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  • 301.
    Skillinghaug, Bobo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Palladium(II)-Catalysed Heck and Addition Reactions: Exploring Decarboxylative and Desulfitative Processes2016Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Palladium complexes have the ability to catalyse cross-coupling of two organic moieties through the formation of transient metal-carbon bonds, thus bringing them closer to each other to facilitate the formation of a new bond. Palladium-catalysed coupling reactions are one of the most important carbon-carbon forming reactions available to organic chemists and many of these reactions rely on the reactivity of aryl-palladium complexes. The investigation of new aryl-palladium precursors is thus of great interest, especially as more sustainable and economic methods can be developed.

    This thesis describes the use of carboxylic acids and sodium arylsulfinates as such new arylating agents. Protocols for microwave-assisted palladium(II)-catalysed decarboxylative synthesis of electron-rich styrenes and 1,1-diarylethenes were developed. However, these transformations had very limited substrate scopes which prompted the investigation of sodium arylsulfinates as alternative arylating agents. These substrates were employed in the microwave-assisted palladium(II)-catalysed desulfitative addition to nitriles, and the substrate scope was demonstrated by combining a wide array of sodium arylsulfinates and nitriles to yield the corresponding aryl ketones. The application of the desulfitative reaction in a continuous flow setup was demonstrated, and aluminium oxide was identified as safe alternative to borosilicate glass as a reactor material. The mechanisms of the decarboxylative and desulfitative transformations were investigated by density functional theory (DFT) calculations. The desulfitative reaction was also investigated by direct electrospray ionization mass spectrometry (ESI-MS), providing further mechanistic insight. Finally, a protocol for the safe and convenient synthesis of a wide range of sodium arylsulfinates was developed.

    Delarbeten
    1. Experimental and Theoretical Investigation of Palladium(II)-Catalyzed Decarboxylative Synthesis of Electron-Rich Styrenes and 1,1-Diarylethenes
    Öppna denna publikation i ny flik eller fönster >>Experimental and Theoretical Investigation of Palladium(II)-Catalyzed Decarboxylative Synthesis of Electron-Rich Styrenes and 1,1-Diarylethenes
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    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Organisk kemi
    Forskningsämne
    Organisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-304720 (URN)
    Tillgänglig från: 2016-10-08 Skapad: 2016-10-08 Senast uppdaterad: 2016-10-10
    2. Palladium(II)-Catalyzed Desulfitative Synthesis of Aryl Ketones from Sodium Arylsulfinates and Nitriles: Scope, Limitations, and Mechanistic Studies
    Öppna denna publikation i ny flik eller fönster >>Palladium(II)-Catalyzed Desulfitative Synthesis of Aryl Ketones from Sodium Arylsulfinates and Nitriles: Scope, Limitations, and Mechanistic Studies
    Visa övriga...
    2014 (Engelska)Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 79, nr 24, s. 12018-12032Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    A fast and efficient protocol for the palladium(II)-catalyzed production of aryl ketones from sodium arylsulfinates and various organic nitriles under controlled microwave irradiation has been developed. The wide scope of the reaction has been demonstrated by combining 14 sodium arylsulfinates and 21 nitriles to give 55 examples of aryl ketones. One additional example illustrated that, through the choice of the nitrile reactant, benzofurans are also accessible. The reaction mechanism was investigated by electrospray ionization mass spectrometry and DFT calculations. The desulfitative synthesis of aryl ketones from nitriles was also compared to the corresponding transformation starting from benzoic acids. Comparison of the energy profiles indicates that the free energy requirement for decarboxylation of 2,6-dimethoxybenzoic acid and especially benzoic acid is higher than the corresponding desulfitative process for generating the key aryl palladium intermediate. The palladium(II) intermediates detected by ESI-MS and the DFT calculations provide a detailed understanding of the catalytic cycle.

    Nationell ämneskategori
    Kemi
    Identifikatorer
    urn:nbn:se:uu:diva-240562 (URN)10.1021/jo501875n (DOI)000346759500020 ()25295849 (PubMedID)
    Tillgänglig från: 2015-01-08 Skapad: 2015-01-07 Senast uppdaterad: 2017-12-05Bibliografiskt granskad
    3. Microwave Heated Continuous Flow Palladium(II)-Catalyzed Desulfitative Synthesis of Aryl Ketones
    Öppna denna publikation i ny flik eller fönster >>Microwave Heated Continuous Flow Palladium(II)-Catalyzed Desulfitative Synthesis of Aryl Ketones
    2016 (Engelska)Ingår i: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 20, nr 11, s. 2005-2011Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    A protocol for Pd(II)-catalyzed desulfitative synthesis of aryl ketones from sodium aryl sulfinates and nitriles in continuous flow has been developed. The reactions proceed with microwave heating using microwave transparent tube reactors, affording the desired aryl ketones in fair to good yields. Microwave transparent aluminum oxide reactors were identified as a safe and thermostable alternative to borosilicate glass reactors.

