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  • 1. Aili, Daniel
    et al.
    Enander, Karin
    Rydberg, Johan
    Lundström, Ingemar
    Baltzer, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    Liedberg, Bo
    Aggregation-Induced Folding of a de novo Designed Polypeptide Immobilized on Gold Nanoparticles2006In: J. Am. Chem. Soc., no 128, p. 2194-2195Article in journal (Refereed)
  • 2. Albrecht, Christiane
    et al.
    Fechner, Peter
    Honcharenko, Dmytro
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Baltzer, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Gauglitz, Günther
    A new assay design for clinical diagnostics based on alternative recognition elements2010In: Biosensors & bioelectronics, ISSN 0956-5663, E-ISSN 1873-4235, Vol. 25, no 10, p. 2302-2308Article in journal (Refereed)
  • 3. Andersson, Theresa
    et al.
    Lundquist, Martin
    Dolphin, Gunnar T.
    Enander, Karin
    Jonsson, Bengt-Harald
    Nilsson, Jonas W.
    Baltzer, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    Cooperative binding of human Carbonic Anhydrase II by functionalized folded polypeptide receptors2005In: Chem. Biol., no 12, p. 1245-1252Article in journal (Refereed)
  • 4.
    Baltzer, Lars
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    Klinman, J.P.
    Hynes, J.T.
    Limbach, H-H.
    Acid base catalysis in designed polypeptides2006In: Handbook of Hydrogen Transfer, Wiley , 2006Chapter in book (Refereed)
  • 5.
    Barletta, Julien
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry.
    [11C]Carbon Monoxide in Rhodium-/Palladium-Mediated Carbonylation Reactions2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Methods for the 11C-labeling of carbonyl compounds applicable in the preparation of radiotracers for Positron Emission Tomography (PET) are described. To this end [11C]carbon monoxide at low concentration was used in transition metal- mediated reactions.

    Stille couplings were employed in the synthesis of [carbonyl-11C]ketones from methyl and aryl halides with [11C]carbon monoxide. The synthesized [carbonyl-11C]ketones were obtained from the corresponding organostannanes with analytical radiochemical yields up to 98%.

    A number of synthetic routes were designed using [11C]carbon monoxide and rhodium complexes. Nitrene intermediates were generated from azides and reacted via a rhodium-mediated carbonylation reaction as a general synthetic route to [carbonyl-11C]isocyanates, versatile precursors. [carbonyl-11C]Isocyanate reacted via nucleophilic attack of an amine to form N,N’-diphenyl[11C]urea in 82% analytical radiochemical yield, ethyl phenyl[11C]carbamate was synthesized by the same route, using ethanol as the nucleophile, in 70% radiochemical yield. [11C]Isocyanate was also able to react in a [2+3] cycloaddition with ethylene oxide to form 3-phenyl[carbonyl-11C]oxazolidin-2-one in over 80% analytical radiochemical yield. This method was applied to the synthesis of a potential efflux system tracer [11C]hydroxyurea in 38% isolated radiochemical yield and the derivative 1-hydroxy-3-phenyl[11C]urea in 35% isolated radiochemical yield. Carbene intermediates, generated from diazo compounds, were reacted with [11C]carbon monoxide in the rhodium-mediated synthesis of [carbonyl-11C]ketenes. [carbonyl-11C]Ketene intermediates were utilised in the synthesis of diethyl[carbonyl-11C]malonate, from ethyl diazoacetate and ethanol. The product was obtained with a 20% isolated radiochemical yield. Alkylation of diethyl[carbonyl-11C]malonate, with ethyliodide and tetrabutylammonium fluoride, was successfully accomplished and diethyl diethyl[carbonyl-11C]malonate was synthesized in 50% analytical radiochemical yield. Several (carbonyl-13C)compounds were also synthesized using the described methods as a way of characterizing the position of the label using 13C-NMR.

    List of papers
    1. Synthesis of 11C-labelled N,N’-diphenylurea and ethyl phenylcarbamate by rhodium-promoted carbonylation reaction via [11C]-isocyanatobenzene using phenyl azide and [11C]carbon monoxide
    Open this publication in new window or tab >>Synthesis of 11C-labelled N,N’-diphenylurea and ethyl phenylcarbamate by rhodium-promoted carbonylation reaction via [11C]-isocyanatobenzene using phenyl azide and [11C]carbon monoxide
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    2004 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 2, no 21, p. 3063-3066Article in journal (Refereed) Published
    Abstract [en]

    The reaction with phenyl azide and [11C]carbon monoxide to give N,N'-diphenyl[11C]urea and ethyl phenyl[11C]carbamate has been studied with the aim of development of a new methodology for carbonylation using [11C]carbon monoxide with high specific radioactivity. The synthesis of 11C-labelled N,N'-diphenylurea from phenyl azide and [11C]carbon monoxide, with 1,2-bis(diphenylphosphino)ethane-bound Rh(I) complex at 120 degrees C at a pressure of 35 MPa in the presence of aniline was accomplished in 82% trapping efficiency and 82% conversion yield. This approach was also useful for the synthesis of ethyl phenyl[11C]carbamate with lithium ethoxide as a nucleophilic reagent giving 90% trapping efficiency and 76% conversion yield. These reactions can be considered to proceed via a [11C]isocyanate or a [11C]isocyanate-coordinated Rh complex to give the corresponding 11C-products. This protocol provides the chemical basis for the synthesis of [11C]urea and [11C]carbamate derived from [11C]isocyanates.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-94170 (URN)10.1039/B409294E (DOI)15505707 (PubMedID)
    Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2017-12-14Bibliographically approved
    2. Palladium-mediated 11C-carbonylative cross coupling of alkyl / aryl iodides with organostannanes. An efficient synthesis of un-symmetrical alkyl - aryl [carbonyl-11C]ketones
    Open this publication in new window or tab >>Palladium-mediated 11C-carbonylative cross coupling of alkyl / aryl iodides with organostannanes. An efficient synthesis of un-symmetrical alkyl - aryl [carbonyl-11C]ketones
    2005 In: Eur.J. Org. Chem., p. 2374-2378Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-94171 (URN)
    Available from: 2006-04-07 Created: 2006-04-07Bibliographically approved
    3. Synthesis of [11C-carbonyl]hydroxyureas by a rhodium-mediated carbonylation reaction using [11C]carbon monoxide
    Open this publication in new window or tab >>Synthesis of [11C-carbonyl]hydroxyureas by a rhodium-mediated carbonylation reaction using [11C]carbon monoxide
    2006 (English)In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 49, no 5, p. 429-436Article in journal (Refereed) Published
    Abstract [en]

    [11C]Hydroxyurea has been successfully labelled using [11C]carbon monoxide at low concentration. The decay-corrected radiochemical yield was 38±3%, and the trapping efficiency of [11C]carbon monoxide in the order of 90±5%. This synthesis was performed by a rhodium-mediated carbonylation reaction starting with azidotrimethylsilane and the rhodium complex being made in situ by chloro(1,5-cyclooctadiene)rhodium(I) dimer ([Rh(cod)Cl]2) and 1,2-bis(diphenylphosphino)ethane (dppe). (13C)Hydroxyurea was synthesized using this method and the position of the labelling was confirmed by 13C-NMR. In order to perform accurate LC–MS identification, the derivative 1-hydroxy-3-phenyl[11C]urea was synthesized in a 35±4% decay-corrected radiochemical yield. After 13 µA h bombardment and 21 min synthesis, 1.6 GBq of pure 1-hydroxy-3-phenyl[11C]urea was collected starting from 6.75 GBq of [11C]carbon monoxide and the specific radioactivity of this compound was in the order of 686 GBq/µmol (3.47 nmol total mass). [11C]Hydroxyurea could be used in conjunction with PET to evaluate the uptake of this anticancer agent into tumour tissue in individual patients.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-94172 (URN)10.1002/jlcr.1062 (DOI)
    Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2017-12-14Bibliographically approved
    4. Synthesis of diethyl [carbonyl-C-11]malonate from [C-11]carbon monoxide by rhodium-promoted carbonylation and its application as a reaction intermediate
    Open this publication in new window or tab >>Synthesis of diethyl [carbonyl-C-11]malonate from [C-11]carbon monoxide by rhodium-promoted carbonylation and its application as a reaction intermediate
    2006 (English)In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 49, no 9, p. 801-809Article in journal (Refereed) Published
    Abstract [en]

    Rhodium-mediated carbonylation reaction was applied to synthesize diethyl [carbonyl-C-11]malonate using [C-11]carbon monoxide at low concentration. The synthesis was performed starting with ethyl diazoacetate, ethanol and the rhodium complex being made in situ by chloro(1,5-cyclooctadiene)rhodium(l) dimer ([Rh(cod)Cl](2)) and 1,2-bis(diphenylphosphino)ethane (dppe), and the reaction is assumed to proceed via a ketene intermediate. The isolated radiochemical yield was 20% (75% analytical radiochemical yield) and the trapping efficiency of [C-11]carbon monoxide in the order of 85%. The specific radioactivity of this compound was measured at 127 GBq/mu mol (7.28 nmol total mass) after 8 mu Ah bombardment and 35 min synthesis. The corresponding C-13-labelled compound was synthesized using (C-13)carbon monoxide to confirm the position of the carbonyl-labelled atom by C-13-NMR. Diethyl [carbonyl-C-11]malonate was further used in subsequent alkylation step using ethyl iodide and tetrabutylammonium fluoride to obtain diethyl diethyl [carbonyl-C-11]malonate in 50% analytical radiochemical yield.

    Keyword
    diethyl [carbonyl-C-11]malonate, [C-11]carbon monoxide, rhodium-mediated carbonylation reaction, ketene
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-94173 (URN)10.1002/jlcr.1098 (DOI)000240473200005 ()
    Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2017-12-14Bibliographically approved
    5. Synthesis of [11C]oxazolidinone via rhodium-mediated carbon-yaltion reaction using [11C]carbon monoxide and [11C]isocyanate intermediate
    Open this publication in new window or tab >>Synthesis of [11C]oxazolidinone via rhodium-mediated carbon-yaltion reaction using [11C]carbon monoxide and [11C]isocyanate intermediate
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-94174 (URN)
    Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2010-01-13Bibliographically approved
  • 6.
    Barman, Jharna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Targeting RNA by the Antisense Approach and a Close Look at RNA Cleavage Reaction2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis summarizes the results of studies on two aspects of nucleic acids. Chemically modified antisense oligonucleotides (AONs) have been evaluated with regards to their suitability for mRNA targeting in an antisense approach (Paper I – III). The chemically modified nucleotidic units 2'-O-Me-T, 2'-O-MOE-T, oxetane-T, LNA-T, azetidine-T, aza-ENA-T, carbocyclic-ENA-T and carbocyclic-LNA-T were incorporated into 15-mer AONs and targeted against a 15-mer RNA chosen from the coding region of SV-40 large T antigen. The comparative study showed that a single modified nucleotide in the AON with North-East locked sugar (oxetane-T and azetidine-T) lowered the affinity for the complementary RNA whereas North locked sugars (LNA-T, aza-ENA-T, carbocyclic-ENA-T, and carbocyclic-LNA-T) significantly improved the affinity. A comparative RNase H digestion study showed that modifications of the same type (North-East type or North type) in different sequences gave rise to similar cleavage patterns. Determination of the Michaelis-Menten parameters by kinetic experiments showed that the modified AONs recruit RNase H resulting in enhanced turnover numbers (kcat) although with weaker enzyme-substrate binding (1/Km) compared to the unmodified AON. The modified AONs were also evaluated with regards to resistance towards snake venom phosphodiesterase and human serum to estimate their stability toward exonucleases. The aza-ENA-T and carbocyclic-ENA-T modified AONs showed improved stability compared to all other modified AONs. In general, the modified AONs with North type nucleotides (except LNA-T) were found to be superior to the North-East type as they showed improved target affinity, comparable RNase H recruitment capability and improved exonuclease stability.

    The second aspect studied in this thesis is based on physicochemical studies of short RNA molecules utilizing NMR based pH titration and alkaline hydrolysis reactions (Paper IV – V). The NMR based (1H and 31P) pH titration studies revealed the effect of guaninyl ion formation, propagated electrostatically through a single stranded chain in a sequence dependent manner. The non-identical electronic character of the internucleotidic phosphodiesters was further verified by alkaline hydrolysis experiments. The internucleotidic phosphodiesters, which were influenced by guaninyl ion formation, were hydrolyzed at a faster rate than those sequences where such guaninyl ion formation was prevented by replacing G with N1-Me-G.

    List of papers
    1. Comparison of the RNase H Cleavage Kinetics and Blood Serum Stability of the North-Conformationally Constrained and 2‘-Alkoxy Modified Oligonucleotides
    Open this publication in new window or tab >>Comparison of the RNase H Cleavage Kinetics and Blood Serum Stability of the North-Conformationally Constrained and 2‘-Alkoxy Modified Oligonucleotides
    2007 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 46, no 19, p. 5635-5646Article in journal (Refereed) Published
    Abstract [en]

    The RNase H cleavage potential of the RNA strand basepaired with the complementary antisense oligonucleotides (AONs) containing NorthEast conformationally constrained 1‘,2‘-methylene-bridged (azetidine-T and oxetane-T) nucleosides, North-constrained 2‘,4‘-ethylene-bridged (aza-ENA-T) nucleoside, and 2‘-alkoxy modified nucleosides (2‘-O-Me-T and 2‘-O-MOE-T modifications) have been evaluated and compared under identical conditions. When compared to the native AON, the aza-ENA-T modified AON/RNA hybrid duplexes showed an increase of melting temperature (ΔTm = 2.5−4 °C per modification), depending on the positions of the modified residues. The azetidine-T modified AONs showed a drop of 4−5.5 °C per modification with respect to the native AON/RNA hybrid, whereas the isosequential oxetane-T modified counterpart, showed a drop of 5−6 °C per modification. The 2‘-O-Me-T and 2‘-O-MOE-T modifications, on the other hand, showed an increased of Tm by 0.5 °C per modification in their AON/RNA hybrids. All of the partially modified AON/RNA hybrid duplexes were found to be good substrates for the RNase H mediated cleavage. The Km and Vmax values obtained from the RNA concentration-dependent kinetics of RNase H promoted cleavage reaction for all AON/RNA duplexes with identical modification site were compared with those of the reference native AON/RNA hybrid duplex. The catalytic activities (Kcat) of RNase H were found to be greater (1.4−2.6-fold) for all modified AON/RNA hybrids compared to those for the native AON/RNA duplex. However, the RNase H binding affinity (1/Km) showed a decrease (1.7−8.3-fold) for all modified AON/RNA hybrids. This resulted in less effective (1.1−3.2-fold) enzyme activity (Kcat/Km) for all modified AON/RNA duplexes with respect to the native counterpart. A stretch of five to seven nucleotides in the RNA strand (from the site of modifications in the complementary modified AON strand) was found to be resistant to RNase H digestion (giving a footprint) in the modified AON/RNA duplex. Thus, (i) the AON modification with azetidine-T created a resistant region of five to six nucleotides, (ii) modification with 2‘-O-Me-T created a resistant stretch of six nucleotides, (iii) modification with aza-ENA-T created a resistant region of five to seven nucleotide residues, whereas (iv) modification with 2‘-O-MOE-T created a resistant stretch of seven nucleotide residues. This shows the variable effect of the microstructure perturbation in the modified AON/RNA heteroduplex depending upon the chemical nature as well as the site of modifications in the AON strand. On the other hand, the enhanced blood serum as well as the 3‘-exonuclease stability (using snake venom phosphodiesterase, SVPDE) showed the effect of the tight conformational constraint in the AON with aza-ENA-T modifications in that the 3‘-exonuclease preferentially hydrolyzed the 3‘-phosphodiester bond one nucleotide away (n + 1) from the modification site (n) compared to all other modified AONs, which were 3‘-exonuclease cleaved at the 3‘-phosphodiester of the modification site (n). The aza-ENA-T modification in the AONs made the 5‘-residual oligonucleotides (including the n + 1 nucleotide) highly resistant in the blood serum (remaining after 48 h) compared to the native AON (fully degraded in 2 h). On the other hand, the 5‘-residual oligonucleotides (including the n nucleotide) in azetidine-T, 2‘-O-Me-T, and 2‘-O-MOE-T modified AONs were more stable compared to that of the native counterpart but more easily degradable than that of aza-ENA-T containing AONs.

