP, a well-known inflammation biomarker. CRP is one of the most frequently quantified targets in diagnostic applications and a target in drug development. With the exception of antibodies, most molecular constructs take advantage of the known affinity for CRP of phosphocholine that depends on Ca2+ for its ability to bind. 4-C25L22-DQ which is unrelated to phosphocholine binds in the absence of Ca2+ with a dissociation constant of 760 nM, an order of magnitude lower than that of phosphocholine, the KD of which is 5 μM. The small organic molecule 2-oxo-1,2-dihydroquinoline-8-carboxylic acid (DQ) was designed based on the structural similarities between three hits from a set of compounds selected from a building block collection and evaluated with regards to affinity for CRP by NMR spectroscopy. 4-C25L22-DQ was shown in a competition experiment to bind CRP three orders of magnitude more strongly than DQ itself, and in a pull-down experiment 4-C25L22-DQ was shown to extract CRP from human serum. The development of a robust and phosphocholine-independent recognition element provides unprecedented opportunities in bioanalytical applications in vivo and in vitro under conditions where the concentration of Ca2+ ions is low, or where Ca2+ binding agents such as EDTA or heparin are needed to prevent blood coagulation. The identification from a compound library of a small organic molecule and its conjugation to a small set of polypeptides, none of which were previously known to bind CRP, illustrates a convenient and general route to selective high-affinity binders for proteins with dissociation constants in the μM to nM range for which no small molecule ligands are known.

  • 158.
    Yang, Jie
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Koruza, Katarina
    Fisher, Zoë
    Knecht, Wolfgang
    Baltzer, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Improved molecular recognition of Carbonic Anhydrase IX by polypeptide conjugation to acetazolamide2017Inngår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 25, nr 20, s. 5838-5848Artikkel i tidsskrift (Fagfellevurdert)
  • 159.
    Yang, Li
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Huang, Xiao
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Gogoll, Adolf
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Strömme, Maria
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Sjödin, Martin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Conducting Redox Polymer Based Anode Materials for High Power Electrical Energy Storage2016Inngår i: Electrochimica Acta, ISSN 0013-4686, E-ISSN 1873-3859, Vol. 204, s. 270-275Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In this report we present the synthesis and characterization of two conducting redox polymers (CRPs) with polythiophene backbone and diethyl terephthalate pendant groups for the use as anode materials in secondary batteries. The materials show excellent rate capability allowing 301,Lm layers to be fully converted within seconds without the use of conductive additives. The high rate capability is traced to the open morphology of the materials that allows for fast ion transport, and to the mediation of electrons through the conducting polymer (CP) backbone. The requirements for the latter are i) that the redox chemistry of the pendant groups and the CP backbone overlaps and ii) that the CP conductivity is not compromised by the presence of the pendant groups. In the CRPs presented herein both these requirements are met and this is thus the first report on successful combination of the redox chemistry of organic redox molecules with the n-doping of conducting polymers.

  • 160.
    Yang, Li
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Huang, Xiao
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Gogoll, Adolf
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Strømme, Maria
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Sjödin, Martin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Effect of the Linker in Terephthalate-Functionalized Conducting Redox Polymers2016Inngår i: Electrochimica Acta, ISSN 0013-4686, E-ISSN 1873-3859, Vol. 222, s. 149-155Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Abstract The combination of high capacity redox active pendent groups and conducting polymers, realized in conducting redox polymers (CRPs), provides materials with high charge storage capacity that are electronically conducting which makes CRPs attractive for electrical energy storage applications. In this report, six polythiophene and poly(3,4-ethylenedioxythiophene)(PEDOT)-based CRPs with a diethyl terephthalate unit covalently bound to the polymer chain by various linkers have been synthesized and characterized electrochemically. The effects of the choice of polymer backbone and of the nature of the link on the electrochemistry, and in particular the cycling stability of these polymers, are discussed. All CRPs show both the doping of the polymer backbone as well as the redox behavior of the pendent groups and the redox potential of the pendent groups in the CRPs is close to that of corresponding monomer, indicating insignificant interaction between the pendant and the polymer backbone. While all CRPs show various degrees of charge decay upon electrochemical redox conversion, the PEDOT-based CRPs show significantly improved stability compared to the polythiophene counterparts. Moreover, we show that by the right choice of link the cycling stability of diethyl terephthalate substituted PEDOT-based CRPs can be significantly improved.

