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  • 1.
    Adrian Meredith, Jenny
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Björklund, Catarina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Adolfsson, Hans
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Edlund, Michael
    Jansson, Katarina
    Lindberg, Jimmy
    Vrang, Lotta
    Hallberg, Anders
    Institutionen för läkemedelskemi, Uppsala universitet.
    Rosenquist, Åsa
    Samuelsson, Bertil
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Design and Synthesis of BACE-1 Inhibitors Containing a New Hydroxyethylene (HE) Scaffold: Potent activities in a cellular assayManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    In a preceding report from our group we disclosed the development of a novel HE transition state isostere with a difluorophenoxymethyl side chain in the P1 position and a methoxy group in the P1’ position furnishing highly potent inhibitors of BACE-1 (i.e. lead compound 1), which moreover exhibit very promising selectivity over cathepsin D. In a continuation of this work with the aim at improving on the cell-based activity and pharmacokinetic properties, we have further developed the SAR for the P1 side chain of inhibitor 1 whereby the P1 side chain oxygen has been substituted for an amine, a carbon or a bond. The chemistry developed for the previous HE inhibitor structure 1 has now been extended to readily accommodate the introduction of new P1 side chains into this new HE scaffold. These modifications have given rise to several highly potent inhibitors where the most potent displayed a BACE-1 Ki value of 0.2 nM and a cell-based Aβ40 IC50 value of 9 nM. Thus, regarding the enzyme inhibition in the cell assay a more than 600-fold improvement compared to compound 1 was achieved via minor structural alterations.

  • 2.
    Adrian Meredith, Jenny
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Björklund, Catarina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Adolfsson, Hans
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Jansson, Katarina
    Hallberg, Anders
    Institutionen för läkemedelskemi, Uppsala universitet.
    Rosenquist, Åsa
    Samuelsson, Bertil
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    P2’-truncated BACE-1 inhibitors with a novel hydroxethylene-like core2010Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 45, nr 2, s. 542-554Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Highly potent BACE-1 protease inhibitors derived from a novel hydroxyethylene-like core structure were recently developed by our group using X-ray crystal structure data and molecular modelling. In a continuation of this work guided by molecular modelling we have explored a truncated core motif where the P2’ amide group is replaced by an ether linkage resulting in a set of alkoxy, aryloxy and alkylaryl groups, with the overall aim to reduce molecular weight and the number of amide bonds to increase permeability and bestow the inhibitors with drug-like features. The most potent of these inhibitors displayed a BACE-1 IC50 value of 140 nM. The synthesis of these BACE-1 inhibitors utilizes readily available starting materials, furnishing the target compounds in good overall yields.

  • 3.
    Adrian Meredith, Jenny
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Wallberg, Hans
    Vrang, Lotta
    Oscarson, Stefan
    Centre for Synthesis and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland.
    Parkes, Kevin
    Hallberg, Anders
    Institutionen för läkemedelskemi, Uppsala universitet.
    Samuelsson, Bertil
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Design and Synthesis of Novel P2 Substituents in Diol-based HIV Protease Inhibitors2010Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 45, nr 1, s. 160-170Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The synthesis and SAR of HIV-1 protease inhibitors containing novel P2 structural elements are presented. The inhibitors were designed having hydrogen bond accepting P2 substituents to probe potential favorable interactions to Asp-29/Asp-30 of the HIV-1 protease backbone utilizing inhibitor 3 as a model template. Several inhibitors were synthesized from an L-Val-methylamide P2 motif by appending hydrogen bonding moieties from either the isopropyl side chain or from the methylamide portion. The most promising inhibitors 4a and 4e displayed Ki values of 1.0 nM and 0.7 nM respectively and EC50 values in the MT4 cell-based assay of 0.17 µM and 0.33 µM respectively, a slight loss in potency compared to lead inhibitor 3. These inhibitors were also tested against an HIV protease inhibitor resistant strain carrying the M46I, V82F, and I84V mutations. Inhibitors 4a and 4e displayed a 3 and 4 fold change respectively compared with HIV wild type, whereas lead inhibitor 3 showed a higher 9 fold change. This study further demonstrate the chemical tractability of the approach where various P2 substituents can be introduced in just one chemical step from lactone x enabling facile modifications of the overall properties in this inhibitor class.

  • 4.
    Aydin, Juhanes
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Senthil, Kumar K
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Sayah, Mahmoud J
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Wallner, Olov A
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Szabó, Kálmán J
    Synthesis and catalytic application of chiral 1,1'-Bi-2-naphthol- and biphenanthrol-based pincer complexes: selective allylation of sulfonimines with allyl stannane and allyl trifluoroborate.2007Ingår i: Journal of Organic Chemistry, Vol. 72, nr 13, s. 4689-4697Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    New easily accessible 1,1'-bi-2-naphthol- (BINOL-) and biphenanthrol-based chiral pincer complex catalysts were prepared for selective (up to 85% enantiomeric excess) allylation of sulfonimines. The chiral pincer complexes were prepared by a flexible modular approach allowing an efficient tuning of the selectivity of the catalysts. By employment of the different enantiomeric forms of the catalysts, both enantiomers of the homoallylic amines could be selectively obtained. Both allyl stannanes and allyl trifluoroborates can be employed as allyl sources in the reactions. The biphenanthrol-based complexes gave higher selectivity than the substituted BINOL-based analogues, probably because of the well-shaped chiral pocket generated by employment of the biphenanthrol complexes. The enantioselective allylation of sulfonimines presented in this study has important implications for the mechanism given for the pincer complex-catalyzed allylation reactions, confirming that this process takes place without involvement of palladium(0) species.