    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-96312 (URN)10.1021/bi0620205 (DOI)000246283600002 ()17411072 (PubMedID)
    Available from: 2007-10-18 Created: 2007-10-18 Last updated: 2017-12-14
    2. Conformationally Constrained 2'-N,4'-C-Ethylene-Bridged Thymidine (Aza-ENA-T): Synthesis, Structure, Physical, and Biochemical Studies of Aza-ENA-T-Modified Oligonucleotides
    Open this publication in new window or tab >>Conformationally Constrained 2'-N,4'-C-Ethylene-Bridged Thymidine (Aza-ENA-T): Synthesis, Structure, Physical, and Biochemical Studies of Aza-ENA-T-Modified Oligonucleotides
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    2006 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 128, no 47, p. 15173-15187Article in journal (Refereed) Published
    Abstract [en]

    The 2'-deoxy-2'-N,4'-C-ethylene-bridged thymidine (aza-ENA-T) has been synthesized using a key cyclization step involving 2'-ara-trifluoromethylsufonyl-4'-cyanomethylene 11 to give a pair of 3',5'-bis-OBn- protected diastereomerically pure aza-ENA-Ts (12a and 12b) with the fused piperidino skeleton in the chair conformation, whereas the pentofuranosyl moiety is locked in the North-type conformation (7 < P < 27 degrees, 44 degrees < phi(m) < 52 degrees). The origin of the chirality of two diastereomerically pure aza-ENA-Ts was found to be due to the endocyclic chiral 2'-nitrogen, which has axial N-H in 12b and equatorial N-H in 12a. The latter is thermodynamically preferred, while the former is kinetically preferred with E-a 25.4 kcal mol(-1), which is thus far the highest observed inversion barrier at pyramidal N-H in the bicyclic amines. The 5'-O-DMTr-aza-ENA-T-3'-phosphoramidite was employed for solid-phase synthesis to give four different singly modified 15-mer antisense oligonucleotides (AONs). Their AON/RNA duplexes showed a T m increase of 2.5-4 degrees C per modification, depending upon the modification site in the AON. The relative rates of the RNase H1 cleavage of the aza-ENA-T-modified AON/RNA heteroduplexes were very comparable to that of the native counterpart, but the RNA cleavage sites of the modified AON/RNA were found to be very different. The aza-ENA-T modifications also made the AONs very resistant to 3' degradation (stable over 48 h) in the blood serum compared to the unmodified AON (fully degraded in 4 h). Thus, the aza-ENA-T modification in the AON fulfilled three important antisense criteria, compared to the native: (i) improved RNA target affinity, (ii) comparable RNase H cleavage rate, and (iii) higher blood serum stability.

    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-96272 (URN)10.1021/ja0634977 (DOI)000242216100046 ()17117869 (PubMedID)
    Available from: 2007-10-16 Created: 2007-10-16 Last updated: 2017-12-14
    3. Five- and Six-Membered Conformationally Locked 2‘,4‘-Carbocyclic ribo-Thymidines: Synthesis, Structure, and Biochemical Studies
    Open this publication in new window or tab >>Five- and Six-Membered Conformationally Locked 2‘,4‘-Carbocyclic ribo-Thymidines: Synthesis, Structure, and Biochemical Studies
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    2007 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 129, no 26, p. 8362-8379Article in journal (Refereed) Published
    Abstract [en]

    Two unusual reactions involving the 5-hexenyl or the 6-heptenyl radical cyclization of a distant double bond at C4' and the radical center at C2' of the ribofuranose ring of thymidine have been used as key steps to synthesize North-type conformationally constrained cis-fused bicyclic five-membered and six-membered carbocyclic analogues of LNA (carbocyclic-LNA-T) and ENA (carbocyclic-ENA-T) in high yields. Their structures have been confirmed unambiguously by long range iH-13C NMR correlation (HMBC), TOCSY, COSY, and NOE experiments. The carbocyclic-LNA-T and carbocyclic-ENA-T were subsequently incorporated into the antisense oligonucleotides (AONs) to show that they enhance the Tm of the modified AON/RNA heteroduplexes by 3.5-5 °C and 1.5 °C/modification for carbocyclic-LNA-T and carbocyclic-ENA-T, respectively. Whereas the relative RNase H cleavage rates with carbocyclic-LNA-T, carbocyclic-ENA-T, aza-ENA-T, and LNA-T modified AON/RNA duplexes were found to be very similar to that of the native counterpart, irrespective of the type and the site modification in the AON strand, a single incorporation of carbocyclic-LNA and carbocyclic-ENA into AONs leads to very much more enhanced nuclease stability in the blood serum (stable >48 h) as compared to that of the native (fully degraded <3 h) and the LNA-modified AONs (fully degraded <9 h) and aza-ENA (≈85% stable in 48 h). Clearly, remarkably enhanced lifetimes of these carbocyclic-modified AONs in the blood serum may produce the highly desired pharmacokinetic properties because of their unique stability and consequently a net reduction of the required dosage. This unique quality as well as their efficient use as the AON in the RNase H-promoted cleavage of the target RNA makes our carbocyclic-LNA and carbocyclic-ENA modifications excellent candidates as potential antisense therapeutic agents.

    National Category
    Biological Sciences Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-96273 (URN)10.1021/ja071106y (DOI)000247563700050 ()17552524 (PubMedID)
    Available from: 2007-10-16 Created: 2007-10-16 Last updated: 2017-12-14Bibliographically approved
    4. Significant pKa Perturbation of Nucleobases Is an Intrinsic Property of the Sequence Context in DNA and RNA
    Open this publication in new window or tab >>Significant pKa Perturbation of Nucleobases Is an Intrinsic Property of the Sequence Context in DNA and RNA
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    2004 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 126, no 28, p. 8674-8681Article in journal (Refereed) Published
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-96321 (URN)10.1021/ja048484c (DOI)
    Available from: 2007-10-18 Created: 2007-10-18 Last updated: 2017-12-14Bibliographically approved
    5. Non-identical electronic characters of the internucleotidic phosphates in RNA modulate the chemical reactivity of the phosphodiester bonds
    Open this publication in new window or tab >>Non-identical electronic characters of the internucleotidic phosphates in RNA modulate the chemical reactivity of the phosphodiester bonds
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    2006 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 4, no 5, p. 928-941Article in journal (Refereed) Published
    Abstract [en]

    We here show that the electronic properties and the chemical reactivities of the internucleotidic phosphates in the heptameric ssRNAs are dissimilar in a sequence-specific manner because of their non-identical microenvironments, in contrast with the corresponding isosequential ssDNAs. This has been evidenced by monitoring the delta H8(G) shifts upon pH-dependent ionization (pK(a1)) of the central 9-guaninyl (G) to the 9-guanylate ion (G(-)), and its electrostatic effect on each of the internucleotidic phosphate anions, as measured from the resultant delta P-31 shifts (pKa(2)) in the isosequential heptameric ssRNAs vis-`a-vis ssDNAs: [d/r( 5'-Cp(1)Ap(2)Q(1)p(3)Gp(4)Q(2)p(5)Ap(6)C-3'): Q(1) = Q(2) = A (5a/5b) or C (8a/8b), Q(1) = A, Q(2) = C (6a/6b), Q(1) = C, Q(2) = A (7a/7b)]. These oligos with single ionizable G in the centre are chosen because of the fact that the pseudoaromatic character of G can be easily modulated in a pH-dependent manner by its transformation to G(-) (the 2'-OH to 2-O- ionization effect is not detectable below pH 11.6 as evident from the N1-Me-G analog), thereby modulating/titrating the nature of the electrostatic interactions of G to G- with the phosphates, which therefore constitute simple models to interrogate how the variable pseudoaromatic characters of nucleobases under different sequence context (J. Am. Chem. Soc., 2004, 126, 8674-8681) can actually influence the reactivity of the internucleotide phosphates as a result of modulation of sequence context-specific electrostatic interactions. In order to better understand the impact of the electrostatic effect of the G to G- on the tunability of the electronic character of internucleotidic phosphates in the heptameric ssRNAs 5b, 6b, 7b and 8b, we have also performed their alkaline hydrolysis at pH 12.5 at 20 degrees C, and have identified the preferences of the cleavage sites at various phosphates, which are p(2), p(3) and p(4) (Fig. 3). The results of these alkaline hydrolysis studies have been compared with the hydrolysis of analogous N1-Me-G heptameric ssRNA sequences 5c, 7c and 8c under identical conditions in order to establish the role of the electrostatic effect of the 9-guanylate ion (and the 2'-OH to 2-O- ionization) on the internucleotidic phosphate. It turned out that the relative alkaline hydrolysis rate at those particular phosphates ( p2, p3 and p(4)) in the N1-Me-G heptamers was reduced from 16-78% compared to those in the native counterparts [Fig. 4, and ESI 2 (Fig. S11)]. Thus, these physico-chemical studies have shown that those p2, p3 and p4 phosphates in the native heptameric RNAs, which show pK(a2) as well as more deshielding ( owing to weaker P-31 screening) in the alkaline pH compared to those at the neutral pH, are more prone to the alkaline hydrolysis because of their relatively enhanced electrophilic character resulting from weaker P-31 screening. This screening effect originates as a result of the systematic charge repulsion effect between the electron cloud in the outermost orbitals of phosphorus and the central guanylate ion, leading to delocalization of the phosphorus pp charge into its d pi orbitals. It is thus likely that, just as in the non-enzymatic hydrolysis, the enzymatic hydrolysis of a specific phosphate in RNA by general base-catalyss in RNA-cleaving proteins (RNase A, RNA phosphodiesterase or nuclease) can potentially be electrostatically influenced by tuning the transient charge on the nucleobase in the steric proximity or as a result of specific sequence context owing to nearest-neighbor interactions.

    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-96322 (URN)10.1039/B516733G (DOI)000235992700023 ()
    Available from: 2007-10-18 Created: 2007-10-18 Last updated: 2017-12-14Bibliographically approved
  • 7.
    Blom, Elisabeth
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Monazzam, Azita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Razifar, Pasha
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Centre for Image Analysis. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Nair, Manoj
    Razifar, Payam
    Vanderheyden, Jean-Luc
    Krivoshein, Arcadius V.
    Backer, Marina
    Backer, Joseph
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Synthesis and characterization of scVEGF-PEG-[68Ga]NOTA and scVEGF-PEG-[68Ga]DOTA PET tracers2011In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 54, no 11, p. 685-692Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial growth factor (VEGF) signaling via vascular endothelial growth factor receptor 2 (VEGFR-2) on tumor endothelial cells is a critical driver of tumor angiogenesis. Novel anti-angiogenic drugs target VEGF/VEGFR-2 signaling and induce changes in VEGFR-2 prevalence. To monitor VEGFR-2 prevalence in the course of treatment, we are evaluating (68)Ga positron emission tomography imaging agents based on macrocyclic chelators, site-specifically conjugated via polyethylene glycol (PEG) linkers to engineered VEGFR-2 ligand, single-chain (sc) VEGF. The (68)Ga-labeling was performed at room temperature with NOTA (2,2', 2 ''-(1,4,7-triazonane-1,4,7-triyl) triacetic acid) conjugates or at 90 degrees C by using either conventional or microwave heating with NOTA and DOTA (2,2', 2 '', 2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl) tetraacetic acid) conjugates. The fastest (similar to 2min) and the highest incorporation (>90%) of (68)Ga into conjugate that resulted in the highest specific radioactivity (similar to 400MBq/nmol) was obtained with microwave heating of the conjugates. The bioactivity of the NOTA-and DOTA-containing tracers was validated in 3-D tissue culture model of 293/KDR cells engineered to express high levels of VEGFR-2. The NOTA-containing tracer also displayed a rapid accumulation (similar to 20s after intravenous injection) to steady-state level in xenograft tumor models. A combination of high specific radioactivity and maintenance of functional activity suggests that scVEGF-PEG-[(68)Ga] NOTA and scVEGF-PEG-[(68)Ga] DOTA might be promising tracers for monitoring VEGFR-2 prevalence and should be further explored.

  • 8.
    Chatterjee, Subhrangsu
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Physicochemical and Structural Aspects of Nucleic Acids2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis consists of seven research publications concerning (i) pKa studies of nucleobases in model nucleotides to understand why RNA duplexes are more stable than DNA duplexes (Paper I), (ii) the role of Me(T)-π interactions in the relative stability of DNA-RNA heteroduplexes (Paper II), (iii) pKa measurements in nucleotides with different 2′-substituents (paper III), (iv) a conformation study of constrained sugars and a pKa study of 1-thyminyl to reveal effect of sugar constraints on the pKa of the nucleobase (paper IV), (v) NMR and MD studies of 1′, 2′-oxetane constrained thymidine incorporated Dickerson Drew dodecamer (paper V), (vi) the sequence dependent pKa perturbation of 9-guaninyl moeity in single stranded (ss) DNA and RNA (paper VI), (vii) the non identical chemical nature of internucleotidic phosphates in (ss) RNA using 31P NMR (paper VI), and an alkaline hydrolysis study of phosphodiesters in ssRNAs (paper VII). The architecture of DNA and RNA molecules is determined by (a) hydrogen bonding (b) base stacking (c) a variety of additional non-covalent interactions. In paper (I) we showed that A-U and G-C base pairings in RNA are more stable than A-T and G-C base pairings in DNA by 4.3 and 1 kJ mol-1 respectively. Me(T)-π interaction plays a dominant role in the relative stability of DNA-RNA duplexes (paper II). In paper III and IV, we have shown that 1′ , 2′- oxetane and azetidine rings have strong inductive effect on pyrimidine bases, and that the H2′-sugar proton can be the marker to understand the pseudoaromaticity of pyrimidine bases, as well as increasing constraints in sugar reducing the basicity of nucleobases. A 1′, 2′-oxetane locked thymidine (T) moiety deforms the local structure of Dickerson-Drew dodecamer, d(CGCGAATTCGCG)2- investigated by High resolution NMR and MD study, as is discussed in the paper V. In papers VI and VII, we showed sequence context dependent pKa (N1) of 9-guaninyl perturbation in (ss) DNAs and RNAs and the non identical chemical nature of inter-nucleotidic phosphate groups in single stranded RNAs.