  • 161.
    Yang, Li
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Huang, Xiao
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Mamedov, Fikret
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Molekylär biomimetik.
    Zhang, Peng
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Gogoll, Adolf
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Strömme, Maria
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Sjödin, Martin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material. Department of Applied Chemistry, Waseda University, Tokyo 169-8555, Japan.
    Conducting redox polymers with non-activated charge transport properties2017Inngår i: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 19, nr 36, s. 25052-25058Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Non-activated charge transport has been demonstrated in terephthalate-functionalized conducting redox polymers. The transition from a temperature-activated conduction mechanism to a residual scattering mechanism was dependent on the doping level. The latter mechanism is associated with apparent negative activation barriers to charge transport and is generally found in polymer materials with a high degree of order. Crystallographic data, however, suggested a low degree of order in this polymer, indicating the existence of interconnected crystal domains in the predominantly amorphous polymer matrix through which the charge was transported. We have thus shown that the addition of bulky pendant groups to conducting polymers does not prevent efficient charge transport via the residual scattering mechanism with low barriers to charge transport.

  • 162.
    Yang, Min
    et al.
    Karolinska Inst, Sect Med Inflammat Res, Dept Med Biochem & Biophys, Scheeles Vag 2, S-17177 Stockholm, Sweden..
    Haase, Claus
    Novo Nordisk AS, Global Res, DK-2880 Bagsvaerd, Denmark..
    Viljanen, Johan V.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Xu, Bingze
    Karolinska Inst, Sect Med Inflammat Res, Dept Med Biochem & Biophys, Scheeles Vag 2, S-17177 Stockholm, Sweden..
    Ge, Changrong
    Karolinska Inst, Sect Med Inflammat Res, Dept Med Biochem & Biophys, Scheeles Vag 2, S-17177 Stockholm, Sweden..
    Kihlberg, Jan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Holmdahl, Rikard
    Karolinska Inst, Sect Med Inflammat Res, Dept Med Biochem & Biophys, Scheeles Vag 2, S-17177 Stockholm, Sweden.;Southern Med Univ, Ctr Med Immunopharmacol Res, Guangzhou 510515, Guangdong, Peoples R China..
    Cutting Edge: Processing of Oxidized Peptides in Macrophages Regulates T Cell Activation and Development of Autoimmune Arthritis2017Inngår i: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 199, nr 12, s. 3937-3942Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    APCs are known to produce NADPH oxidase (NOX) 2-derived reactive oxygen species; however, whether and how NOX2-mediated oxidation affects redox-sensitive immunogenic peptides remains elusive. In this study, we investigated a major immunogenic peptide in glucose-6-phosphate isomerase (G6PI), a potential autoantigen in rheumatoid arthritis, which can form internal disulfide bonds. Ag presentation assays showed that presentation of this G6PI peptide was more efficient in NOX2-deficient (Ncf1(m1J/m1J) mutant) mice, compared with wild-type controls. IFN-gamma-inducible lysosomal thiol reductase (GILT), which facilitates disulfide bond-containing Ag processing, was found to be upregulated in macrophages from Ncf1 mutant mice. Ncf1 mutant mice exhibited more severe G6PI peptide-induced arthritis, which was accompanied by the increased GILT expression in macrophages and enhanced Ag-specific T cell responses. Our results show that NOX2-dependent processing of the redox-sensitive autoantigens by APCs modify T cell activity and development of autoimmune arthritis.

  • 163. Yaouba, Souaibou
    et al.
    Valkonen, Arto
    Coghi, Paolo
    Gao, Jiaying
    Guantai, Eric M
    Derese, Solomon
    Wong, Vincent K W
    Erdélyi, Máté
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi. The Swedish NMR Centre, Gothenburg, Sweden; Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden .
    Yenesew, Abiy
    Crystal Structures and Cytotoxicity of ent-Kaurane-Type Diterpenoids from Two Aspilia Species.2018Inngår i: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 23, nr 12, artikkel-id 3199Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A phytochemical investigation of the roots of Aspilia pluriseta led to the isolation of ent-kaurane-type diterpenoids and additional phytochemicals (123). The structures of the isolated compounds were elucidated based on Nuclear Magnetic Resonance (NMR) spectroscopic and mass spectrometric analyses. The absolute configurations of seven of the ent-kaurane-type diterpenoids (36, 6b, 7 and 8) were determined by single crystal X-ray diffraction studies. Eleven of the compounds were also isolated from the roots and the aerial parts of Aspilia mossambicensis. The literature NMR assignments for compounds 1 and 5 were revised. In a cytotoxicity assay, 12α-methoxy-ent-kaur-9(11),16-dien-19-oic acid (1) (IC50 = 27.3 ± 1.9 µM) and 9β-hydroxy-15α-angeloyloxy-ent-kaur-16-en-19-oic acid (3) (IC50 = 24.7 ± 2.8 µM) were the most cytotoxic against the hepatocellular carcinoma (Hep-G2) cell line, while 15α-angeloyloxy-16β,17-epoxy-ent-kauran-19-oic acid (5) (IC50 = 30.7 ± 1.7 µM) was the most cytotoxic against adenocarcinomic human alveolar basal epithelial (A549) cells.