  • 5.
    Aydin, Juhanes
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Szabó, Kálmán
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Palladium-pincer complex catalyzed C-C coupling of allyl nitriles with tosyl imines via regioselective allylic C-H bond functionalization2008Ingår i: Organic Letters, ISSN 1523-7060, Vol. 10, nr 13, s. 2881-2884Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A mechanistically new palladium-pincer complex catalyzed allylation of sulfonimines is presented. This reaction involves C-H bond functionalization of allyl nitriles under mild conditions. The reaction proceeds with a high regioselectivity, without allyl rearrangement of the product. Modeling studies indicate that the carbon-carbon bond formation process proceeds via (η1-allyl)palladium pincer complex intermediates.

  • 6.
    Ayesa, Susana
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Lindquist, Charlotta
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Agback, Tatiana
    Benkestock, Kurt
    Classon, Björn
    Henderson, Ian
    Hewitt, Ellen
    Jansson, Katarina
    Kallin, Anders
    Sheppard, Dave
    Samuelsson, Bertil
    Solid-phase parallel synthesis and SAR of 4-amidofuran-3-one inhibitors of cathepsin S: Effect of sulfonamides P3 substituents on potency and selectivity.2009Ingår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 17, nr 3, s. 1307-1324Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Highly potent and selective 4-amidofuran-3-one inhibitors of cathepsin S are described. The synthesis and structure–activity relationship of a series of inhibitors with a sulfonamide moiety in the P3 position is presented. Several members of the series show sub-nanomolar inhibition of the target enzyme as well as an excellent selectivity profile and good cellular potency. Molecular modeling of the most interesting inhibitors describes interactions in the extended S3 pocket and explains the observed selectivity towards cathepsin K.

  • 7.
    Bielawski, Marcin
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Olofsson, Berit
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Efficient one-pot synthesis of bis(4-tert-butylphenyl)iodonium triflate2009Ingår i: Organic Syntheses, ISSN 0078-6209, Vol. 86, s. 308-314Artikel i tidskrift (Refereegranskat)
  • 8.
    Björklund, Catarina
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Adolfsson, Hans
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Jansson, Katarina
    Lindberg, Jimmy
    Vrang, Lotta
    Hallberg, Anders
    Rosenquist, Åsa
    Samuelsson, Bertil
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Discovery of Potent BACE-1 Inhibitors Containing a New Hydroxyethylene (HE) Scaffold: Exploration of P1’ Alkoxy Residues and an Aminoethylene (AE) Central Core2010Ingår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 18, nr 4, s. 1711-1723Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In a preceding study we have described the development of a new hydroxyethylene (HE) core motif displaying P1 aryloxymethyl and P1’ methoxy substituents delivering potent BACE-1 inhibitors. In a continuation of this work we have now explored the SAR of the S1’ pocket by introducing a set of P1’ alkoxy groups and evaluated them as BACE-1 inhibitors. Previously the P1 and P1’ positions of the classical HE template have been relatively little explored due to the complexity of the chemical routes involved in modifications at these positions. However, the chemistries developed for the current HE template renders substituents in both the P1 and P1’ positions readily available for SAR exploration. The BACE-1 inhibitors prepared displayed IC50 values in the range of 4-45 nM, where the most potent compounds featured small P1’ groups. The cathepsin D selectivity which was high for the smallest P1’ sustituents (P1’=ethoxy, fold selectively >600) dropped for larger groups (P1’=benzyloxy, fold selectivity of 1.6). We have also confirmed the importance of both the hydroxyl group and its stereochemistry preference for this HE transition state isostere by preparing both the deoxygenated analogue and by inverting the configuration of the hydroxyl group to the R-configuration, which as expected resulted in large activity drops. Finally substituting the hydroxyl group by an amino group having the same configuration (S), which previously have been described to deliver potent BACE-1 inhibitors with advantageous properties, surprisingly resulted in a large drop in the inhibitory activity.

  • 9.
    Björklund, Catarina
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Oscarson, Stefan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Benkestock, Kurt
    Borkakoti, Neera
    Jansson, Katarina
    Lindberg, Jimmy
    Vrang, Lotta
    Hallberg, Anders
    Rosenquist, Åsa
    Samuelsson, Bertil
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Design and synthesis of potent and selective BACE-1 inhibitors2010Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, nr 4, s. 1458-1464Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Several highly potent BACE-1 protease inhibitors have been developed from an inhibitor series containing a novel hydroxyethylene (HE) core structure displaying aryloxymethyl or benzyloxymethyl P1 side chains and a methoxy P1’ side chain. The target molecules were readily synthesized from chiral carbohydrate starting materials, furnishing the inhibitor compounds in good overall yields. The inhibitors show both high BACE-1 potency and good selectivity against cathepsin D, where the most potent inhibitor furnish a BACE-1 IC50 value of 0.32 nM and displays > 3000 fold selectivity over cathepsin D.