    List of papers
    1. Measurement of nucleobase pKa values in model mononucleotides shows RNA-RNA duplexes to be more stable than DNA-DNA duplexes
    Open this publication in new window or tab >>Measurement of nucleobase pKa values in model mononucleotides shows RNA-RNA duplexes to be more stable than DNA-DNA duplexes
    Show others...
    2004 In: J. Am. Chem. Soc., Vol. 126, p. 2862-2869Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-96570 (URN)
    Available from: 2007-12-20 Created: 2007-12-20Bibliographically approved
    2. The 5-Me of thyminyl (T) interaction with the neighboring nucleobases dictate the relative stability of isosequential DNA-RNA hybrid duplexes.
    Open this publication in new window or tab >>The 5-Me of thyminyl (T) interaction with the neighboring nucleobases dictate the relative stability of isosequential DNA-RNA hybrid duplexes.
    2005 In: Org. Biomol. Chem., Vol. 3, p. 3911-3915Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-96571 (URN)
    Available from: 2007-12-20 Created: 2007-12-20Bibliographically approved
    3. The chemical nature of the 2'-substituent in the pentose-sugar dictates the pseudoaromatic character of the nucleobase (pKa) in DNA/RNA.
    Open this publication in new window or tab >>The chemical nature of the 2'-substituent in the pentose-sugar dictates the pseudoaromatic character of the nucleobase (pKa) in DNA/RNA.
    Show others...
    2006 In: Org. Biomol. Chem., Vol. 4, p. 1675-1686Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-96572 (URN)
    Available from: 2007-12-20 Created: 2007-12-20Bibliographically approved
    4. Chemical and Structural Implications of 1‘,2‘- versus 2‘,4‘- Conformational Constraints in the Sugar Moiety of Modified Thymine Nucleosides
    Open this publication in new window or tab >>Chemical and Structural Implications of 1‘,2‘- versus 2‘,4‘- Conformational Constraints in the Sugar Moiety of Modified Thymine Nucleosides
    Show others...
    2007 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 72, no 13, p. 4716-4726Article in journal (Refereed) Published
    Abstract [en]

    In order to understand how the chemical nature of the conformational constraint of the sugar moiety in ON/RNA(DNA) dictates the duplex structure and reactivity, we have determined molecular structures and dynamics of the conformationally constrained 1‘,2‘-azetidine- and 1‘,2‘-oxetane-fused thymidines, as well as their 2‘,4‘-fused thymine (T) counterparts such as LNA-T, 2‘-amino LNA-T, ENA-T, and aza-ENA-T by NMR, ab initio (HF/6-31G** and B3LYP/6-31++G**), and molecular dynamics simulations (2 ns in the explicit aqueous medium). It has been found that, depending upon whether the modification leads to a bicyclic 1‘,2‘-fused or a tricyclic 2‘,4‘-fused system, they fall into two distinct categories characterized by their respective internal dynamics of the glycosidic and the backbone torsions as well as by characteristic North-East type sugar conformation (P = 37° ± 27°, φm = 25° ± 18°) of the 1‘,2‘-fused systems, and (ii) pure North type (P = 19° ± 8°, φm = 48° ± 4°) for the 2‘,4‘-fused nucleosides. Each group has different conformational hyperspace accessible, despite the overall similarity of the North-type conformational constraints imposed by the 1‘,2‘- or 2‘,4‘-linked modification. The comparison of pKas of the 1-thyminyl aglycon as well as that of endocyclic sugar-nitrogen obtained by theoretical and experimental measurements showed that the nature of the sugar conformational constraints steer the physicochemical property (pKa) of the constituent 1-thyminyl moiety, which in turn can play a part in tuning the strength of hydrogen bonding in the basepairing.

    National Category
    Chemical Sciences Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-96274 (URN)10.1021/jo070356u (DOI)000247246100014 ()
    Available from: 2007-10-16 Created: 2007-10-16 Last updated: 2017-12-14Bibliographically approved
    5. Oxetane locked thymidine in the Dickerson-Drew dodecamer causes local base pairing distortions: an NMR structure and hydration study
    Open this publication in new window or tab >>Oxetane locked thymidine in the Dickerson-Drew dodecamer causes local base pairing distortions: an NMR structure and hydration study
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    2005 (English)In: Journal of Biomolecular Structure and Dynamics, ISSN 0739-1102, E-ISSN 1538-0254, Vol. 23, no 3, p. 299-330Article in journal (Refereed) Published
    Abstract [en]

    The introduction of a North-type sugar conformation constrained oxetane T block, 1-(1',3'-O-anhydro-beta-D-psicofuranosyl) thymine, at the T(7) position of the self-complementary Dickerson-Drew dodecamer, d[(5'-C(1)G(2)C(3)G(4)A(5)A(6)T(7)T(8)C(9)G(10)C(11)G(12)-3')](2), considerably perturbs the conformation of the four central base pairs, reducing the stability of the structure. UV spectroscopy and 1D NMR display a drop in melting temperature of approximately 10 degrees C per modification for the T(7) oxetane modified duplex, where the T(7) block has been introduced in both strands, compared to the native Dickerson-Drew dodecamer. The three dimensional structure has been determined by NMR spectroscopy and has subsequently been compared with the results of 2.4 ns MD simulations of the native and the T(7) oxetane modified duplexes. The modified T(7) residue is found to maintain its constrained sugar- and the related glycosyl torsion conformations in the duplex, resulting in staggered and stretched T(7).A(6) and A(6).T(7) non-linear base pairs. The stacking is less perturbed, but there is an increased roll between the two central residues compared to the native counterpart, which is compensated by tilts of the neighboring base steps. The one dimensional melting profile of base protons of the T(7) and T(8) residues reveals that the introduction of the North-type sugar constrained thymine destabilizes the core of the modified duplex, promoting melting to start simultaneously from the center as well as from the ends. Temperature dependent hydration studies by NMR demonstrate that the central T(7).A(6)/A(6).T(7) base pairs of the T(7) oxetane modified Dickerson-Drew dodecamer have at least one order of magnitude higher water exchange rates (correlated to the opening rate of the base pair) than the corresponding base pairs in the native duplex.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-96275 (URN)10.1080/07391102.2005.10507067 (DOI)16218756 (PubMedID)
    Available from: 2007-10-16 Created: 2007-10-16 Last updated: 2017-12-14Bibliographically approved
    6. VI.Significant pKa Perturbation of Nucleobases Is an Intrinsic Property of the Sequence Context in DNA and RNA.
    Open this publication in new window or tab >>VI.Significant pKa Perturbation of Nucleobases Is an Intrinsic Property of the Sequence Context in DNA and RNA.
    Show others...
    2004 In: J. Am. Chem. Soc., Vol. 126, p. 8674-8681Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-96575 (URN)
    Available from: 2007-12-20 Created: 2007-12-20Bibliographically approved
    7. Non-identical electronic characters of the internucleotidic phosphates in RNA modulate the chemical reactivity of the phosphodiester bonds.
    Open this publication in new window or tab >>Non-identical electronic characters of the internucleotidic phosphates in RNA modulate the chemical reactivity of the phosphodiester bonds.
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    2006 In: Org. Biomol. Chem., Vol. 4, p. 928-941Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-96576 (URN)
    Available from: 2007-12-20 Created: 2007-12-20 Last updated: 2010-03-03Bibliographically approved
  • 9. Coleman, V. A.
    et al.
    Knut, Ronny
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and condensed matter physics.
    Karis, Olof
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and condensed matter physics.
    Grennberg, H.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Jansson, U.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry.
    Quinlan, R.
    Holloway, B. C.
    Sanyal, Biplab
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Materials Science, Materials Theory.
    Eriksson, Olle
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Materials Science, Materials Theory.
    Defect Formation In Graphene Nanosheets By Acid Treatment: An X-Ray Absorption Spectroscopy And Density Functional Theory Study2008In: Journal of Physics D: Applied Physics, ISSN 0022-3727, E-ISSN 1361-6463, Vol. 41, no 6, p. 062001-4Article in journal (Refereed)
    Abstract [en]

    In-plane defects have been introduced into graphene nanosheets by treatment with hydrochloric acid. Acid treatment induces bond cleavage in the C–C network via electrophilic attack. These resultant vacancy sites will then undergo further reactions with the surrounding ambient to produce C–O and C–H bonds. A σ* resonance at 287 eV in the carbon K-edge x-ray absorption spectra is observed with acid treatment and is assigned to C–O states. Theoretical modelling of a di-vacancy in a graphene bilayer reproduces all essential features of this resonance and in addition predicts a metallic conductivity of states around this vacancy. The possibility of engineering the properties of graphene via the routes explored here is an important step towards establishing strategies for building devices based on this material.

  • 10.
    Eklöf, Anders M.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Lowcoordinated Silicon and Hypercoordinated Carbon: Structure and Stability of Silicon Analogs of Alkenes and Carbon Analogs of Silicates2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Quantum chemical studies on lowcoordinated group 14-16 compounds have been performed. This thesis focuses particularly on silenes influenced by reverse Siδ-=Cδ+ bond polarization. Hypercoordinated carbon compounds are also studied.

    The geometries from calculations with several common computationally inexpensive methods have been tested against high level CCSD/cc-pVTZ geometries for a series of substituted silenes. Hybrid HF/DFT methods performed best among the inexpensive methods tested for silenes.

    Heavy alkenes strongly influenced by reverse polarization are found to have less exothermic dimerization energies for both head-to-head and head-to-tail dimerizations, and to have higher activation energies for water addition than naturally polarized heavy alkenes.

    We also investigated solvated lithium, magnesium and potassium silenolates and found that lithium and magnesium ions coordinate preferably to O, giving their SiC bond some double bond character.

    Reverse polarized 2-siloxy-, 2-thiosiloxy-, and 2-(N-sila-N-methyl)-silenes could according to calculations be formed thermolytically from the corresponding tetrasilanes as transient species. It was, however, found that silenes highly influenced by π-conjugative reverse polarization have low barriers for the back-reaction, and thus these silenes are more difficult to form as stable species than naturally polarized silenes.

    It is also found that conjugated 1-siladienes, formed by electrocyclic ring-opening of 1-silacyclobut-2-enes, which are highly influenced by π-conjugative reverse polarization, have higher barriers for electrocyclization back to starting material than naturally polarized 1-siladienes.

    It is found that CHe54+, CHe64+, CNe54+, and CNe64+ are the closest carbon analogs of SiH5-, SiH62-, SiF5- and SiF62-, respectively. However, due to their exothermic dissociation reaction, these very high-lying local minima will be impossible to reach experimentally.

    List of papers
    1. An Assessment of the Performance of Inexpensive Quantum Chemical Methods for the Calculation of Substituted Silenes and Stannenes
    Open this publication in new window or tab >>An Assessment of the Performance of Inexpensive Quantum Chemical Methods for the Calculation of Substituted Silenes and Stannenes
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-97584 (URN)
    Available from: 2008-10-03 Created: 2008-10-03 Last updated: 2010-01-13Bibliographically approved
    2. On the Role of the π-Contribution to Reverse Polarization for Structure and Stability of Heavy group 14-16 Alkene, Imine, and Carbonyl analogs
    Open this publication in new window or tab >>On the Role of the π-Contribution to Reverse Polarization for Structure and Stability of Heavy group 14-16 Alkene, Imine, and Carbonyl analogs
    In: Journal of the American Chemical SocietyArticle in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-97585 (URN)
    Available from: 2008-10-03 Created: 2008-10-03Bibliographically approved
    3. Effects of Substituents and Counterions on the Structures of Silenolates: A Computational Investigation
    Open this publication in new window or tab >>Effects of Substituents and Counterions on the Structures of Silenolates: A Computational Investigation
    2009 (English)In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 65, no 28, p. 5521-5526Article in journal (Refereed) Published
    Abstract [en]

    The structures and charge distributions of substituted silenolates   [H2SiC(=O)X](-) (X-H, SiH3, Me, t-Bu, OMe, NMe2; group A),  [Y2SiC(=O)H](-) (Y=H, F, Me, Ph, SiH3, SiMe3; group B), and [Y2SiC(=O)X](-) (Y=Me, X=t-Bu, and Y=SiMe3; X=t-Bu, OMe, NMe2; group C)   were examined through density functional theory calculations. The effects of the solvated counterion (K+, Li+, or MgCl+) and coordination site (O or Si) on the properties of group C silenolates were also Studied. The variation in the degree of pi-conjugative reverse SiC bond   polarization, Sigma Phi(RP)(pi) calculated by natural resonance theory,   was determined. The Sigma Phi(RP)(pi) correlated with r(SiC) for both   group A and B silenolates, and the correlation between Sigma   Phi(RP)(pi) and the Sum of valence angles at Si, Sigma alpha(Si), was   good for group A but poor for group B due to strong influence of the   inductive effect. The SiC charge difference correlated well with Sigma   Phi(RP)(pi) for group A, but not for group B, again an effect of   inductive substituent effects. The group C silenolates were Coordinated   to Li(THF)(3)(+), MgCl(THF)(4)(+), and K(THF)(5)(+) either via the O or   Si atom. The coordination energies show that coordination to the hard O   is preferred for Li+ and MgCl+, but the K+ ion coordinated   simultaneously to Si and O. Coordination of the solvated metal ion to O  resulted in shorter SiC bond length, an increased Sigma alpha(Si)   value, and lower Delta q(SiC) when compared to the naked silenolate.  Choice Of counterion and substituent provides a means to extensively vary the properties of silenolates such as their reactivity.