  • 164.
    Yngve, Ulrika
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Khan, Tanweera Shaheena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Bergström, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Långstrom, Bengt
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Labelling of octreotide using Br-76-prosthetic groups2001Inngår i: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 44, nr 8, s. 561-573Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A method for labelling the octapeptide octreotide (D-Phe-Cys-Phe-D-TrpLys-Thr-Cys-Thr(ol)) with the positron emitting Br-76 (T-1/2 = 16 h) is presented. epsilon -Boc-protected octreotide was conjugated to N-succinimidyl 4-[Br-76]bromobenzoate 1 and N-succinimidyl 5-[Br-76]bromo-3-pyridinecarboxylate 3 using microwave heating. The conjugates 4 and 5 were isolated in 50-55% radiochemical yield after the removal of the protecting Boc-group. Compound 3 was synthesised from the corresponding trimethylstannyl-precursor in 25% radiochemical yield. The synthesis of methyl-4-[Br-76] bromobenzimidate 8 in 40% radiochemical yield from the precursor methyl -4-trimethylstannylbenzimidate is also described. Experiments were performed to react 8 with Boc-octreotide but no product was obtained. The binding-properties of Br-76-conjugates 4 and 5 to meningiomas were investigated using frozen section autoradiography. Compound 5 showed better binding properties than 4.

  • 165.
    Zhang, Jian
    et al.
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Poongavanam, Vasanthanathan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi. Univ Southern Denmark, Dept Phys Chem & Pharm, DK-5230 Odense M, Denmark..
    Kang, Dongwei
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Bertagnin, Chiara
    Univ Padua, Dept Mol Med, Via Gabelli 63, I-35121 Padua, Italy..
    Lu, Huamei
    Shandong Acad Agr Sci, Inst Poultry Sci, 1 Jiaoxiao Rd, Jinan 250023, Shandong, Peoples R China..
    Kong, Xiujie
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Ju, Han
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Lu, Xueyi
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Gao, Ping
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Tian, Ye
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Jia, Haiyong
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Desta, Samuel
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Ding, Xiao
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Sun, Lin
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Fang, Zengjun
    Shandong Univ, Hosp 2, 247 Beiyuan Ave, Jinan 250033, Shandong, Peoples R China..
    Huang, Boshi
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Liang, Xuewu
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Jia, Ruifang
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Ma, Xiuli
    Shandong Acad Agr Sci, Inst Poultry Sci, 1 Jiaoxiao Rd, Jinan 250023, Shandong, Peoples R China..
    Xu, Wenfang
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Murugan, Natarajan Arul
    KTH Royal Inst Technol, Sch Biotechnol, Div Theoret Chem & Biol, S-10691 Stockholm, Sweden..
    Loregian, Arianna
    Univ Padua, Dept Mol Med, Via Gabelli 63, I-35121 Padua, Italy..
    Huang, Bing
    Shandong Acad Agr Sci, Inst Poultry Sci, 1 Jiaoxiao Rd, Jinan 250023, Shandong, Peoples R China..
    Zhan, Peng
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Liu, Xinyong
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Optimization of N-Substituted Oseltamivir Derivatives as Potent Inhibitors of Group-1 and-2 Influenza A Neuraminidases, Including a Drug-Resistant Variant2018Inngår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, nr 14, s. 6379-6397Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    On the basis of our earlier discovery of N1-selective inhibitors, the 150-cavity of influenza virus neuraminidases (NAs) could be further exploited to yield more potent oseltamivir derivatives. Among the synthesized compounds, 15b and 15c were exceptionally active against both group-1 and -2 NAs. Especially for 09N1, N2, N6, and N9 subtypes, they showed 6.80-12.47 and 1.20-3.94 times greater activity than oseltamivir carboxylate (OSC). They also showed greater inhibitory activity than OSC toward H274Y and E119V variant. In cellular assays, they exhibited greater potency than OSC toward H5N1, H5N2, H5N6, and H5N8 viruses. 15b demonstrated high metabolic stability, low cytotoxicity in vitro, and low acute toxicity in mice. Computational modeling and molecular dynamics studies provided insights into the role of R group of 15b in improving potency toward group-1 and -2 NAs. We believe the successful exploitation of the 150-cavity of NAs represents an important breakthrough in the development of more potent anti-influenza agents.