  • 10. Cribiù, Riccardo
    et al.
    Borbas, K. Eszter
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Cumpstey, Ian
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    On the synthesis of vinyl and phenyl C-furanosides by stereospecific debenzylative cycloetherification2009Ingår i: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 65, nr 10, s. 2022-2031Artikel i tidskrift (Refereegranskat)
  • 11.
    Córdova, Armando
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Ibrahem, Ismail
    Casas, Jesús
    Sundén, Henrik
    Engqvist, Magnus
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Reyes, Efraim
    Amino Acid-Catalyzed Neogenesis of Carbohydrates: A Plausible Ancient Transformation2005Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 11, nr 16, s. 4772-4784Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hexose sugars play a fundamental role in vital biochemical processes and their biosynthesis is achieved through enzyme-catalyzed pathways. Herein we disclose the ability of amino acids to catalyze the asymmetric neogenesis of carbohydrates by sequential cross-aldol reactions. The amino acids mediate the asymmetric de novo synthesis of natural L- and D-hexoses and their analogues with excellent stereoselectivity in organic solvents. In some cases, the four new stereocenters are assembled with almost absolute stereocontrol. The unique feature of these results is that, when an amino acid is employed as the catalyst, a single reaction sequence can convert a protected glycol aldehyde into a hexose in one step. For example, proline and its derivatives catalyze the asymmetric neogenesis of allose with >99 % ee in one chemical manipulation. Furthermore, all amino acids tested catalyzed the asymmetric formation of natural sugars under prebiotic conditions, with alanine being the smallest catalyst. The inherent simplicity of this catalytic process suggests that a catalytic prebiotic “gluconeogenesis” may occur, in which amino acids transfer their stereochemical information to sugars. In addition, the amino acid catalyzed stereoselective sequential cross-aldol reactions were performed as a two-step procedure with different aldehydes as acceptors and nucleophiles. The employment of two different amino acids as catalysts for the iterative direct aldol reactions enabled the asymmetric synthesis of deoxysugars with >99 % ee. In addition, the direct amino acid catalyzed C2+C2+C2 methodology is a new entry for the short, highly enantioselective de novo synthesis of carbohydrate derivatives, isotope-labeled sugars, and polyketide natural products. The one-pot asymmetric de novo syntheses of deoxy and polyketide carbohydrates involved a novel dynamic kinetic asymmetric transformation (DYKAT) mediated by an amino acid.

  • 12.
    Dziedzic, Pawel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Amino acid-catalyzed synthesis of amino acid derivatives: Application and semi-synthesis of Paclitaxel, Docetaxel and their derivatives2010Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    This thesis deals with different applications of organocatalysis, where amino acid derivatives and small peptides are applied as catalysts. First, the development of environmentally friendly aldol reactions, carried out in aqueous media is illustrated. The corresponding β-hydroxy ketones are formed with ee´s up to 99%. Chapter 3 describes the ability of β3-amino acids to selectively catalyze Mannich-type reactions and govern the formation of products with high anti-selectivity (up to >19:1) and ee´s up to 99%. In the following chapter, an amino acid-catalyzed one-pot three component Mannich reaction between dihydroxyacetone and PMP-protected imines, is presented. The corresponding a,a’-dihydroxy-b-aminoketones are obtained in high yields and with 82-95% ee. Next, an aza-Morita-Baylis-Hillman reaction was investigated where L-proline is the catalyst. The reaction proceeds with excellent chemo- and enantioselectivity to give the corresponding compounds in good yields and with 97-99% ee. Finally, the last part describes development of a proline-catalyzed Mannich reation between N-acyl imines and protected α-hydroxyaldehyes, providing access to different α-hydroxy-β-amino acids in good yields and high enantioselctivity (92-99% ee). The obtained amino acids were further applied in the semisynthesis of paclitaxel and docetaxel derivatives.

  • 13.
    Dziedzic, Pawel
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Weibiao, Zou
    Hafrén, Jonas
    Córdova, Armando
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    The small peptide-catalyzed direct asymmetric aldol reaction in water2006Ingår i: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 4, s. 38-40Artikel i tidskrift (Refereegranskat)
  • 14.
    Dziedzic, Pawel
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Zhao, Gui-ling
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Córdova, Armando
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Practical amino acid-catalyzed asymmetric synthesis pf protected α-hydroxy-amino aldehydes and acidsManuskript (preprint) (Övrigt vetenskapligt)
  • 15. George, Riham F.
    et al.
    Ismail, Nasser S. M.
    Stawinski, Jacek
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Girgis, Adel S.
    Design, synthesis and QSAR studies of dispiroindole derivatives as new antiproliferative agents2013Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 68, s. 339-351Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A variety of 4'-ary1-3-(arylmethylidene)-1 ''-[(cyclic-amino)methylene]-1'-methyl-dispiro[cyclohexane-1,3'-pyrrolidine-2',3 ''-[3H]indole]-2,2 ''(1H)-diones 4a-u were prepared via reaction of 2E,6E-bis(arylidene)-1-cyclohexanones 1a-i with azomethine ylides, generated in situ via a decarboxylative condensation of isatins 2a-c and sarcosine (3). Single crystal X-ray study of 4a, revealed structural and stereochemical features of these derivatives. While most of the synthesized compounds exhibit mild antitumor properties when tested against various human tumor cell lines (HEPG2 liver, HELA cervical and PD prostate cancers), three of them, 4d and 4p (active against HEPG2), and compound 4g (active against HELA), demonstrated higher activities, that were close or even higher than that of the reference standard Doxorubicin. QSAR studies revealed good predictive and statistically significant 3 descriptor models (r(2) = 0.903-0.812, r(adjusted)(2) = 0.855-0.672, r(prediction)(2) = 0.773-0.605).