    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-97586 (URN)10.1016/j.tet.2009.02.088 (DOI)000268128000010 ()
    Available from: 2008-10-03 Created: 2008-10-03 Last updated: 2017-12-14Bibliographically approved
    4. Relation between the π-Contribution to Reversed Si═C Bond Polarization and the Reaction Profile for the Thermolytic Formation of Silenes
    Open this publication in new window or tab >>Relation between the π-Contribution to Reversed Si═C Bond Polarization and the Reaction Profile for the Thermolytic Formation of Silenes
    2008 (English)In: Organometallics, ISSN 0276-7333, E-ISSN 1520-6041, Vol. 27, no 20, p. 5203-5211Article in journal (Refereed) Published
    Abstract [en]

    A quantum chemical investigation of the reaction profiles for the thermal formation of silenes Z2Si═C(XSiH3)Y from silanes Z2(H3Si)Si−C(═X)Y (X = O, S, NMe; Y = NMe2, OMe, SMe, Me; Z = SiH3, Me) has been performed. Focus was put on the influence of the π-conjugative contribution to reversed Si═C bond polarization (Siδ−═Cδ+) as determined by natural resonance theory (NRT) at the B3LYP density functional theory level. Good linear correlations between the weights of π-conjugated reverse polarized resonance structures (ΣΦRP(π)) in the electronic structure and the Si═C bond lengths were found for the two classes of silenes with Z = SiH3 and Me (r2 = 0.957 and 0.955, respectively). Silenes that are strongly influenced by the π-conjugative reverse polarization have low barriers for back-reaction to the silanes, making these silenes more difficult to isolate when formed through a [1,3]-silyl shift than those that are naturally polarized. Modest exponential dependencies of the activation barriers for the reverse reactions on ΣΦRP(π) are found (r2 = 0.685 for Z = SiH3 and r2 = 0.699 for Z = Me). Species with the silyl groups replaced by trimethylsilyl groups, e.g., the Brook-type silene (Me3Si)2Si═C(OSiMe3)t-Bu, have lower contributions of ΣΦRP(π) by 3−23% than the corresponding model silenes, a result of steric bulk. The weight ΣΦRP(π) to the electronic structure of (Me3Si)2Si═C(OSiMe3)t-Bu was calculated to be 7.4%. With Z = Me, the silenes are in general not equally influenced by ΣΦRP(π) as with Z = SiH3, their energies relative to the silanes are higher, and they have higher activation barriers for both forward and backward reactions.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-97587 (URN)10.1021/om800477j (DOI)
    Available from: 2008-10-03 Created: 2008-10-03 Last updated: 2017-12-14Bibliographically approved
    5. A Computational Investigation of the Retrocyclization Reaction of Silacyclo-but-2-enes to 1-silabuta-1,3-dienes: Focus on the effect of the substituents
    Open this publication in new window or tab >>A Computational Investigation of the Retrocyclization Reaction of Silacyclo-but-2-enes to 1-silabuta-1,3-dienes: Focus on the effect of the substituents
    2007 (English)In: Journal of Molecular Structure: THEOCHEM, ISSN 0166-1280, Vol. 811, no 1-3, p. 153-160Article in journal (Refereed) Published
    Abstract [en]

    Substituent effects on the reaction profile of the thermal retrocyclization reaction of silacyclobut-2-enes to 1-silabuta-1,3-dienes were studied using B3LYP hybrid density functional theory as well as CCSD and CCSD(T) ab initio calculations. Several different substituents (–CF3, –SiH3, –CN, –OCH3, –OH, and –NH2) were used to investigate their effects on the relative energies of the transition states of the retrocyclization reaction as well as of the 1-silabutadiene products. It was found that π-donor groups at the 4-position greatly reduce the energy barriers, and also stabilize the 1-silabutadienes relative to the silacyclobut-2-enes. Silyl substituents at the silicon atom will facilitate the reaction when compared to alkyl substituents. The results thus indicate that the ring-opening reaction of 4,4-disubstituted 1,1-disilylsilacyclobut-2-enes with π-donor substituents are particularly suitable entries for formation of 1-silabutadienes of low relative energy.

    Keyword
    Silicon, Retrocyclization, Density functional theory, Ab initio, Silene, Silacyclobut-2-ene, 1-Silabutadiene
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-97588 (URN)10.1016/j.theochem.2007.02.024 (DOI)000247053500018 ()
    Available from: 2008-10-03 Created: 2008-10-03 Last updated: 2017-12-14Bibliographically approved
  • 11. Enander, Karin
    et al.
    Aili, D.
    Baltzer, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    Lundström, I.
    Liedberg, B.
    Alpha helix-inducing dimerization of synthetic plypeptide scaffolds on gold2005In: Langmuir, no 21, p. 2480-2487Article in journal (Refereed)
  • 12. Enander, Karin
    et al.
    Dolphin, Gunnar T.
    Baltzer, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    Designed, functionalized helix-loop-helix motifs that bind human Carbonic Anhydrase II - a new class of synthetic receptor molecules2004In: J. Am. Chem. Soc., no 126, p. 4464-4465Article in journal (Refereed)
  • 13. Enander, Karin
    et al.
    Dolphin, Gunnar T.
    Liedberg, Bo
    Lundström, Ingemar
    Baltzer, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    A versatile polypeptide platform for integrated recognition and reporting - affinity arrays for protein-ligand interaction2004In: Chem. Eur. J., no 10, p. 2375-2385Article in journal (Refereed)
  • 14.
    Engman, Mattias
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Chemo- and Enantioselective Hydrogenations: The Struggle of Expanding the Substrate Scope of Iridium Catalyzed Asymmetric Hydrogenations of Olefins2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The asymmetric hydrogenation of olefins is a facile and popular method of reaching chiral products. Whereas ruthenium- and rhodium-catalyzed asymmetric hydrogenations have a long history, the use of iridium in this area is new but fast-growing. Since the first chiral N,P-ligated iridium catalyst was created in the late 1990s, the growing pool of N,P ligands has filled up rapidly, but most have been tested with a limited range of standard olefins. To extract the full potential of these complexes, new methods using substrates having many possible applications must be developed. This thesis focuses on the iridium-catalyzed asymmetric hydrogenation of three different new substrate classes to yield very high conversions and enantiomeric excesses (ee's). As the use of fluorine has recently become common in many different fields of chemistry, the asymmetric reduction of fluoroolefins to reach chiral products having fluorine at the stereogenic centers is highly interesting. We studied this reaction and eventually obtained very high ee values and lower degree of defluorination (Paper I and Paper II). The hydrogenations of trifluoromethylated olefins to reach products useful in applications reaching from pharmaceuticals to additives in liquid crystal displays (LCDs) were also challenging, but fruitful (Paper III). As asymmetric hydrogenation usually demands differences in the substituents of the double bond, the highly selective reduction of 1,1-diaryl olefins having similar aryls give a new perspective on the broad scope of substrates that N,P-ligated iridium complexes can reduce selectively (paper IV).

    List of papers
    1. Iridium-Catalyzed Asymmetric Hydrogenation of Fluorinated Olefins Using N,P-Ligands: A struggle with hydrogenolysis and selectivity
    Open this publication in new window or tab >>Iridium-Catalyzed Asymmetric Hydrogenation of Fluorinated Olefins Using N,P-Ligands: A struggle with hydrogenolysis and selectivity
    2007 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 129, no 15, p. 4536-4537Article in journal (Refereed) Published
    Abstract [en]

    To broaden the substrate scope of asymmetric iridium-catalyzed hydrogenation, fluorine-functionalized olefins were synthesized and hydrogenated with iridium complexes. Preliminary results showed high levels of fluorine elimination together with low selectivity. The loss of vinylic fluorine at first seemed difficult to handle, but further studies revealed that a catalyst with an azanorbornyl scaffold in the ligand gave more promising results. With this in mind, a new ligand was developed. This gave among the best results published to date for fluorine asymmetric hydrogenation, yielding high conversion and very high ee's with very little fluorine elimination. Further increasing the selectivity, the trials also revealed that tetrasubstituted fluorine-containing olefins can be hydrogenated with high ee's, despite that this class of compounds has usually shown low reactivity in this reaction type.

    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-97352 (URN)10.1021/ja0686763 (DOI)000245739700016 ()17375924 (PubMedID)
    Available from: 2008-05-13 Created: 2008-05-13 Last updated: 2017-12-14Bibliographically approved
    2. Iridium Catalysts with Chiral Imidazole-Phosphine Ligands for Asymmetric Hydrogenation of Vinyl Fluorides and other Olefins
    Open this publication in new window or tab >>Iridium Catalysts with Chiral Imidazole-Phosphine Ligands for Asymmetric Hydrogenation of Vinyl Fluorides and other Olefins
    Show others...
    2008 (English)In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 350, no 7-8, p. 1168-1176Article in journal (Refereed) Published
    Abstract [en]

    New chiral bidentate imidazole-phosphine ligands have been prepared and evaluated for the iridium-catalysed asymmetric hydrogenation of olefins. The imidazole-phosphine-ligated iridium catalysts hydrogenated trisubstituted olefins with the same sense of enantiodiscrimination as known iridium catalysts possessing oxazole and thiazole as N-donors. The imidazole-based catalysts were shown to hydrogenate vinyl fluorides, in some cases with the highest ee values published to date.

    Keyword
    asymmetric hydrogenation, iridium, N, P donating ligand, vinyl fluorides
    National Category
    Analytical Chemistry Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-99805 (URN)10.1002/adsc.200800062 (DOI)
    Available from: 2009-03-20 Created: 2009-03-20 Last updated: 2017-12-13Bibliographically approved
    3.
    The record could not be found. The reason may be that the record is no longer available or you may have typed in a wrong id in the address field.
    4. Iridium-Catalyzed Asymmetric Hydrogenation yielding Chiral Diarylmethines with Weakly Coordinating or Noncoordinating Substituents
    Open this publication in new window or tab >>Iridium-Catalyzed Asymmetric Hydrogenation yielding Chiral Diarylmethines with Weakly Coordinating or Noncoordinating Substituents
    Show others...
    2009 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 131, no 25, p. 8855-8860Article in journal (Refereed) Published
    Abstract [en]

    Diarylimethine-containing stereocenters are present in pharmaceuticals   and natural products, making the synthetic methods that form these   chiral centers are important in industry. We have applied iridium   complexes with novel N,P-chelating ligands to the asymmetric  hydrogenation of trisubstituted olefins, forming diarylmethine chiral   centers in high conversions and excellent enantioselectivities (up to   99% ee) for a broad range of substrates. Our results support the hypothesis that steric hindrance in one specific area of the catalyst   is playing a key role in stereoselection, as the hydrogenation of   substrates differing little at the prochiral carbon occurred with high enantioselectivity. As a result, excellent stereodiscrimination was obtained even when the prochiral carbon bore, for example, phenyl and p-tolyl groups.

    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-99807 (URN)10.1021/ja9013375 (DOI)000267631000039 ()19552449 (PubMedID)
    Available from: 2009-03-20 Created: 2009-03-20 Last updated: 2017-12-13Bibliographically approved
  • 15.
    Erlandsson, Maria
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    Karimi, Farhad
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    Takahashi, Kayo
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    Långström, Bengt
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    18F-Labelled vorozole analogues as PET tracer for aromatase2008In: J. Label Compd Radiopharm, no 51, p. 207-212Article in journal (Refereed)
  • 16. Fang, Yao-ren
    et al.
    MacMillar, Susanna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Kolodziejska-Huben, Magdalena
    Dybala-Defratyka, Agnieszka
    Paneth, Piotr
    Matsson, Olle
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    Westaway, Kenneth Charles
    The Effect of Solvent on the Structure of the Transition State for the SN2 Reaction between Cyanide Ion and Ethyl Chloride in DMSO and THF Probed with Six Different Kinetic Isotope Effects2006In: J. Org. Chem, no 71, p. 4742-4747Article in journal (Refereed)
    Abstract [en]

    The secondary a- and B-deuterium, the a-carbon, the nucleophile carbon, the nucleophile nitrogen, and the chlorine leaving group kinetic isotope effects forthe SN2 reaction between cyanide ion an dethyl chloride were determined in the very slightly polar solvent THF at 30 C. A comparison of these KIEs with those reported earlier for the same reaction in the polar solvent DMSO shows that the transition state in THF is only sligthly tighter with very slightly shorter NC-Ca-CI bonds. This minor change in transition state structure does not account for the different transition structures that were earlier suggested by interpreting the experimental KIEs and the gas-phase calculations, respectively. It therefore seems unlikely that the different transition states suggested by the two methods are due to the lack of appropriate solvent modeling in the theoretical calculations. Previously it was predicted that the transition state of SN2 reactions where the nucleophile and the leaving group have the same charge would be unaffected by a charge in solvent. The experimental KIEs support this view.

  • 17.
    Govender, Thavendran
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
    Hojabri, Leila
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
    Matloubi Moghaddam, Firouz
    Arvidsson, Per I.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
    Organocatalytic synthesis of chiral benzopyrans2006In: Tetrahedron: Asymmetry, no 17, p. 1763-1767Article in journal (Refereed)
    Abstract [en]

    Benzopyrans, or chromenes, are widespread in nature and are considered to be a privileged scaffold in medicinal chemistry. Herein, we report the first organocatalyzed asymmetric synthesis of chiral benzopyrans. The benzopyran unit is constructed through a domino reaction involving an oxa-Michael attack of salicylic aldehyde derivatives onto a,B-unsaturated aldehydes, activated through iminium-ion formation with the organocatalyst, followed by an intramolecular aldol reaction and subsequent elimination of water. This overall reaction sequence provides benzopyrans with aromatic C-2 substituents in up to 60% enantioselectivity, while C-2 aliphatic analogues can be obtained in 90% enantiomeric excess, but with only 20% yield. The role of additives, as well as the possible racemization of the benzopyran, was also investigated.

  • 18.
    Hartikka, Antti
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry.
    Towards Rational Design of Asymmetric Catalyst for Organometallic and Organocatalytic Reactions2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis deals with synthetically modified chiral molecules and their application in asymmetric catalysis. The first part of the thesis describes the use of commercially available chiral diamine ligands in the iridium catalyzed transfer hydrogenation of aromatic ketones. The chiral diamine ligands were mixed with an appropriate transition-metal complex, which after addition of suitable base provided a chiral transition metal complex capable of reducing a range of different aromatic ketones in high yields and enantioselectivities. The developed methodology constitutes a cost effective and readily available procedure for transfer hydrogenation reactions. The following chapters in the thesis are completely devoted to rational design of small organic molecules acting as catalyst in various organocatalytic transformations. Organocatalytic methodology, represent a new and complementary approach to asymmetric organic synthesis, as compared to e.g. transition metal based methodology. Advantages of this methodology typically include mild and less stringent reaction conditions. This, in combination with the lack of toxic transition metal by-products, makes the process more environmentally benign; the organocatalytic methodology, therefore represent a promising approach towards implementation of green chemistry in organic synthesis. Despite this promise, typical drawbacks of the current methodology are long reaction times and the need for high catalyst loadings. Thus, a large demand exists for enhancing reactivity and increasing selectivity in organocatalytic reactions. The present thesis describes several efforts where we have tried to rationally design improved catalysts for various enantioselective organocata-lytic reactions. First, a structurally modified L-proline, incorporating a 1H-tetrazolic acid, was synthesized and evaluated in the direct asymmetric organocatalytic aldol reaction. As shown in Paper II, the catalyst displayed very high reactivity and subsequent studies were initiated in order to rationalize the reactivity enhancement (Paper III). Delightfully, the design principle of a 1H-tetrazolic acid as replacement for a carboxylic acid has since been widely used in the community, including our own efforts in organocatalytic asymmetric cyclopropanations (Paper V)and Diels-Alder reactions (Paper VII). Novel catalysts, including other functionalizations, were also designed for organocatalytic asymmetric addition of nitroalkanes to α,β-unsaturated aldehydes (Paper IV) and for cyclopropanations (Paper VI).