  • 166.
    Zhou, Yang
    et al.
    AlbaNova Univ Ctr, KTH Royal Inst Technol, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden.
    Zou, Rongfeng
    AlbaNova Univ Ctr, KTH Royal Inst Technol, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden.
    Kuang, Guanglin
    AlbaNova Univ Ctr, KTH Royal Inst Technol, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden.
    Långström, Bengt
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Halldin, Christer
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, S-17176 Stockholm, Sweden;Stockholm Cty Council, S-17176 Stockholm, Sweden.
    Ågren, Hans
    AlbaNova Univ Ctr, KTH Royal Inst Technol, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden;Henan Univ, Coll Chem & Chem Engn, Kaifeng 475004, Henan, Peoples R China.
    Tu, Yaoquan
    AlbaNova Univ Ctr, KTH Royal Inst Technol, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden.
    Enhanced Sampling Simulations of Ligand Unbinding Kinetics Controlled by Protein Conformational Changes2019Inngår i: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 59, nr 9, s. 3910-3918Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Understanding unbinding kinetics of protein-ligand systems is of great importance for the design of ligands with desired specificity and safety. In recent years, enhanced sampling techniques have emerged as effective tools for studying unbinding kinetics of protein-ligand systems at the atomistic level. However, in many protein-ligand systems, the ligand unbinding processes are strongly coupled to protein conformational changes and the disclosure of the hidden degrees of freedom closely related to the protein conformational changes so that sampling is enhanced over these degrees of freedom remains a great challenge. Here, we show how potential-scaled molecular dynamics (sMD) and infrequent metadynamics (InMetaD) simulation techniques can be combined to successfully reveal the unbinding mechanism of 3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-[F-18]fluorodibenzo[b,d]thiophene 5,5-dioxide ([F-18]ASEM) from a chimera structure of the alpha 7-nicotinic acetylcholine receptor. By using sMD simulations, we disclosed that the "close to "open" conformational change of loop C plays a key role in the ASEM unbinding process. By carrying out InMetaD simulations with this conformational change taken into account as an additional collective variable, we further captured the key states in the unbinding process and clarified the unbinding mechanism of ASEM from the protein. Our work indicates that combining sMD and InMetaD simulation techniques can be an effective approach for revealing the unbinding mechanism of a protein-ligand system where protein conformational changes control the unbinding process.

  • 167.
    Zou, Rongfeng
    et al.
    AlbaNova Univ Ctr, Royal Inst Technol KTH, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden.
    Kuang, Guanglin
    AlbaNova Univ Ctr, Royal Inst Technol KTH, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden.
    Ågren, Hans
    AlbaNova Univ Ctr, Royal Inst Technol KTH, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden;Henan Univ, Coll Chem & Chem Engn, Kaifeng 475004, Henan, Peoples R China.
    Nordberg, Agneta
    Karolinska Univ Hosp, Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res,Clin Geriatr Neo & Theme Aging, S-14183 Huddinge, Sweden.
    Långström, Bengt
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Tu, Yaoquan
    AlbaNova Univ Ctr, Royal Inst Technol KTH, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden.
    Free Energy Profile for Penetration of Pittsburgh Compound-B into the Amyloid β Fibril2019Inngår i: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 10, nr 3, s. 1783-1790Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The amyloid β (Aβ) fibril is a hallmark of Alzheimer's disease (AD) and has therefore served as an important target for early diagnosis of AD. The Pittsburgh Compound-B (PiB) is one of the most famous positron emission tomography (PET) tracers commonly used for in vivo detection of Aβ fibrils. Many theoretical studies have predicted the existence of various core binding sites with different microenvironments for probes binding to the Aβ fibril. However, little attention has been devoted to how the probes actually penetrate into the different core binding sites. In this study, an integrated molecular modeling scheme is used to study the penetration of PiB into the core binding sites of the Aβ1-42 fibril structure recently obtained by cryogenic electron microscopy. We find that there are two core binding sites for PiB with dramatic differences in cavity size and microenvironment properties, and furthermore that the penetration of PiB into site-1 is energetically prohibitive, whereas the penetration into site 2 is much more favorable. Therefore, the binding capacity at site-2 may be larger than that at site-1 despite its lower binding affinity. Our results thus suggest that site-2 may be a major binding site for PiB binding to Aβ fibril and emphasize the importance to adopt a full dynamical picture when studying tracer fibril binding problems in general, something that in turn can be used to guide the development of tracers with higher affinity and selectivity for the Aβ fibril.

1234 151 - 167 of 167
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