  • 16. Hammarström, Lars G. J.
    et al.
    Harmel, Robert K.
    Granath, Mikael
    Ringom, Rune
    Gravenfors, Ylva
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Färnegårdh, Katarina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Svensson, Per H.
    Wennman, David
    Lundin, Göran
    Roddis, Ylva
    Kitambi, Satish S.
    Bernlind, Alexandra
    Lehmann, Fredrik
    Ernfors, Patrik
    The Oncolytic Efficacy and in Vivo Pharmacokinetics of [2-(4-Chlorophenyl)quinolin-4-yl](piperidine-2-yl)methanol (Vacquinol-1) Are Governed by Distinct Stereochemical Features2016Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 59, nr 18, s. 8577-8592Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Glioblastoma remains an incurable brain cancer. Drugs developed in the past 20 years have not improved the prognosis for patients, necessitating the development of new treatments. We have previously reported the therapeutic potential of the quinoline methanol Vacquinol-1 (1) that targets glioblastoma cells and induces cell death by catastrophic vacuolization. Compound 1 is a mixture of four stereoisomers due to the two adjacent stereogenic centers in the molecule, complicating further development in the preclinical setting. This work describes the isolation and characterization of the individual isomers of 1 and shows that these display stereospecific pharmacokinetic and pharmacodynamic features. In addition, we present a stereoselective synthesis of the active isomers, providing a basis for further development of this compound series into a novel experimental therapeutic for glioblastoma.

  • 17.
    Jonsson, Hanna
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Säwén, Elin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Studies on the conformational flexibility of α-L-Rhap-(1→2)-α-L-Rhap-OMe using molecular simulation and 13C-site-specific labeling: a model for a commonly occurring disaccharide in bacterial polysaccharidesManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Bacterial polysaccharides are comprised of a variety of monosaccharides, L-rhamnose (6-deoxy-Lmannose) being one of them. This sugar is often part of α-(1→2)- and/or α-(1→3)-linkages and wehave therefore studied the disaccharide α-L-Rhap-(1→2)-α-L-Rhap-OMe to obtain information onconformational preferences at this glycosidic linkage. The target disaccharide was synthesized with 13C site-specific labeling at C1' and at C2', i.e., in the terminal group. 2D 1H,13C-HSQC-HECADE and 1H,13C-J-HMBC NMR experiments, 1D 13C and 1H NMR spectra together with total line-shape analysis were used to extract conformationally dependent hetero- and homonuclear spin-spincoupling constants. This resulted in the determination of 2JC2',H1' , 3JC1',C1 , 3JC1',C3 , 3JC2',C2 , 2JC1',C2 ,1JC1',C2' , and 1JC1',H1' . These data together with previously determined JC,H and 1H,1H NOEs result in fourteen conformationally dependent NMR parameters that are available for analysis of glycosidiclinkage flexibility and conformational preferences. A molecular dynamics simulation of the disaccharide with explicit water molecules as solvent showed a major conformational state at ΦH =40° and ψH = –35°, consistent with experimental NMR data.

  • 18.
    Jonsson, Hanna
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    NMR analysis of conformationally dependent nJCH and nJCC in the trisaccharide α-L-Rhap-(1→2)[α-L-Rhap-(1→3)]-α-L-Rhap-OMe and a site-specifically labeled isotopologue thereofManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    An array of NMR spectroscopy experiments have been carried out to obtain conformationallydependent 1H,13C- and 13C,13C-spin-spin coupling constants in the trisaccharide a-L-Rhap-(1®2)[a-LRhap-(1®3)]-a-L-Rhap-OMe. The trisaccharide was synthesized with 13C site-specific labeling at C2'and C2'', i.e., in the rhamnosyl groups in order to alleviate 1H spectral overlap. Using both the naturalabundance compound and the 13C-labeled sample 2D 1H,13C-J-HMBC and 1H,13C-HSQC-HECADENMR experiments, total line-shape analysis of 1H NMR spectra and 1D 13C NMR experiments wereemployed to extract 3C,H J , 2C,H J , 3C,C J , and1C,C J . The 13C site-specific labeling facilitates straightforward determination of nC,C J as the splitting of the 13C natural abundance resonances. This studyresulted in seven conformationally dependent coupling constants for the trisaccharide and illustrates theuse of 13C site-specific labeling as a valuable tool that extends the 1D and 2D NMR methods in currentuse to attain both hetero- and homonuclear spin-spin coupling constants.

  • 19.
    Jonsson, K. Hanna M.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Weintraub, Andrej
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Structural determination of the O-antigenic polysaccharide from Escherichia coli O742009Ingår i: Carbohydrate Research, ISSN 0008-6215, E-ISSN 1873-426X, Vol. 344, nr 12, s. 1592-1595Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The structure of the O-antigen polysaccharide (PS) from Escherichia coli O74 has been determined. Component analysis, together with 1H and 13C NMR spectroscopy as well as 1H,15N-HSQC experiments were employed to elucidate the structure. Inter-residue correlations were determined by 1H,1H-NOESY and 1H,13C-heteronuclear multiple-bond correlation experiments. The PS is composed of tetrasaccharide repeating units with the following structure:

    Full-size image (5K)

    Cross-peaks of low intensity from an α-linked N-acetylglucosamine residue were present in the NMR spectra, and spectral analysis indicates that they originate from the penultimate residue in the polysaccharide. Consequently, the biological repeating unit has a 3-substituted N-acetyl-d-glucosamine residue at its reducing end. The 1H, 13C and 15N NMR chemical shifts of the α- and β-anomeric forms of d-Fucp3NAc are also reported. The repeating unit of the E. coli O74 O-antigen is identical to that of the capsular polysaccharide from E. coli K45.