    List of papers
    1. Cinchona alkaloid derived ligands in catalytic asymmetric transfer hydrogenation
    Open this publication in new window or tab >>Cinchona alkaloid derived ligands in catalytic asymmetric transfer hydrogenation
    2003 In: Organic and biomolecular chemistry, ISSN 1477-0520, Vol. 1, no 14, p. 2522-2526Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-95936 (URN)
    Available from: 2007-05-11 Created: 2007-05-11Bibliographically approved
    2. Rational design of asymmetric organocatalysts-Increased reactivity and solvent scope with a tetrazolic acid
    Open this publication in new window or tab >>Rational design of asymmetric organocatalysts-Increased reactivity and solvent scope with a tetrazolic acid
    2004 In: Tetrahedron: Asymmetry, ISSN 0957-4166, Vol. 15, no 12, p. 1831-1834Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-95937 (URN)
    Available from: 2007-05-11 Created: 2007-05-11Bibliographically approved
    3. 5-(Pyrrolidine-2-yl)tetrazole: Rationale for the Increased Reactivity of the Tetrazole Analogue of Proline in Organocatalyzed Aldol Reaction
    Open this publication in new window or tab >>5-(Pyrrolidine-2-yl)tetrazole: Rationale for the Increased Reactivity of the Tetrazole Analogue of Proline in Organocatalyzed Aldol Reaction
    2005 In: European Journal of Organic Chemistry, ISSN 1434-193X, no 20, p. 4287-4295Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-95938 (URN)
    Available from: 2007-05-11 Created: 2007-05-11Bibliographically approved
    4. A new Imidazole-Containing Imidazolidinone Catalyst for Organocatalyzed Asymmetric Conjugate Addition of Nitroalkanes to Aldehydes
    Open this publication in new window or tab >>A new Imidazole-Containing Imidazolidinone Catalyst for Organocatalyzed Asymmetric Conjugate Addition of Nitroalkanes to Aldehydes
    2007 (English)In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 349, no 4-5, p. 740-748Article in journal (Refereed) Published
    Abstract [en]

    Herein we report a new organocatalyst for the asymmetric Michael addition of nitroalkanes to α,β-unsaturated aldehydes. This catalyst incorporates a basic imidazole group in addition to the secondary amine responsible for activation of the α,β-unsaturated carbonyl compounds via iminium ion formation. The new organocatalyst is capable of catalyzing the enantioselective carbon-carbon bond formation with a high degree of enantiocontrol providing products in enantiomeric excesses of up to 92% and yields of up to to 91 %. These results constitute the best results so far reported for organocatalyzed Michael additions of nitroalkanes to α,β-unsaturated aldehydes, and provide proof of principle that organocatalysts incorporating two internal basic moieties may find broad application in organocatalyzed Michael additions.

    Keyword
    α, β-unsaturated aldehydes, Asymmetric catalysis, C-C coupling, Iminium ion activation, Michael addition, Organocatalysis
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-95939 (URN)10.1002/adsc.200600316 (DOI)000245379400035 ()
    Available from: 2007-05-11 Created: 2007-05-11 Last updated: 2017-12-14Bibliographically approved
    5. Tetrazolic Acid Functionalized Dihydroindol: Rational Design of a Highly Selective Cyclopropanation Organocatalyst
    Open this publication in new window or tab >>Tetrazolic Acid Functionalized Dihydroindol: Rational Design of a Highly Selective Cyclopropanation Organocatalyst
    2007 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 72, no 15, p. 5874-5877Article in journal (Refereed) Published
    Abstract [en]

    Herein we wish to report our development of an improved catalyst (S)-(-)-indoline-2-yl-1H-tetrazole (1) for the enantioselective organocatalyzed cyclopropanation of α,β-unsaturated aldehydes with sulfur ylides. The new organocatalyst readily facilitates the enantioselective organocatalytic cyclopropanation, providing cyclized product in excellent diastereoselectivities ranging from 96% to 98% along with enantioselectivities exceeding 99% enantiomeric excess for all reacted α,β-unsaturated aldehydes. The new catalyst provides the best results so far reported for intermolecular enantioselective organocatalyzed cyclopropanation.

    Keyword
    Nitrogen heterocycle, Diastereoselectivity, Cyclization, Ylide, Organic sulfide, Aldehyde, Unsaturated compound, Enantioselectivity, Tetrazole derivatives, Enantiomeric excess, Catalyst, Cyclopropanation, Selectivity, Indole derivatives, Functionalization
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-95940 (URN)10.1021/jo070519e (DOI)000247992800059 ()
    Available from: 2007-05-11 Created: 2007-05-11 Last updated: 2017-12-14Bibliographically approved
    6. VI.
    Open this publication in new window or tab >>VI.
    In: Tetrahedron: Asymmetry, ISSN 0957-4166Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-95941 (URN)
    Available from: 2007-05-11 Created: 2007-05-11Bibliographically approved
    7. VII.
    Open this publication in new window or tab >>VII.
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-95942 (URN)
    Available from: 2007-05-11 Created: 2007-05-11 Last updated: 2010-01-13Bibliographically approved
  • 19. Hederos, Sofia
    et al.
    Baltzer, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    Nucleophile selectivity in the enzyme catalyzed acyl transfer reaction of a thiol ester2005In: Biopolymers, no 79, p. 292-299Article in journal (Refereed)
  • 20. Holmgren, Arne
    et al.
    Lu, Jun
    Vlamis-Gardikas, Alexios
    Zhao, Rong
    Kandasamy, Karuppasamy
    Engman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
    Hoffner, Sven
    Bacterial Thioredoxin Reductase Inhibitors and Methods for Use Thereof2007Patent (Other (popular scientific, debate etc.))
  • 21.
    Ilovich, Ohad
    et al.
    Hadassah/ Hebrew University Hospital, Jerusalem, Israel.
    Åberg, Ola
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Mishani, Eyal
    Hadassah/ Hebrew University Hospital, Jerusalem, Israel.
    Rhodium-mediated [11C]Carbonylation: A library of N-phenyl-N′-{4-(4-quinolyloxy)-phenyl}-[11C]-urea derivatives as potential PET angiogenic probes2009In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 52, no 5, p. 151-157Article in journal (Refereed)
    Abstract [en]

    As part of our ongoing investigation into the imaging of angiogenic processes, a small library of eight vascular endothelial growth factor receptor-2 (VEGFR-2)/platelet-derived growth factor receptor beta dual inhibitors based on the N-phenyl-N'-4-(4-quinolyloxy)-phenyl-urea was labelled with C-11 (beta(+), t(1/2) = 20.4 min) in the urea carbonyl position via rhodium-mediated carbonylative cross-coupling of an aryl azide and different anilines. The decay-corrected radiochemical yields of the isolated products were in the range of 38-81% calculated from [C-11]carbon monoxide. Starting with 10.7+/-0.5 GBq of [C-11]carbon monoxide, 1-[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-3-(4-fluoro-phenyl)-[C-11]-urea (2.1 GBq) was isolated after total reaction time of 45 min with a specific activity of 92+/-4 GBq mu mol(-1).

  • 22.
    Itsenko, Oleksiy
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    Kihlberg, Tor
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    Långström, Bengt
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    Carboxylation of Alkyl Iodides with [11C] and (13C)Carbon Monoxide: Using Sulfoxides as Oxygen Nucleophiles2005In: Synlett, no 20, p. 3154-3156Article in journal (Refereed)
    Abstract [en]

    11C-Labeled carboxylic acids were prepared from alkyl iodides and [11C]carbon monoxide by irradiation by UV light in anhydrous DMSO solutions in the presence of triethylamine. Sulfoxides other than DMSO can be used and may be used in stoichiometric amounts using inert solvents.

  • 23.
    Itsenko, Oleksiy
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    Kihlberg, Tor
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    Långström, Bengt
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    Synthesis of Aliphatic [carbony.-11C]Esters Using [11C]Carbon Monoxide2005In: Eur. J. Org. Chem., p. 3830-3834Article in journal (Refereed)
    Abstract [en]

    Aliphatic esters were labelled with a short-lived radionuclide,11C with t½=20.3 min, at the carbonyl position using [11C]carbon monoxide via rapid (6 min) photoinduced radical-mediated carbonylation reactions. The esters were prepared from primary, secondary, and tertiary alkyl iodides, and various alcohols, including tert-butyl alcohol and phenol. The use of strong bases was necessary to achieve good radiochemical yields in short reaction time. Isolated decay-corrected radiochemical yields were in the range of 40-68%. For example, methyl hydrogen dodecanoate was labelled at the ester carbonyl in 61% isolated decay-corrected radiochemical yield with a specific radioactivity of 158 GBq/umol within approcimately 25 min of the production of [11C]carbon monoxide. Two (13C]substituted esters were synthesised using this method to verify the labelling position.

  • 24.
    Johansson, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Exploring Novel Catalytic Chalcogenide Antioxidants2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis is concerned with the synthesis and evaluation of regenerable chalcogen containing antioxidants. Variously substituted 2,3-dihydrobenzo[b]selenophene-5-ol antioxidants were evaluated in order to gain information about structure/reactivity-relationships. Within the series explored, the most regenerable unsubstituted compound inhibited lipid peroxidation for more than 320 minutes when assayed in a two-phase lipid peroxidation model in the presence of N-acetylcysteine (NAC). α-Tocopherol which could inhibit lipid peroxidation for 90 minutes under similar conditions was therefore easily outperformed. The antioxidant activity of the parent was also documented in an aqueous environment. The best catalyst quenched/inhibited ROS production by neutrophils and PMA-stimulated macrophages more efficiently than Trolox. In addition, over a period of seven days, no disruption in proliferation for the cell lines used was observed when exposed to our synthetic compound or Trolox at a concentration of 60 µM.

    3-Pyridinols substituted with alkyltelluro groups in the ortho-position were more regenerable in the two-phase model than their corresponding para-substituted analogues in the presence of NAC and also inhibited autoxidation of styrene in a catalytic fashion in homogenous phase in the presence of N-tert-butoxycarbonyl cysteine methyl ester (LipCys), a lipid-soluble analogue of NAC. The best inhibitors quenched peroxyl radicals more efficiently than α-tocopherol. They could also catalyze reduction of organic hydroperoxides in the presence of thiols and therefore mimic the action of the glutathione peroxidase enzymes. Mechanisms for the catalysis are proposed.

    Octylthio, octylseleno and octyltelluro analogues of butylated hydroxyanisole (BHA) were synthesized and evaluated. Among these, the tellurium compound was superior to α-tocopherol in the presence of NAC both when it comes to quenching capacity and regenerability.  Organochalcogen substituent effects in phenolic compounds were studied by using EPR, IR and computational methods.

    List of papers
    1. Regenerable Chain-Breaking 2,3-Dihydrobenzo[b]selenophene-5-ol Antioxidants
    Open this publication in new window or tab >>Regenerable Chain-Breaking 2,3-Dihydrobenzo[b]selenophene-5-ol Antioxidants
    Show others...
    2007 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 72, no 7, p. 2583-2595Article in journal (Refereed) Published
    Abstract [en]

    A series of 2,3-dihydrobenzo[b]selenophene-5-ol antioxidants was prepared by subjecting suitably substituted allyl 4-methoxyphenyl selenides to microwave-induced seleno-Claisen rearrangement/intramolecular Markovnikov hydroselenation followed by boron tribromide-induced O-demethylation. The novel antioxidants were assayed for their capacity to inhibit azo-initiated peroxidation of linoleic acid in a water/chlorobenzene two-phase system containing N-acetylcysteine as a thiol reducing agent in the aqueous phase. Antioxidant efficiency as determined by the inhibited rate of peroxidation, Rinh, increased with increasing methyl substitution (Rinh = 46−26 μM/h), but none of the compounds could match α-tocopherol (Rinh = 22 μM/h). Regenerability as determined by the inhibition time, Tinh, in the presence of the thiol regenerating agent decreased with increasing methyl substitution. Thus, under conditions where the unsubstituted compound 5a inhibited peroxidation for more than 320 min, α-tocopherol worked for 90 min and the trimethylated antioxidant 5g for 60 min only. Sampling of the aqueous phase at intervals during peroxidation using antioxidant 5a showed that N-acetylcysteine was continuously oxidized with time to the corresponding disulfide. In the absence of the regenerating agent, compounds 5 inhibited peroxidation for 50−60 min only. A (RO)B3LYP/LANL2DZdp//B3LYP/LANL2DZ model was used for the calculation of homolytic O−H bond dissociation enthalpies (BDE) and adiabatic ionization potentials (IP) of phenolic antioxidants 5. Both BDE (80.6−76.3 kcal/mol) and IP (163.2−156.0 kcal/mol) decrease with increasing methyl substitution. The phenoxyl radical corresponding to phenol 5g gave an intense ESR signal centered at g = 2.0099. The H−O bond dissociation enthalpy of the phenol was determined by a radical equilibration method using BHA as an equilibration partner. The observed BDE (77.6 ± 0.5 kcal/mol) is in reasonable agreement with calculations (76.3 kcal/mol). As judged by calculated log P values, the lipophilicity of compounds 5 increased slightly when methyl groups were introduced into the phenolic moiety (2.9 > C log P < 4.2). The capacity of compounds 5a (kinh = 3.8 × 105 M-1 s-1) and 5g (kinh = 1.5 × 106 M-1 s-1) to inhibit azo-initiated autoxidation of styrene in the homogeneous phase (chlorobenzene) was also studied. More efficient regeneration at the lipid−aqueous interphase is the most likely explanation why the intrinsically poorest antioxidant 5a can outperform its analogues as well as α-TOC in the two-phase system. Possible mechanisms of regeneration are discussed and evaluated.

    Keyword
    Sulfur containing aminoacid, Reaction mechanism, Lipids, Regeneration, Styrene derivatives, Autoxidation, Lipophilicity, EPR spectrometry, Organic free radical, Phenols, Ionization potential, Heat of dissociation, Hydrogen bond, Homolysis, Theoretical study, Density functional method, Organic disulfide, Oxidation, Inhibition, α-Tocopherol, Reaction rate, Reducing agent, Thiol, Acetylcysteine, Water, Peroxidation, Azo compound, Demethylation, Markownikoff rule, Intramolecular reaction, Claisen rearrangement, Microwave, Organic selenide, Allylic compound, Chemical synthesis, Antioxidant
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-10499 (URN)10.1021/jo0700023 (DOI)000245118900041 ()17335240 (PubMedID)
    Available from: 2007-03-27 Created: 2007-03-27 Last updated: 2017-12-11Bibliographically approved
    2. Exploring a synthetic organoselenium compound for antioxidant pharmacotherapy: toxicity and effects on ROS-production
    Open this publication in new window or tab >>Exploring a synthetic organoselenium compound for antioxidant pharmacotherapy: toxicity and effects on ROS-production
    Show others...
    2010 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 18, no 5, p. 1783-1788Article in journal (Refereed) Published
    Abstract [en]

    The organoselenium antioxidant 1 was previously found to act as a catalytic antioxidant in a two-phase lipid peroxidation system. In aqueous environment, selenide 1 quenched ABTS-radicals more efficiently than Trolox and ascorbic acid. The selenide dose-dependently scavenged reactive oxygen and nitrogen species more efficiently than Trolox for neutrophils and PMA-stimulated macrophages, with 50% inhibitory concentrations in the low micromolar range. In addition no sign of toxicity or effect on cell viability was seen when culturing five human cell lines in concentrations up to 200 microM of selenide 1 for up to seven days. We therefore feel that the compound would be a good candidate for future drug development for prevention or treatment of disorders caused by or involving free radical-mediated or oxidative tissue damage.