  • 20. Kiss, Anita
    et al.
    Herman, Bianka Edina
    Görbe, Tamás
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Mernyak, Erzsebet
    Molnar, Barnabas
    Wolfling, Janos
    Szecsi, Mihaly
    Schneider, Gyula
    Synthesis of novel 17-triazolyl-androst-5-en-3-ol epimers via Cu(I)-catalyzed azide-alkyne cycloaddition and their inhibitory effect on 17 alpha-hydroxylase/ C-17,C-20-lyase2018Ingår i: Steroids, ISSN 0039-128X, E-ISSN 1878-5867, Vol. 135, s. 79-91Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The regioselective Cu(I)-catalyzed 1,3-dipolar cycloaddition of 17 alpha- and 17 beta-azidoandrost-5-en-3 beta-ol epimers (3b and 5b) with different terminal alkynes afforded novel 1,4-substituted triazolyl derivatives (8a-k and 9a-k). For the preparation of 5'-iodo-l',2',3'-triazoles (8m-n and 9m-n), an improved method was developed, directly from steroidal azides and terminal alkynes, in reaction mediated by Cul and IC1 as iodinating agents. Acetolysis and subsequent hydrolysis of 8n and 9n yielded 5'-hydroxy-l',2',3'-triazoles 8o and 9o. The inhibitory effect of 8a-o, 9a-o, 3, and 5 on rat testicular C-17,C-20-lyase was investigated by means of an in vitro radioincubation technique. The results revealed that the C-17 epimers of steroidal triazoles influence the C-17,C-20-lyase effect. Inhibitors were found only in the 17 alpha-triazolyl series (8a-o), whereas in the C-17 azide pair the 17 beta compound (5b) was more potent.

  • 21.
    Kjellberg, Alexandra
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Studies of oligosaccharides and carbon-13 enriched bacterial polysaccharides using NMR spectroscopy and computer simulations1998Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The conformation and dynamics of the trisaccharide methyl β-D-Glcp-(1--> 2)[β-D-Glcp-(1 --> 3)] α-D-Manp and its constituent disaccharides methyl β-D-Glcp-(1 --> 2) α-D-Manp and methyl β-D-Glcp-(1 --> 3) α-D-Manp have been studied using computer simulations and NMR spectroscopy. The computer simulations applied were Metropolis Monte Carlo simulations employing the HSEA force field and Langevin dynamics simulations using the PARM22 and CHEAT95 force fileds. The NMR methods used were measurement of long-range heteronuclear coupling constants across the glycosidic linkages, measurement of carbon-13 nuclear relaxation rates for the determination of dynamical parameters according the Lipari-Szabo "model free" approach and measurements of homonuclear NOE and TROE cross relaxation rates for the determination of proton-proton distances. Experimental data were then compared to the corresponding parameters extracted from the various computer simulations.

    Studies of the carbon-13 labelled O-polysaccharides from Escherichia coli O25 and O91 have also been performed. 13C-13C TOCSY experiments, with the spin-lock on the carbon-13 nuclei, were applied to sugar residues of different geometries. This circumvented the problem of hampered magnetisation transfer encountered in residues with 3JHH < 2Hz when the spin-lock is applied on the protons.The carbon-13 labelling was also used to demonstrate the biosynthesis of one of the substituents in the Escherichia coli O91 O-polysaccharide.

  • 22.
    Lavén, Gaston
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Stawinski, Jacek
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Palladium(0)-catalyzed benzylation of H-phosphonate diesters: An efficient entry to benzylphosphonates2009Ingår i: Synlett: Accounts and Rapid Communications in Synthetic Organic Chemistry, ISSN 0936-5214, E-ISSN 1437-2096, nr 2, s. 225-228Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A new, efficient method for the synthesis of benzylphosphonate diesters via a palladium(0)-catalyzed cross-coupling reaction between benzyl halides and H-phosphonate diesters, using Pd(OAc)2 as a palladium source and Xantphos as a supporting ligand, has been developed.

  • 23.
    Lavén, Gaston
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Stawinski, Jacek
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Synthetic Studies on the Preparation of Dinucleoside Phenyl-Phosphonates and Phenyl-Phosphonothioates via Palladium(0) Catalyzed Cross-Coupling2005Ingår i: / [ed] Michal Hocek, 2005, s. 195-199Konferensbidrag (Refereegranskat)
    Abstract [en]

    Separate diastereomers of protected dithymidine (3'-5')-phenylphosphonates and dithymidine (3'-5')phenylphosphonothioate were obtained via a palladium(0) catalysed stereo-specific cross-coupling reaction of separate diastereomers of corresponding dinucleoside H-phosphonate and dinucleoside H-phosphonothioate with halobenzenes.

  • 24.
    Liao, Rong-Zhen
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Yu, Jian-Guo
    Liu, Ruo-Zhuang
    Theoretical study of the RNA hydrolysis mechanism of the dinuclear zinc enzyme RNase Z2009Ingår i: European Journal of Inorganic Chemistry, ISSN 1434-1948, E-ISSN 1099-1948, Vol. 2009, nr 20, s. 2967-2972Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    RNase Z is a dinuclear zinc enzyme that catalyzes the removal of the tRNA 3'-end trailer. Density functional theory is used to investigate the phosphodiester hydrolysis mechanism of this enzyme with a model of the active site constructed on the basis of the crystal structure. The calculations imply that the reaction proceeds through two steps. The first step is a nucleophihc attack by a bridging hydroxide coupled with protonation of the leaving group by a Glu-His diad. Subsequently, a water molecule activated by the same Glu-His diad makes a reverse attack, regenerating the bridging hydroxide. The second step is calculated to be the rate-limiting step with a barrier of 18 kcal/mol, in good agreement with experimental kinetic studies. Both zinc ions participate in substrate binding and orientation, facilitating nucleophilic attack. In addition, they act as electrophilic catalysts to stabilize the pentacoordinate trigonal-bipyramidal transition states.

  • 25.
    Maliniak, Arnold
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Structural Analysis of Carbohydrates by Nuclear Magnetic Resonance Spectroscopy and Molecular Simulations: Application to Human Milk Oligosaccharides2014Ingår i: FOOD OLIGOSACCHARIDES: PRODUCTION, ANALYSIS AND BIOACTIVITY, OXFORD: BLACKWELL SCIENCE PUBL , 2014, s. 320-349Kapitel i bok, del av antologi (Refereegranskat)
  • 26. Mbunde, Mourice Victor Nyangabo
    et al.
    Innocent, Ester
    Mabiki, Faith
    Andersson, Pher G.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Ethnobotanical survey and toxicity evaluation of medicinal plants used for fungal remedy in the Southern Highlands of Tanzania2017Ingår i: Journal of Intercultural Ethnopharmacology, ISSN 2146-8397, Vol. 6, nr 1, s. 84-96Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background/Aim: Some of the antifungal drugs used in the current treatments regime are responding to antimicrobial resistance. In rural areas of Southern Tanzania, indigenous people use antifungal drugs alone or together with medicinal plants to curb the effects of antibiotic resistance. This study documented ethnobotanical information of medicinal plants used for managing fungal infections in the Southern Highlands of Tanzania and further assess their safety. Materials and Methods: Ethnobotanical survey was conducted in Makete and Mufindi districts between July 2014 and December 2015 using semi-structured questionnaires followed by two focus group discussions to verify respondents' information. Cytotoxicity study was conducted on extracts of collected plants using brine shrimp lethality test and analyzed by MS Excel 2013 program. Results: During this survey about 46 plant species belonging to 28 families of angiosperms were reported to be traditionally useful in managing fungal and other health conditions. Among these, Terminalia sericea, Aloe nutii, Aloe lateritia, Zanthoxylum chalybeum, Zanthoxylum deremense, and Kigelia africana were frequently mentioned to be used for managing fungal infections. The preparation of these herbals was mostly by boiling plant parts especially the leaves and roots. Cytotoxicity study revealed that most of the plants tested were nontoxic with LC50 > 100 which implies that most compounds from these plants are safe for therapeutic use. The dichloromethane extract of Croton macrostachyus recorded the highest with LC50 value 12.94 mu g/ml. The ethnobotanical survey correlated well with documented literature from elsewhere about the bioactivity of most plants. Conclusions: The ethnobotanical survey has revealed that traditional healers are rich of knowledge to build on for therapeutic studies. Most of the plants are safe for use; and thus can be considered for further studies on drug discovery.

  • 27.
    Merritt, Eleanor A.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Malmgren, Joel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Klinke, Felix J.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Olofsson, Berit
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Synthesis of diaryliodonium triflates using environmentally benign oxidizing agents2009Ingår i: Synlett: Accounts and Rapid Communications in Synthetic Organic Chemistry, ISSN 0936-5214, E-ISSN 1437-2096, nr 14, s. 2277-2280Artikel i tidskrift (Refereegranskat)
  • 28. Nilsson, Magnus
    et al.
    Belfrage, Anna Karin
    Lindström, Stefan
    Wähling, Horst
    Lindquist, Charlotta
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Ayesa Alvarez, Susana
    Kahnberg, Pia
    Pelcman, Mikael
    Vrang, Lotta
    Terselius, Ylva
    Wikström, Kristina
    Hamelink, Elizabeth
    Rydergård, Christina
    Edlund, Michael
    Eneroth, Anders
    Raboisson, Pierre
    Lin, Tse-I.
    de Kock, Herman
    Wigerinck, Piet
    Simmen, Kenneth
    Samuelsson, Bertil
    Rosenquist, Åsa
    Synthesis and SAR of potent inhibitors of the Hepatitis C virus NS3/4A protease: exploration of P2 quinazoline substituents.Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Novel NS3/4A protease inhibitors comprising quinazoline derivatives as P2 substituent were synthesized. High potency inhibitors displaying advantageous PK properties have been obtained through the optimization of quinazoline P2 substituents in three series of macrocyclic P2 cyclopentane dicarboxylic acid and P2 proline urea motifs. For the quinazoline moiety it was found that 8-methyl substitution for the P2 cyclopentane dicarboxylic acid series improved on the stability in human liver microsomes. By comparison, the proline urea series displayed advantageous Caco-2 permeability over the cyclopentane series. properties were assessed in rat on selected compounds. Excellent exposure and liver–to-plasma ratios were demonstrated for a member of the 14-membered quinazoline substituted P2 proline urea series. In vivo pharmacokinetic properties were assessed in rat on selected compounds. Excellent exposure and liver–to-plasma ratios were demonstrated for a member of the 14-membered quinazoline substituted P2 proline urea series.