    Keyword
    Antioxidant, organoselenium compound, toxicity, ROS, neutrophil, macrophage, ABTS
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-119635 (URN)10.1016/j.bmc.2010.01.057 (DOI)000274957100004 ()20156690 (PubMedID)
    Available from: 2010-02-26 Created: 2010-02-26 Last updated: 2017-12-12Bibliographically approved
    3. Catalytic Chain-breaking Pyridinol Antioxidants
    Open this publication in new window or tab >>Catalytic Chain-breaking Pyridinol Antioxidants
    Show others...
    2008 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 10, no 21, p. 4895-4898Article in journal (Refereed) Published
    Abstract [en]

    When assayed for their capacity to inhibit azo-initiated peroxidation of linoleic acid in a water/chlorobenzene two-phase system, tellurium-containing 3-pyridinols were readily regenerable by N-acetylcysteine contained in the aqueous phase. The best inhibitors quenched peroxyl radicals more efficiently than alpha-tocopherol, and the duration of inhibition was limited only by the availability of the thiol reducing agent. The compounds were also found to catalyze reduction of hydrogen peroxide in the presence of thiol reducing agent.

    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-105658 (URN)10.1021/ol801983n (DOI)000260534500047 ()18828593 (PubMedID)
    Available from: 2009-06-05 Created: 2009-06-05 Last updated: 2017-12-13Bibliographically approved
    4. Catalytic chain-breaking pyridinol antioxidants
    Open this publication in new window or tab >>Catalytic chain-breaking pyridinol antioxidants
    Show others...
    2010 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 75, no 3, p. 716-725Article in journal (Refereed) Published
    Abstract [en]

    The synthesis of 3-pyridinols carrying alkyltelluro, alkylseleno, and alkylthio groups is described together with a detailed kinetic, thermodynamic, and mechanistic Study of their antioxidant activity. When assayed for their capacity to inhibit azo-initiated peroxidation of linoleic acid in a water/chlorobenzene two-phase system, tellurium-containing 3-pyridinols were readily regenerable by N-acetylcysteine contained in the aqueous phase. The best inhibitors quenched peroxyl radicals more efficiently than alpha-tocopherol, and the duration of inhibition was limited only by the availability of the thiol reducing agent. fn homogeneous phase, inhibition of styrene autoxidation absolute rate constants k(inh) for quenching of peroxyl radical were as large as 1 x 10(7) M-1 s(-1), thus Outperforming the best phenolic antioxidants including alpha-tocopherol. Tellurium-containing 3-pyridinols could be quantitatively regenerated in homogeneous phase by N-tert-butoxycarbonyl cysteine methyl ester, a lipid-soluble analogue of N-acetylcysteine. In the presence of an excess of the thiol, a catalytic mode of action was observed, similar to the one in the two-phase system. Overall, compounds bearing the alkyltelluro moiety ortho to the OH group were much more effective antioxidants than the corresponding para isomers. The origin of the high reactivity of these compounds was explored using pulse-radiolysis thermodynamic measurements, and a mechanism for their unusual antioxidant activity was proposed. The tellurium-containing 3-pyridinols were also found to catalyze reduction of hydrogen peroxide in the presence of thiol reducing agents, thereby acting as multifunctional (preventive and chain-breaking) catalytic antioxidants.

    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-115972 (URN)10.1021/jo902226t (DOI)000273982900022 ()20073487 (PubMedID)
    Available from: 2010-02-17 Created: 2010-02-17 Last updated: 2017-12-12Bibliographically approved
    5. Never Ending Antioxidant Protection - A Regenerable BHA-Analogue
    Open this publication in new window or tab >>Never Ending Antioxidant Protection - A Regenerable BHA-Analogue
    (English)Manuscript (preprint) (Other (popular science, discussion, etc.))
    Identifiers
    urn:nbn:se:uu:diva-122481 (URN)
    Available from: 2010-04-13 Created: 2010-04-13 Last updated: 2010-05-11
    6. Organochalcogen Substituents in Phenolic Antioxidants
    Open this publication in new window or tab >>Organochalcogen Substituents in Phenolic Antioxidants
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    2010 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 12, no 10, p. 2326-2329Article in journal (Refereed) Published
    Abstract [en]

    Little is known about the ED/EW character of organochalcogen substituents and their contribution to the O-H bond dissociation enthalpy (BDE) in phenolic compounds. A series of ortho- and para-(S,Se,Te)R-substituted phenols were prepared and investigated by EPR, IR, and computational methods. Substituents lowered the O-H BDE by >3 kcal/mol in the para position, while the ortho-effect was modest due to hydrogen bonding ( approximately 3 kcal/mol) to the O-H group.

    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-122483 (URN)10.1021/ol100683u (DOI)000277531000040 ()20405887 (PubMedID)
    Available from: 2010-04-13 Created: 2010-04-13 Last updated: 2017-12-12Bibliographically approved
    7. Appendix: Supplementary Material
    Open this publication in new window or tab >>Appendix: Supplementary Material
    (English)Manuscript (preprint) (Other (popular science, discussion, etc.))
    Identifiers
    urn:nbn:se:uu:diva-122484 (URN)
    Available from: 2010-04-13 Created: 2010-04-13 Last updated: 2010-05-11
  • 25.
    Kaukoranta, Päivi
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Engman, Mattias
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Hedberg, Christian
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
    Andersson, Pher G.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Iridium Catalysts with Chiral Imidazole-Phosphine Ligands for Asymmetric Hydrogenation of Vinyl Fluorides and other Olefins2008In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 350, no 7-8, p. 1168-1176Article in journal (Refereed)
    Abstract [en]

    New chiral bidentate imidazole-phosphine ligands have been prepared and evaluated for the iridium-catalysed asymmetric hydrogenation of olefins. The imidazole-phosphine-ligated iridium catalysts hydrogenated trisubstituted olefins with the same sense of enantiodiscrimination as known iridium catalysts possessing oxazole and thiazole as N-donors. The imidazole-based catalysts were shown to hydrogenate vinyl fluorides, in some cases with the highest ee values published to date.

  • 26.
    Källström, Klas
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
    Munslow, Ian
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
    Andersson, Pher
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
    Ir-Catalysed Asymmetric Hydrogenation: Ligands, Substrates and Mechanism2006In: Chem. Eur. J., no 12, p. 3194-3200Article in journal (Refereed)
  • 27.
    Källström, Klas
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
    Munslow, Ian
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
    Hedberg, Christian
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Andersson, Pher
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
    Iridium-Catalysed Asymmetric Hydrogenation of Vinylsilanes as a Route to Optically Active Silanes2006In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 348, no 18, p. 2575-2578Article in journal (Refereed)
    Abstract [en]

    The first use of vinylsilanes as substrates in the asymmetric iridium-catalysed hydrogenation is reported, providing products with enantioselectivities of up to 98%.

  • 28.
    Lampa, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Bergman, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Ehrenberg, Angelica E.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Alogheli, Hiba
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Åkerblom, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Novel Peptidomimetic HCV NS3 Protease Inhibitors Spanning the P2–P1´ RegionManuscript (preprint) (Other academic)
  • 29.
    Lampa, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Grandin, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Ehrenberg, Angelica E.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Alogheli, Hiba
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Åkerblom, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Diversely Vinylated Acyclic Pyrimidinyloxyphenylglycine-based Inhibitors of the HCV NS3 Protease and Corresponding Macrocycles: Beneficial use of an Aromatic P1 moietyManuscript (preprint) (Other academic)
  • 30.
    Li, Junxin
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
    Grennberg, Helena
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
    Microwave-Assisted Covalent Sidewall Functionalization of Multiwalled Carbon Nanotubes2006In: Chem. Eur. J., no 12, p. 3869-3875Article in journal (Refereed)
  • 31.
    Matsson, Olle
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    Isotope Effects for Exotic Nuclei2006In: Isotope Effects in Chemistry and Biology, CRC Press, Taylor & Francis Group, NW , 2006, p. 417-431Chapter in book (Refereed)
  • 32.
    Matsson, Olle
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    Dybala-Defratyka, A.
    Rostkowski, M.
    Paneth, P.
    Westaway, K.C.
    A Theoretical Ivnestigation of a-Carbon Kinetic Isotope Effects and Their Relationship to the Transition-State Structure of SN2 Reactions2005In: J. Org. Chem., no 70, p. 4022-4027Article in journal (Refereed)
    Abstract [en]

    The transition structures and a-carbon 12C/13C kinetic isotope for 22 SN2 reactions between methyl chloride and a wide variety of nucleophiles have been calculated using the B1LYP/aug-cc-pVDZ level of theory. Anionic, neutral, and radical anion nucleophiles were used to give a wide range of SN2 transition states so the relationship between the magnitude of the a-carbon kinetic isotope effect and trasition-state structure could be determined. The results suggest that the a-carbon 12C/13C kinetic isotope effects for SN2 reactions will be large (near the experimental maximum) and that the curve relating the magnitude of the KIE to the percent transfer of the a-carbon from the nucleophile to the leaving group in the transition state has a broad maximum. This means very similar KIEs will be found for early, symmetric, and late transition states and that one cannot use the magnitude of these KIEs to estimate transition-state structure.

  • 33.
    Mirpourzadeh, Sara
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Development of new mimetics for the Tyr-pair of the Epoxide Hydrolase2007Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
  • 34.
    Obaidur, Rahman
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry.
    Erlandsson, Maria
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry.
    Blom, Elisabeth
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry.
    Långström, Bengt
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry.
    Automated synthesis of 18F-labelled analogues of etomidate, vorozole and harmine using commercial synthesizer TRACERLab FXFNManuscript (Other academic)
    Abstract [en]

    18F-Labelled analogues of three biologically interesting compounds, ethyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate (ETO), 6-[(S)-(4-chlorophenyl)-(1H)-1,2,4-triazol-1-yl)methyl]-1-methyl-1H-benzotriazole (VOZ) and 7-methoxy-1-methyl-9H-β-carboline (HAR) were synthesized by one-step nucleophilic fluorination. The 18F-labelled products were obtained with 20–30% isolated decay-corrected radiochemical yields and the radiochemical purities were over 99% in all cases. The labelling syntheses were performed using fully automated commercial synthesizer TRACERLab FXFN. The automation of the syntheses of these three promising PET tracers using a commercial synthesizer will make them accessible for clinical applications.       

  • 35.
    Ottosson, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Eklöf, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Silenes: Connectors between classical alkenes and nonclassical heavy alkenes2008In: Coordination chemistry reviews, ISSN 0010-8545, E-ISSN 1873-3840, Vol. 252, no 12-14, p. 1287-1314Article, review/survey (Refereed)
    Abstract [en]

    Forty years have passed since the first publication of the experimental evidence for formation of a SiC double bonded compound, a silene. Since then, a large number of transient as well as isolable silenes have been studied, both experimentally and theoretically. Herein, we focus on the impact of the substituents on the electronic and geometric structure, reactivity, and other properties of (formally) SiC double bonded compounds. Qualitative quantum chemical models for the bonding are reviewed, and applied to rationalize experimental observations. Silenes can have planar (classical) structures similar to alkenes, or nonplanar (nonclassical) structures similar to the heavier alkene congeners, and their substituents are pivotal in determining which of these structures is adopted. Silene properties, ranging from charge distribution and NMR chemical shifts to reactivities, are strongly connected to the electronic structure of the silene, and thus to its substitution pattern.

  • 36.
    Ottosson, Henrik
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    Steel, Patrick G.
    Silylenes, Silenes, and Disilenes: Novel Silicon-Based Reagents for Organic Synthesis?2006In: Chem. Eur. J., no 12, p. 1576-1585Article in journal (Refereed)
  • 37. Peter, K.
    et al.
    Nilsson, R.
    Rydberg, Johan
    Baltzer, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    Inganäs, Olle
    Twisting macromolecular chains-self-assembly of a chiral supermolecule from non-chiral polythiophene polyanions and random coil synthetic peptides2004In: Proc. Nat. Acad. Sci., no 101, p. 11197-11202Article in journal (Refereed)
  • 38. Rossi, Paola
    et al.
    Tecilla, Paolo
    Baltzer, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    Scrimin, Paolo
    De novo Metallonucleases based on Helix-loop-helix Motifs2004In: Chem. Eur. J., no 10, p. 4163-4170Article in journal (Refereed)
  • 39.
    Rouf, Alvi Muhammad
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Ottosson, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Silaphenolates and Silaphenylthiolates: Two Unexplored Unsaturated Silicon Compound Classes Influenced by Aromaticity2012In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 17, no 1, p. 369-389Article in journal (Refereed)
    Abstract [en]

    Monosilicon analogs of phenolates and phenylthiolates are studied by quantum chemical calculations. Three different silaphenolates and three different silaphenylthiolates are possible; the ortho-, meta-, and para-isomers. For the silaphenolates, the meta- isomer is the thermodynamically most stable, regardless if the substituent R at Si is H, t-Bu or SiMe3. However, with R = H and SiMe3 the energy differences between the three isomers are small, whereas with R = t-Bu the meta- isomer is similar to 5 kcal/mol more stable than the ortho- isomer. For the silaphenylthiolates the ortho- isomer is of lowest energy, although with R = H the ortho- and meta- isomers are isoenergetic. The calculated nucleus independent chemical shifts (NICS) indicate that the silaphenolates and silaphenylthiolates are influenced by aromaticity, but they are less aromatic than the parent silabenzene. The geometries and charge distributions suggest that all silaphenolates and silaphenylthiolates to substantial degrees are described by resonance structures with an exocyclic C=O double bond and a silapentadienyl anionic segment. Indeed, they resemble the all-carbon phenolate and phenylthiolate. Silaphenylthiolates are less bond alternate and have slightly more negative NICS values than analogous silaphenolates, suggesting that this compound class is a bit more aromatic. Dimerization of the silaphenolates and silaphenylthiolates is hampered due to intramolecular Coulomb repulsion in the dimers, and silaphenolates with a moderately bulky SiMe3 group as substituent at Si should prefer the monomeric form.

  • 40. Scrimin, Paolo
    et al.
    Baltzer, LarsUppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    Model Systems2005Collection (editor) (Other scientific)
  • 41.
    Shokeer, Abeer
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Design of Glutathione Transferase Variants for Novel Activities with Alternative Substrates2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Glutathione transferases (GSTs) play a pivotal role in cellular defense, since they are main contributors to the inactivation of genotoxic compounds of exogenous and endogenous origins. Directed evolution was used to improve the catalytic activities of Theta class GST T1-1 toward different substrates. The library was constructed by recombination of cDNA coding for human GST T1-1 and rodent Theta class GSTs, resulting in the F2-F5 generations. The clones were heterologously expressed in Escherichia coli and screened for variants with enhanced alkyltransferase activity. A mutant, F2:1215, with a 70-fold increased catalytic efficiency with 4-nitrophenethyl bromide (NPB) compared to human GST T1-1, was isolated from the second generation. NPB was used as a surrogate substrate of the anticancer drug 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in order to facilitate the screening process. The catalytic efficiency of the F2:1215 with BCNU had improved 170-fold compared to wild-type human GST T1-1, suggesting that NPB is a suitable model substrate for the anticancer drug BCNU. The sequence of the F2:1215 mutant differs from wild-type human GST T1-1 by three residues; one of these differences is Arg234, which corresponds to Trp in the human enzyme. Upon replacing the Trp234 in the human GST T1-1 with Arg, the resulting mutant (hTrp234Arg) showed enhanced alkyltransferase activity with a wide range of substrates (e.g. haloalkanes and other typical GSTs substrates). The three-dimensional structures of both wild-type human GST T1-1 and hTrp234Arg mutant help to explain the higher activity showed by of hTrp234Arg mutant compared to wild-type enzyme. The reciprocal mutation of the residue 234 in mouse GST T1-1 to that found in human, mArg234Trp, caused a dramatic decrease in the activity of the mouse enzyme to be similar to human GST T1-1. This indicates that residue 234 can be considered as a master switch of activities between human and rodent GST T1-1. Another important residue in the C-terminal helix of GST T1-1 is Met232. Although residue 232 points away from the H-site, it influences the catalytic activity and substrate selectivity of the mouse GST T1-1. A minor modification of Met232 induces major changes in the substrate-activity profile of the mouse GST T1-1 to favor novel substrates such as isothiocyanates and hydroperoxides and decreases the activity toward substrates that catalyzed by the wild-type enzyme.