  • 29.
    Olsson, Vilhelm
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Functionalization of Unactivated Alkenes trough Iridium-Catalyzed Borylation of Carbon-Hydrogen Bonds. Mechanism and Synthetic ApplicationsManuskript (Övrigt vetenskapligt)
  • 30.
    Olsson, Vilhelm
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Sebelius, Sara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Selander, Nicklas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Szabó, Kálmán
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Direct Boronation of Allyl Alcohols with Diboronic Acid Using Palladium Pincer-Complex Catalysis. A Remarkably Facile Allylic Displacement of the Hydroxy Group under Mild Reaction Conditions2006Ingår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 128, nr 14, s. 4588-4589Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Allyl alcohols were converted to allyl boronic acids and subsequently to trifluoro(allyl)borates with tetrahydroxy diboron using palladium pincer-complex catalysis. These reactions are regio- and stereoselective proceeding with high isolated yields. Competitive boronation experiments indicate that under the applied reaction conditions the allylic displacement of a hydroxy group is faster than the displacement of an acetate leaving group. It is assumed that the hydroxy group of the allyl alcohol is converted to a diboronic acid ester functionality, which can easily be substituted.

  • 31.
    Privalov, Timofei
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Boschloo, Gerrit
    Hagfeldt, Anders
    Svensson, Per H.
    Kloo, Lars
    A study of the interactions between I-/I3- redox , mediators amd organometallic sensitizing dyes in solar cells2009Ingår i: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 113, nr 2, s. 783-790Artikel i tidskrift (Refereegranskat)
  • 32.
    Samec, Joseph S M
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Mony, Laetitia
    Bäckvall, Jan-E
    Efficient Ruthenium-Catalyzed Transfer Hydrogenation of Functionalized Imines by Isopropanol under Controlled Microwave Heating2005Ingår i: Canadian journal of chemistry (Print), ISSN 0008-4042, E-ISSN 1480-3291, Vol. 83, nr 6, s. 909-916Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Transfer hydrogenation of various functionalized imines by isopropanol catalyzed by [Ru(CO)(2)(Ph4C4CO)](2) (3) has been studied. The use of either an oil bath or controlled microwave heating in toluene led to an efficient procedure with high turnover frequencies and the product amines were obtained in high yields. An advantage with catalyst 3 over the conventional [Ru-2(CO)(4)(mu-H)(Ph4C4COHOCC4Ph4)] (1) is the absence of an initiation period, which results in a faster reaction with 3 as compared to 1.

  • 33. Sjödin, Martin
    et al.
    Styring, Stenbjörn
    Wolpher, Henriette
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Xu, Yunhua
    Sun, Licheng
    Hammarström, Leif
    Switching the redox mechanism: Models for proton coupled electron transfer from tyrosine and tryptophan2005Ingår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 127, nr 11, s. 3855-3863Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The coupling of electron and proton transfer is an important controlling factor in radical proteins, such as photosystem II, ribinucleotide reductase, cytochrome oxidases, and DNA photolyase. This was investigated in model complexes in which a tyrosine or tryptophan residue was oxidized by a laser-flash generated trisbipyridine-Ru-III moiety in an intramolecular, proton-coupled electron transfer (PCET) reaction. The PCET was found to proceed in a competition between a stepwise reaction, in which electron transfer is followed by deprotonation of the amino acid radical (ETPT), and a concerted reaction, in which both the electron and proton are transferred in a single reaction step (CEP). Moreover, we found that we could analyze the kinetic data for PCET by Marcus' theory for electron transfer. By altering the solution pH, the strength of the Ru-III oxidant, or the identity of the amino acid, we could induce a switch between the two mechanisms and obtain quantitative data for the parameters that control which one will dominate. The characteristic pH-dependence of the CEP rate (M. Sjodin et al. J. Am. Chem. Soc. 2000, 122, 3932) reflects the pH-dependence of the driving force caused by proton release to the bulk. For the pH-independent ETPT on the other hand, the driving force of the rate-determining ET step is pH-independent and smaller. On the other hand, temperature-dependent data showed that the reorganization energy was higher for CEP, while the pre-exponential factors showed no significant difference between the mechanisms. Thus, the opposing effect of the differences in driving force and reorganization energy determines which of the mechanisms will dominate. Our results show that a concerted mechanism is in general quite likely and provides a low-barrier reaction pathway for weakly exoergonic reactions. In addition, the kinetic isotope effect was much higher for CEP (k(H)/k(D) &GT; 10) than for ETPT (k(H)/k(D) = 2), consistent with significant changes along the proton reaction coordinate in the rate-determining step of CEP.

  • 34.
    Stenutz, Roland
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    The structure and conformation of saccharides determined by experiment and simulation1997Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    A computer program, CASPER, for sequence determination of oligosaccharides and regular polysaccharides using NMR-data, has been extended to support multiply branched structures. The program has been modified to allow the use of incomplete experimental data since spectral overlap can be a problem even at high fields. The resulting program was tested and used in the structure determination of the capsular polysaccharide from Klebsiella type K52.

    Four carboxyethyl-substituted sugars, methyl 4-O-[(R)- and (S)-1-carboxyethyl]-a-L-rhamnopyranoside and methyl 6-O-[(R)- and (S)-1-carboxyethyl]-a-D-galactopyranoside have been synthesized. The conformational properties of the latter two have been investigated by both NMR spectroscopy and molecular modelling studies. For the NMR-studies stereospecifically deuterated compounds were prepared.

  • 35. Wangsell, Fredrik
    et al.
    Nordeman, Patrik
    Savmarker, Jonas
    Emanuelsson, Rikard
    Jansson, Katarina
    Lindberg, Jimmy
    Rosenquist, Asa
    Samuelsson, Bertil
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Larhed, Mats
    Investigation of alpha-phenylnorstatine and alpha-benzylnorstatine as transition state isostere motifs in the search for new BACE-1 inhibitors2011Ingår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 19, nr 1, s. 145-155Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Inhibition of the BACE-1 protease enzyme has over the recent decade developed into a promising drug strategy for Alzheimer therapy. In this report, more than 20 new BACE-1 protease inhibitors based on alpha-phenylnorstatine, alpha-benzylnorstatine, iso-serine, and beta-alanine moieties have been prepared. The inhibitors were synthesized by applying Fmoc solid phase methodology and evaluated for their inhibitory properties. The most potent inhibitor, tert-alcohol containing (R)-12 (IC(50) = 0.19 mu M) was co-crystallized in the active site of the BACE-1 protease, furnishing a novel binding mode in which the N-terminal amine makes a hydrogen bond to one of the catalytic aspartic acids.

  • 36. Zerbetto, Mirco
    et al.
    Polimeno, Antonino
    Kotsyubynskyy, Dmytro
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för fysikalisk kemi, oorganisk kemi och strukturkemi.
    Ghalebani, Leila
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för fysikalisk kemi, oorganisk kemi och strukturkemi.
    Kowalewski, Jozef
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för fysikalisk kemi, oorganisk kemi och strukturkemi, Avdelningen för fysikalisk kemi.
    Meirovitch, Eva
    Olsson, Ulrika
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    An integrated approach to NMR spin relaxation in flexible biomolecules: Application to β-D-glucopyranosyl-(1→6)-α-D-mannopyranosyl-OMe2009Ingår i: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 131, nr 23, s. p234501-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The description of the reorientational dynamics of flexible molecules is a challenging task, in particular when the rates of internal and global motions are comparable. The commonly used simple mode-decoupling models are based on the assumption of statistical independence between these motions. This assumption is not valid when the time scale separation between their rates is small, a situation that was found to arise in oligosaccharides in the context of certain internal motions. To make possible the interpretation of NMR spin relaxation data from such molecules, we developed a comprehensive approach generally applicable to flexible rotators with one internal degree of freedom. This approach integrates a stochastic description of coupled global tumbling and internal torsional motion, quantum chemical calculations of the local potential and the local geometry at the site of the restricted torsion, and hydrodynamics-based calculations of the diffusive properties. The method is applied to the disaccharide -D-Glcp-(16)--D-[6-13C]-Manp-OMe dissolved in a DMSO-d6/D2O cryosolvent. The experimental NMR relaxation parameters, associated with the 13CH2 probe residing at the glycosidic linkage, include 13C T1 and T2 and 13C-{1H} nuclear Overhauser enhancement (NOE) as well as longitudinal and transverse dipole-dipole cross-correlated relaxation rates, acquired in the temperature range of 253–293 K. These data are predicted successfully by the new theory with only the H–C–H angle allowed to vary. Previous attempts to fit these data using mode-decoupling models failed.

  • 37. Zovko, Ana
    et al.
    Novak, Metka
    Haag, Petra
    Kovalerchick, Dimitry
    Holmlund, Teresa
    Färnegårdh, Katarina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Ilan, Micha
    Carmeli, Shmuel
    Lewensohn, Rolf
    Viktorsson, Kristina
    Compounds from the marine sponge Cribrochalina vasculum offer a way to target IGF-1R mediated signaling in tumor cells2016Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, nr 31, s. 50258-50276Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In this work two acetylene alcohols, compound 1 and compound 2, which were isolated and identified from the sponge Cribrochalina vasculum, and which showed antitumor effects were further studied with respect to targets and action mechanisms. Gene expression analyses suggested insulin like growth factor receptor (IGF-1R) signaling to be instrumental in controlling anti-tumor efficacy of these compounds in non-small cell lung cancer (NSCLC). Indeed compounds 1 and 2 inhibited phosphorylation of IGF-1R beta as well as reduced its target signaling molecules IRS-1 and PDK1 allowing inhibition of pro-survival signaling. In silico docking indicated that compound 1 binds to the kinase domain of IGF-1R at the same binding site as the well known tyrosine kinase inhibitor AG1024. Indeed, cellular thermal shift assay (CETSA) confirmed that C. vasculum compound 1 binds to IGF-1R but not to the membrane localized tyrosine kinase receptor EGFR. Importantly, we demonstrate that compound 1 causes IGF-1R beta but not Insulin Receptor degradation specifically in tumor cells with no effects seen in normal diploid fibroblasts. Thus, these compounds hold potential as novel therapeutic agents targeting IGF-1R signaling for anti-tumor treatment.

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