     

    List of papers
    1. Molecular evolution of Theta-class glutathione transferase for enhanced activity with the anticancer drug 1,3-bis-(2-chloroethyl)-1-nitrosourea and other alkylating agents
    Open this publication in new window or tab >>Molecular evolution of Theta-class glutathione transferase for enhanced activity with the anticancer drug 1,3-bis-(2-chloroethyl)-1-nitrosourea and other alkylating agents
    2010 (English)In: Archives of Biochemistry and Biophysics, ISSN 0003-9861, E-ISSN 1096-0384, Vol. 497, no 1-2, p. 28-34Article in journal (Refereed) Published
    Abstract [en]

    Glutathione transferase (GST) displaying enhanced activity with the cytostatic drug 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) and structurally related alkylating agents was obtained by molecular evolution. Mutant libraries created by recursive recombination of cDNA coding for human and rodent Theta-class GSTs were heterologously expressed in Escherichia coli and screened with the surrogate substrate 4-nitrophenethyl bromide (NPB) for enhanced alkyltransferase activity. A mutant with a 70-fold increased catalytic efficiency with NPB, compared to human GST T1-1, was isolated. The efficiency in degrading BCNU had improved 170-fold, significantly more than with the model substrate NPB. The enhanced catalytic activity of the mutant GST was also 2-fold higher with BCNU than wild-type mouse GST T1-1, which is 80-fold more efficient than wild-type human GST T1-1. We propose that GSTs catalyzing inactivation of anticancer drugs may find clinical use in protecting sensitive normal tissues to toxic side-effects in treated patients, and as selectable markers in gene therapy.

    Keyword
    Glutathione transferase (GST), 1, 3-Bis-(2-chloroethyl)-1-nitrosourea (BCNU) Chloroethylnitrosoureas (CENUs), Directed evolution, Alkyltransferase, Alkylating agents
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-119509 (URN)10.1016/j.abb.2010.03.001 (DOI)000277537800004 ()
    Available from: 2010-02-26 Created: 2010-02-26 Last updated: 2017-12-12Bibliographically approved
    2. Residue 234 in glutathione transferase T1-1 plays a pivotal role in the catalytic activity and the selectivity against alternative substrates
    Open this publication in new window or tab >>Residue 234 in glutathione transferase T1-1 plays a pivotal role in the catalytic activity and the selectivity against alternative substrates
    2005 (English)In: Abstracts of the 30th FEBS Congress: FEBS journal Special issue (Vol. 272, Issue s1), 2005, Vol. 272, p. 99 Suppl-Conference paper, Published paper (Refereed)
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-76722 (URN)10.1111/j.1742-4658.2005.4739_3.x (DOI)
    Conference
    30th FEBS Congress
    Available from: 2006-03-07 Created: 2006-03-07 Last updated: 2010-03-02Bibliographically approved
    3. Structural basis of the suppressed catalytic activity of wild-type human glutathione transferase T1-1 compared to its W234R mutant
    Open this publication in new window or tab >>Structural basis of the suppressed catalytic activity of wild-type human glutathione transferase T1-1 compared to its W234R mutant
    Show others...
    2006 (English)In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 355, no 1, p. 96-105Article in journal (Refereed) Published
    Abstract [en]

    The crystal structures of wild-type human theta class glutathione-S-transferase (GST) T1-1 and its W234R mutant, where Trp234 was replaced by Arg, were solved both in the presence and absence of S-hexyl-glutathione. The W234R mutant was of interest due to its previously observed enhanced catalytic activity compared to the wild-type enzyme. GST T1-1 from rat and mouse naturally contain Arg in position 234, with correspondingly high catalytic efficiency. The overall structure of GST T1-1 is similar to that of GST T2-2, as expected from their 53% sequence identity at the protein level. Wild-type GST T1-1 has the side-chain of Trp234 occupying a significant portion of the active site. This bulky residue prevents efficient binding of both glutathione and hydrophobic substrates through steric hindrance. The wild-type GST T1-1 crystal structure, obtained from co-crystallization experiments with glutathione and its derivatives, showed no electron density for the glutathione ligand. However, the structure of GST T1-1 mutant W234R showed clear electron density for S-hexyl-glutathione after co-crystallization. In contrast to Trp234 in the wild-type structure, the side-chain of Arg234 in the mutant does not occupy any part of the substrate-binding site. Instead, Arg234 is pointing in a different direction and, in addition, interacts with the carboxylate group of glutathione. These findings explain our earlier observation that the W234R mutant has a markedly improved catalytic activity with most substrates tested to date compared to the wild-type enzyme. GST T1-1 catalyzes detoxication reactions as well as reactions that result in toxic products, and our findings therefore suggest that humans have gained an evolutionary advantage by a partially disabled active site.

    Keyword
    glutathione transferase, T1-1, protein X-ray crystallography, protein–ligand interaction, Binding Sites/genetics, Catalysis, Crystallography; X-Ray, Glutathione/analogs & derivatives/chemistry, Glutathione Transferase/*chemistry/genetics/metabolism, Humans, Mutation; Missense, Protein Conformation, Research Support; Non-U.S. Gov't
    National Category
    Structural Biology Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-76733 (URN)10.1016/j.jmb.2005.10.049 (DOI)16298388 (PubMedID)
    Available from: 2006-12-15 Created: 2006-12-15 Last updated: 2017-12-14Bibliographically approved
    4. Residue 234 is a master switch of the alternative-substrate activity profile of human and rodent theta class glutathione transferase T1-1
    Open this publication in new window or tab >>Residue 234 is a master switch of the alternative-substrate activity profile of human and rodent theta class glutathione transferase T1-1
    2010 (English)In: Biochimica et Biophysica Acta - General Subjects, ISSN 0304-4165, E-ISSN 1872-8006, Vol. 1800, no 4, p. 466-473Article in journal (Refereed) Published
    Abstract [en]

    Background: The Theta class glutathione transferase GST T1-1 is a ubiquitously occurring detoxication enzyme. The rat and mouse enzymes have high catalytic activities with numerous electrophilic compounds, but the homologous human GST T1-1 has comparatively low activity with the same substrates. A major structural determinant of substrate recognition is the H-site, which binds the electrophile in proximity to the nucleophilic sulfur of the second substrate glutathione. The H-site is formed by several segments of amino acid residues located in separate regions of the primary structure. The C-terminal helix of the protein serves as a lid over the active site, and contributes several residues to the H-site. Methods: Site-directed mutagenesis of the H-site in GST T1-1 was used to create the mouse Arg234Trp for comparison with the human Trp234Arg mutant and the wild-type rat, mouse, and human enzymes. The kinetic properties were investigated with an array of alternative electrophilic substrates to establish substrate selectivity profiles for the different GST T1-1 variants. Results: The characteristic activity profile of the rat and mouse enzymes is dependent on Arg in position 234, whereas the human enzyme features Trp. Reciprocal mutations of residue 234 between the rodent and human enzymes transform the substrate-selectivity profiles from one to the other. Conclusions: H-site residue 234 has a key role in governing the activity and substrate selectivity profile of GST T1-1. General significance: The functional divergence between human and rodent Theta class GST demonstrates that a single point mutation can enable or suppress enzyme activities with different substrates.

    Keyword
    Glutathione transferase, active site residue, alternative substrates, detoxication, haloalkanes
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-119506 (URN)10.1016/j.bbagen.2010.01.003 (DOI)000275843100006 ()20097269 (PubMedID)
    Available from: 2010-02-26 Created: 2010-02-26 Last updated: 2017-12-12Bibliographically approved
    5. Minor Modifications of the C-terminal Helix Reschedule the Favored Chemical Reactions Catalyzed by Theta Class Glutathione Transferase T1-1:
    Open this publication in new window or tab >>Minor Modifications of the C-terminal Helix Reschedule the Favored Chemical Reactions Catalyzed by Theta Class Glutathione Transferase T1-1:
    2010 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 285, no 8, p. 5639-5645Article in journal (Refereed) Published
    Abstract [en]

    Adaptive responses to novel toxic challenges provide selective advantages to organisms in evolution. Glutathione transferases (GSTs) play a pivotal role in the cellular defense because they are main contributors to the inactivation of genotoxic compounds of exogenous as well as of endogenous origins. GSTs are promiscuous enzymes catalyzing a variety of chemical reactions with numerous alternative substrates. Despite broad substrate acceptance, individual GSTs display pronounced selectivities such that only a limited number of substrates are transformed with high catalytic efficiency. The present study shows that minor structural changes in the C-terminal helix of mouse GST T1-1 induce major changes in the substrate-activity profile of the enzyme to favor novel chemical reactions and to suppress other reactions catalyzed by the parental enzyme.

    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-119507 (URN)10.1074/jbc.M109.074757 (DOI)000275327200056 ()20022951 (PubMedID)
    Available from: 2010-02-26 Created: 2010-02-26 Last updated: 2017-12-12Bibliographically approved
  • 42.
    Tibbelin, Julius
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Organic Heavy Group 14 Element Compounds: A Study of Their Chemical Bonding Properties Directed Towards Applications as Molecular Wires and in Synthesis2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The research described herein includes synthesis, spectroscopy, and quantum chemical calculations with focus on the characteristic properties of compounds with bonds between carbon and the heavier Group 14 elements.

    The chapters based on the first four papers concern σ- and σ/π-conjugated compounds, although the focus of the first paper is on ring strain of bicyclo[1.1.1]pentanes with C, Si, Ge or Sn at the bridgeheads. The relationship between calculated homodesmotic ring strain energies and through-space distances between the bridgehead atoms was evaluated, and it was found that replacing one of the methylene bridges with phospha-methyl gave both low strain and short through-space distance.

    Two kinds of σ/π-interacting systems were analysed with the difference that the σ- and π-bonded segments were either allowed to rotate freely relative each other or frozen into a conformer with maximal σ/π-interaction. The freely rotating systems are star-shaped oligothiophenes linked by heavy alkane segments. Density functional theory (DFT) calculations of hole reorganization energies support the measured hole mobilites. In summary, longer central oligosilane linkages, when compared to shorter, facilitate intermolecular hole-transfer between oligothiophene units.

    In 1,4-disilacyclohexa-2,5-dienes, the strength of the π- and pseudo-π interaction depends on the substituents at Si. Vapour phase UV absorption spectroscopy of 2,3,5,6-tetraethyl-1,1,4,4-tetrakis(trimethylsilyl)-1,4-disilacyclohexa-2,5-diene reveals a strong absorption at 273 nm (4.50 eV). Time-dependent DFT calculations further indicate that octastannylated 1,4-disilacyclohexa-2,5-diene has is lowest excited state at 384 nm (3.23 eV). The electronic, geometric and optical properties of substituted 1,4-disilacyclohexa-2,5-dienes were compared with those of the correspondingly substituted siloles. It was found that the lowest excitations of siloles are less tunable than those of 1,4-disilacyclohexa-2,5-dienes.

    The final section concerns strongly reverse-polarised 2-amino-2-siloxysilenes formed thermally from carbamylpolysilanes, and their lack of reaction with alcohols. Instead, the carbamylsilane reacts with alcohols giving silyl ethers, leading to a new benign route for alcohol protection.

    List of papers
    1. In search of 1,3-disila/germa/stannabicyclo[1.1.1]pentanes with short bridgehead-bridgehead distances and low ring strain energies
    Open this publication in new window or tab >>In search of 1,3-disila/germa/stannabicyclo[1.1.1]pentanes with short bridgehead-bridgehead distances and low ring strain energies
    2005 In: Silicon Chemistry, ISSN 1569-0660, Vol. 3, no 3-4, p. 165-173Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-95448 (URN)
    Available from: 2007-02-14 Created: 2007-02-14 Last updated: 2010-05-12Bibliographically approved
    2. Synthesis of star-shaped oligothiophenes with an organosilicon core. Effects of the core structures on their hole mobility
    Open this publication in new window or tab >>Synthesis of star-shaped oligothiophenes with an organosilicon core. Effects of the core structures on their hole mobility
    Show others...
    (English)Manuscript (preprint) (Other (popular science, discussion, etc.))
    Identifiers
    urn:nbn:se:uu:diva-123074 (URN)
    Available from: 2010-04-23 Created: 2010-04-23 Last updated: 2010-05-12
    3. The 1,4-Disilacyclohexa-2,5-diene Cycle: A Molecular Building Block which Allows for Strong σ/π-Interaction
    Open this publication in new window or tab >>The 1,4-Disilacyclohexa-2,5-diene Cycle: A Molecular Building Block which Allows for Strong σ/π-Interaction
    Show others...
    (English)Manuscript (preprint) (Other (popular science, discussion, etc.))
    Identifiers
    urn:nbn:se:uu:diva-123079 (URN)
    Available from: 2010-04-23 Created: 2010-04-23 Last updated: 2010-05-12
    4. A Computational Investigation of the Substituent Effects on Geometric, Electronic, and Optical Properties of Siloles and 1,4-Disilacyclohexa-2,5-dienes
    Open this publication in new window or tab >>A Computational Investigation of the Substituent Effects on Geometric, Electronic, and Optical Properties of Siloles and 1,4-Disilacyclohexa-2,5-dienes
    2017 (English)In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 22, no 3, article id 370Article in journal (Refereed) Published
    Abstract [en]

    Thirty two differently substituted siloles 1a–1p and 1,4-disilacyclohexa-2,5-dienes 2a–2p were investigated by quantum chemical calculations using the PBE0 hybrid density functional theory (DFT) method. The substituents included σ-electron donating and withdrawing, as well as π-electron donating and withdrawing groups, and their effects when placed at the Si atom(s) or at the C atoms were examined. Focus was placed on geometries, frontier orbital energies and the energies of the first allowed electronic excitations. We analyzed the variation in energies between the orbitals which correspond to HOMO and LUMO for the two parent species, here represented as ΔεHL, motivated by the fact that the first allowed transitions involve excitation between these orbitals. Even though ΔεHL and the excitation energies are lower for siloles than for 1,4-disilacyclohexa-2,5-dienes the latter display significantly larger variations with substitution. The ΔεHL of the siloles vary within 4.57–5.35 eV (ΔΔεHL = 0.78 eV) while for the 1,4-disilacyclohexa-2,5-dienes the range is 5.49–7.15 eV (ΔΔεHL = 1.66 eV). The excitation energy of the first allowed transitions display a moderate variation for siloles (3.60–4.41 eV) whereas the variation for 1,4-disilacyclohexa-2,5-dienes is nearly doubled (4.69–6.21 eV). Cyclobutadisiloles combine the characteristics of siloles and 1,4-disilacyclohexa-2,5-diene by having even lower excitation energies than siloles yet also extensive variation in excitation energies to substitution of 1,4-disilacyclohexa-2,5-dienes (3.47–4.77 eV, variation of 1.30 eV).

    National Category
    Nano Technology
    Research subject
    Engineering Science with specialization in Nanotechnology and Functional Materials
    Identifiers
    urn:nbn:se:uu:diva-335095 (URN)10.3390/molecules22030370 (DOI)000398743500031 ()
    Note

    Title of manuscript in list of papers in Julius Tibbelin´s thesis: A comparative computational investigation of the substituent effects on geometric, electronic, and optical properties of 1,4-disilacyclo-hexa-2,5- dienes and siloles

    Available from: 2017-11-30 Created: 2017-11-30 Last updated: 2018-02-16Bibliographically approved
    5. Unsuccessful attempts to add alcohols to transient 2-amino-2-siloxy- silenes - leading to a new benign route for base-free alcohol protection
    Open this publication in new window or tab >>Unsuccessful attempts to add alcohols to transient 2-amino-2-siloxy- silenes - leading to a new benign route for base-free alcohol protection
    2010 (English)In: Dalton Transactions, ISSN 1477-9226, E-ISSN 1477-9234, Vol. 39, no 39, p. 9379-9385Article in journal (Refereed) Published
    Abstract [en]

    Thermolytic formation of transient   1,1-bis(trimethylsilyl)-2-dimethylamino-2-trimethylsiloxysilene (2)  from N,N-dimethyl(tris(trimethylsilyl) silyl) methaneamide (1) in presence of a series of alcohols was investigated. The products are,  however, not the expected alcohol-silene addition adducts but   silylethers formed in nearly quantitative yields. Thermolysis of 1 in   the presence of both alcohols (MeOH or iPrOH) and 1,3-dienes   (1,3-butadiene or 2,3-dimethyl-1,3-butadiene) gives   alkyl-tris(trimethylsilyl)silylethers and the [4+2] cycloadducts   between the silene and diene, which confirms the presence of 2 and that   it is unreactive towards alcohols. The observed silylethers are substitution adducts where the amide group of the silylamide is replaced by an alkoxy group, and the reaction time is reflected in the   steric bulk of the alcohol. Indeed, the formation of silylethers from   the reaction of alcohols with silylamide represents a new base-free   method for protection of alcohols. The protection reactions using 1   progresses at elevated temperatures, or alternatively, under acid   catalysis at ambient temperature, and similar protections can be   carried out with N-cyclohexyl(triphenylsilyl) methaneamide and N,   N-dimethyl(trimethylsilyl) methaneamide. The latter silylamide can be used under neutral conditions at room temperature. The only by-products  are formamides (N,N-dimethylformamide (DMF) or N-cyclohexylformamide), and the reactions can be performed without solvent. In addition to alcohols we also examined the method for protection of diols, thiols   and carboxylic acids,and also these reactions proceeded in high yields and with good selectivities.

    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-123086 (URN)10.1039/c0dt00323a (DOI)000282220500030 ()20733993 (PubMedID)
    Note
    Uppdaterad från Manuskript till Artikel 20101201Available from: 2010-04-23 Created: 2010-04-23 Last updated: 2017-12-12Bibliographically approved
  • 43.
    Tolmachev, Vladimir
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Bruskin, Alexander
    Sivaev, Igor
    Lundqvist, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Sjöberg, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Radiobromination of closo-dodecaborate anion. Aspects of labelling chemistry in aqueous solutions using Chloramine-T2002In: Radiochimica Acta, ISSN 0033-8230, E-ISSN 2193-3405, Vol. 90, no 4, p. 229-235Article in journal (Refereed)
    Abstract [en]

    Closo-dodecaborate dianion is a three-dimensional aromatic inorganic molecule, which can be easily halogenated forming a stable halogen-boron bond. Derivatives of closo-dodecaborate were considered as a convenient chemical form of delivery of enriched 10B to malignant tumors for boron neutron capture therapy (BNCT). Some properties of closo-dodecaborate (hydrophilicity, strength of halogen-boron bond, charge at lysosomal pH) make it attractive as a potential prosthetic group for attachment of radioactive halogens to tumor-targeting proteins. Bromine radioisotopes possess a variety of useful nuclear characteristics, and can be used in different areas of clinical diagnostics and therapy. In this work, a basic chemistry of closo-dodecaborate radiobromination was studied. It was found, that di(triethylamonium) dodecahydro-closo-dodecaborate can be labelled in high yield, more then 90%, in a wide pH range. By decreasing the pH, the bromination can be directed to closo-dodecaborate in the presence of phenolic compounds. The results of the study indicate a possibility of using the radioactive bromine label for investigation of pharmacokinetics of boronated compounds for BNCT.

  • 44.
    Toom, Lauri
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Grennberg, Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Gogoll, Adolf
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Microwave-Assisted Raney Nickel Reduction of Bispidinone Thioketals to N,N’-Dialkylbispidines2006In: Synthesis (Stuttgart), ISSN 0039-7881, E-ISSN 1437-210X, no 12, p. 2064-2068Article in journal (Refereed)
    Abstract [en]

    A series of N,N′-dialkyl-3,7-diazabicyclo[3.3.1]nonanes was prepared by microwave-assisted reduction of a common dithiolane precursor with Raney nickel, using the corresponding alkanol as solvent. The method avoids the use of hydrazine.

  • 45.
    Trifonova, Anna
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
    Diesen, Jarle
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
    Andersson, Pher
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
    Asymmetric Hydrogenation of Imines and Olefins Using Phosphine-Oxazoline Iridium Complexes as Catalysts2006In: Chem. Eur. J., no 12, p. 2318-2328Article in journal (Refereed)
  • 46.
    Varedian, Miranda
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Photoswitchable Peptidomimetics: Synthesis and Photomodulation of Functional Peptides2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The secondary structure of peptides is of pivotal importance for their biological function. The introduction of photoswitchable moieties into the backbones of peptides provides a unique way of regulating their conformation using an external stimulus, i.e., light. This thesis addresses the design, synthesis, and conformational analysis of photoswitchable peptidomimetics (PSPM). Examples of photomodulation of their functional properties are given.

    PSPM were prepared by incorporation of stilbene and thioaurone chromophores (switches) into dipeptides. Synthetic schemes for preparing these chromophores have been developed. Their suitability for incorporation into peptidomimetics has been demonstrated, and the resulting PSPM have been subjected to photoisomerization as well as computational and spectroscopic conformational analysis. The chromophore’s potential as a β-hairpin inducer was particularly interesting.

    To investigate the factors that govern the formation of β-hairpins, a series of decapeptides were prepared. Turn regions consisting of amino acids or chromophores were combined with antiparallel peptide strands with hydrophobic side chains. Linear tryptophan zipper peptidomimetics and cyclic peptidomimetics with a second, hairpin-inducing turn region were particularly promising. Comparison between switches revealed that the more flexible stilbene is a better choice for upholding the β-hairpin conformation than the thioaurone.

    The catalytic properties of an artificial hydrolase with a helix-loop-helix structure can be improved by introducing a stilbene photoswitch into the loop region. Photoisomerization regulates the catalytic activity of this peptidomimetic, and provides a means to control its aggregation state.

    The activity of the enzyme Mycobacterium tuberculosis ribonucleotide reductase was realized by incorporating a stilbene moiety into a linear peptide. Here, one photoisomer proved to be an inhibitor at nM concentrations. A significantly lower effect was observed for the other isomer.

    Finally, the decomposition of thioaurones, mainly to thioflavonols and thiaindenes, under conditions used for solid-phase peptide synthesis has been mapped. These findings are expected to have implications for future use of this chromophore.

    List of papers
    1. Chemistry and folding of photomodulable peptides: stilbene and thioaurone-type candidates for conformational switches
    Open this publication in new window or tab >>Chemistry and folding of photomodulable peptides: stilbene and thioaurone-type candidates for conformational switches
    Show others...
    2008 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 6, no 23, p. 4356-4373Article in journal (Refereed) Published
    Abstract [en]

    Optimized synthetic strategies for the preparation of photoswitchable molecular scaffolds based on stilbene or on thioaurone chromophores and their conformationally directing properties, as studied by computations and by NMR spectroscopy, are addressed. For the stilbene peptidomimetics 1, 2 and 3, the length of connecting linkers between the chromophore and the peptide strands was varied, resulting in photochromic dipeptidomimetics with various flexibility. Building blocks of higher rigidity, based on para-substituted thioaurone ( 4 and 6) and meta-substituted thioaurone chromophores ( 5 and 7) are shown to have a stronger conformationally directing effect. Design, synthesis, theoretical and experimental conformational analyses are presented.

    National Category
    Pharmaceutical Sciences Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-97699 (URN)10.1039/b812001c (DOI)000261744800012 ()19005595 (PubMedID)
    Available from: 2008-11-04 Created: 2008-11-04 Last updated: 2018-01-13Bibliographically approved
    2. Interplaying factors for the formation of photoswitchable β-hairpins: The advantage of a flexible switch
    Open this publication in new window or tab >>Interplaying factors for the formation of photoswitchable β-hairpins: The advantage of a flexible switch
    2009 (English)In: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 15, no 2, p. 107-113Article in journal (Refereed) Published
    Abstract [en]

    A series of peptidomimetics intended to promote the β-hairpin motif have been studied. Structural variations include a turn region with and without a photoswitchable chromophore, and strands with amino acid side chains supporting various degrees of interstrand interactions for hairpin stabilisation. The propensity of the compounds to form β-hairpinswas evaluated experimentally by NMR spectroscopy, translational self-diffusion studies and CD spectroscopy. In the presence of hairpin stabilising interstrand interactions, the structurally flexible stilbene chromophore appeared to be well compatible with the imposed secondary structure.

    Keyword
    peptidomemetics, conformational analysis, photoswitches, diffusion coefficients, CD
    National Category
    Organic Chemistry
    Research subject
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-97700 (URN)10.1002/psc.1103 (DOI)000262837000008 ()19090532 (PubMedID)
    Available from: 2008-11-04 Created: 2008-11-04 Last updated: 2017-12-14Bibliographically approved
    3. Photochemical Regulation of an Artificial Hydrolase by a Backbone Incorporated Tertiary Structure Switch
    Open this publication in new window or tab >>Photochemical Regulation of an Artificial Hydrolase by a Backbone Incorporated Tertiary Structure Switch
    2009 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 15, no 2, p. 501-505Article in journal (Refereed) Published
    Abstract [en]

    A stilbene chromophore has been incorporated into the turn region of a 42 amino acid peptide, linking two helical peptide sections. Spatial proximity between these sections, as well as aggregation into dimers, is required to facilitate the catalytic function of this artificial hydrolase. Photomodulation of the hydrolase activity results in an increase of the activity of 42 % upon switching from the trans to the cis isomer of the chromophore. This is rationalized by a change in the aggregation state of the peptidomimetic, which is supported by diffusion coefficients obtained from PFG-NMR experiments. The results show that incorporation of a small, relatively flexible chromophore into a large peptide is capable of inducing a considerable change in tertiary structure and thus, functionality.

    Keyword
    aggregation, chromophores, enzyme catalysis, peptidomimetics
    National Category
    Organic Chemistry
    Research subject
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-99821 (URN)10.1002/chem.200801808 (DOI)000262491500025 ()
    Available from: 2009-03-31 Created: 2009-03-20 Last updated: 2017-12-13Bibliographically approved
    4. Photoswitchable peptidomimetics for the inhibition of Mycobacterium tuberculosis ribonucleotide reductase
    Open this publication in new window or tab >>Photoswitchable peptidomimetics for the inhibition of Mycobacterium tuberculosis ribonucleotide reductase
    Show others...
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-97702 (URN)
    Available from: 2008-11-04 Created: 2008-11-04 Last updated: 2010-01-13Bibliographically approved
    5. An unexpected triethylsilane-triggered rearrangement of thioaurones to thioflavonols under SPPS conditions
    Open this publication in new window or tab >>An unexpected triethylsilane-triggered rearrangement of thioaurones to thioflavonols under SPPS conditions
    2008 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 49, no 42, p. 6033-6035Article in journal (Refereed) Published
    Abstract [en]

    Thioaurones are converted to a mixture of thiaindenes and thioflavonols when exposed to reaction conditions employed in SPPS, that is, treatment with trifluoroacetic acid in the presence of triethylsilane.

    Keyword
    Peptidomimetics, Chromophores, Rearrangement, Reduction, Silanes, Hemithioindigo, Thioaurone
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-97703 (URN)10.1016/j.tetlet.2008.07.054 (DOI)000259883800001 ()
    Available from: 2008-11-04 Created: 2008-11-04 Last updated: 2017-12-14Bibliographically approved
  • 47.
    Varedian, Miranda
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Persson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Gogoll, Adolf
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Interplaying factors for the formation of photoswitchable β-hairpins: The advantage of a flexible switch2009In: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 15, no 2, p. 107-113Article in journal (Refereed)
    Abstract [en]

    A series of peptidomimetics intended to promote the β-hairpin motif have been studied. Structural variations include a turn region with and without a photoswitchable chromophore, and strands with amino acid side chains supporting various degrees of interstrand interactions for hairpin stabilisation. The propensity of the compounds to form β-hairpinswas evaluated experimentally by NMR spectroscopy, translational self-diffusion studies and CD spectroscopy. In the presence of hairpin stabilising interstrand interactions, the structurally flexible stilbene chromophore appeared to be well compatible with the imposed secondary structure.

  • 48.
    Widenkvist, Erika
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Inorganic Chemistry.
    Boukhvalov, Danil
    Institute for Molecules and Materials, Radboud University of Nijmegen.
    Rubino, Stefano
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Experimental Physics.
    Akhtar, Sultan
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Experimental Physics.
    Lu, Jun
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry.
    Quinlan, Ronald
    Department of Applied Science, The College of William and Mary.
    Katsnelson, Mikhail I.
    Institute for Molecules and Materials, Radboud University .
    Leifer, Klaus
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Experimental Physics.
    Grennberg, Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Jansson, Ulf
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Inorganic Chemistry.
    Mild sonochemical exfoliation of bromine-intercalated graphite a new route towards graphene2009In: Journal of Physics D: Applied Physics, ISSN 0022-3727, E-ISSN 1361-6463, Vol. 42, no 11, p. 112003-Article in journal (Refereed)
    Abstract [en]

    A method to produce suspensions of graphene sheets by combining solution-based bromine intercalation and mild sonochemical exfoliation is presented. Ultrasonic treatment of graphite in water leads to the formation of suspensions of graphite flakes. The delamination is dramatically improved by intercalation of bromine into the graphite before sonication. The bromine intercalation was verified by Raman spectroscopy as well as by x-ray photoelectron spectroscopy (XPS), and density functional theory (DFT) calculations show an almost ten times lower interlayer binding energy after introducing Br2 into the graphite. Analysis of the suspended material by transmission and scanning electron microscopy (TEM and SEM) revealed a significant content of few-layer graphene with sizes up to 30 µm, corresponding to the grain size of the starting material

  • 49.
    Winander, Cecilia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.