    Ort, förlag, år, upplaga, sidor
    American Chemical Society (ACS), 2016
    Nyckelord
    Heck-Type Reaction, Direct Esi-Ms, Organic-Synthesis, Sulfinic Acids, High-Speed, Chemistry, Arylation, Nitriles, Hydrogenation, Temperature
    Nationell ämneskategori
    Organisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-304719 (URN)10.1021/acs.oprd.6b00306 (DOI)000388430300017 ()
    Tillgänglig från: 2016-10-08 Skapad: 2016-10-08 Senast uppdaterad: 2017-11-30Bibliografiskt granskad
    4. Synthesis of sodium aryl sulfinates from aryl bromides employing 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO) as a bench-stable, gas-free alternative to SO2
    Öppna denna publikation i ny flik eller fönster >>Synthesis of sodium aryl sulfinates from aryl bromides employing 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO) as a bench-stable, gas-free alternative to SO2
    2016 (Engelska)Ingår i: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 57, nr 5, s. 533-536Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Abstract A convenient two-step protocol for the synthesis of sodium aryl sulfinates from aryl bromides and the SO2 surrogate 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO) has been developed. A wide range of aryl bromides with respect to electronic properties were employed to give the corresponding sodium arylsulfinates in good to excellent yields. The protocol is especially efficient for electron poor aryl bromides which are often difficult to prepare using existing methods.

    Nyckelord
    Sodium sulfinate, Sulfur dioxide surrogate, DABSO
    Nationell ämneskategori
    Organisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-276924 (URN)10.1016/j.tetlet.2015.12.073 (DOI)000369557300007 ()
    Forskningsfinansiär
    Knut och Alice Wallenbergs Stiftelse
    Tillgänglig från: 2016-02-16 Skapad: 2016-02-16 Senast uppdaterad: 2017-11-30Bibliografiskt granskad
  • 302.
    Skillinghaug, Bobo
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Rydfjord, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Odell, Luke R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Synthesis of sodium aryl sulfinates from aryl bromides employing 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO) as a bench-stable, gas-free alternative to SO22016Ingår i: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 57, nr 5, s. 533-536Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Abstract A convenient two-step protocol for the synthesis of sodium aryl sulfinates from aryl bromides and the SO2 surrogate 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO) has been developed. A wide range of aryl bromides with respect to electronic properties were employed to give the corresponding sodium arylsulfinates in good to excellent yields. The protocol is especially efficient for electron poor aryl bromides which are often difficult to prepare using existing methods.

  • 303.
    Skillinghaug, Bobo
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Rydfjord, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sävmarker, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Larhed, Mats
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Microwave Heated Continuous Flow Palladium(II)-Catalyzed Desulfitative Synthesis of Aryl Ketones2016Ingår i: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 20, nr 11, s. 2005-2011Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A protocol for Pd(II)-catalyzed desulfitative synthesis of aryl ketones from sodium aryl sulfinates and nitriles in continuous flow has been developed. The reactions proceed with microwave heating using microwave transparent tube reactors, affording the desired aryl ketones in fair to good yields. Microwave transparent aluminum oxide reactors were identified as a safe and thermostable alternative to borosilicate glass reactors.

  • 304.
    Skillinghaug, Bobo
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sköld, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Behrends, Malte
    Sävmarker, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Rydfjord, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sjöberg, Per
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Palladium(II) catalyzed desulfitative coupling reactions of sodium aryl sulfinates and nitriles: Scope, limitations, and mechanistic studies2014Ingår i: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 248Artikel i tidskrift (Övrigt vetenskapligt)
  • 305.
    Skillinghaug, Bobo
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sköld, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi. ORGFARM.
    Rydfjord, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Svensson, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Behrends, Malte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sävmarker, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sjöberg, Per J R
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Palladium(II)-Catalyzed Desulfitative Synthesis of Aryl Ketones from Sodium Arylsulfinates and Nitriles: Scope, Limitations, and Mechanistic Studies2014Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 79, nr 24, s. 12018-12032Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A fast and efficient protocol for the palladium(II)-catalyzed production of aryl ketones from sodium arylsulfinates and various organic nitriles under controlled microwave irradiation has been developed. The wide scope of the reaction has been demonstrated by combining 14 sodium arylsulfinates and 21 nitriles to give 55 examples of aryl ketones. One additional example illustrated that, through the choice of the nitrile reactant, benzofurans are also accessible. The reaction mechanism was investigated by electrospray ionization mass spectrometry and DFT calculations. The desulfitative synthesis of aryl ketones from nitriles was also compared to the corresponding transformation starting from benzoic acids. Comparison of the energy profiles indicates that the free energy requirement for decarboxylation of 2,6-dimethoxybenzoic acid and especially benzoic acid is higher than the corresponding desulfitative process for generating the key aryl palladium intermediate. The palladium(II) intermediates detected by ESI-MS and the DFT calculations provide a detailed understanding of the catalytic cycle.

  • 306.
    Skogh, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Fransson, Rebecca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sköld, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sandström, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Aminocarbonylation of 4-Iodo-1H-imidazoles with an Amino Acid Amide Nucleophile: Synthesis of Constrained H-Phe-Phe-NH2 Analogues2013Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 78, nr 23, s. 12251-12256Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A simple and an expedient process to prepare 5-aryl-1benzyl-1H-imidazole-4-carboxamides by the aminocarbonylation of 5aryl-4-iodo-1H-imidazoles using ex situ generation of CO from Mo(CO)(6) with an amino acid amide nucleophile is reported. Furthermore, a microwave-assisted protocol for the direct C-5 arylation of 1-benzyl-1H-imidazole and a regioselective C-4 iodination method to acquire starting material for our aminocarbonylation are presented. The method can be used to prepare imidazole based peptidomimetics, herein exemplified by the synthesis of constrained H-Phe-Phe-NH2 analogues.

  • 307.
    Skogh, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Friis, Stig D.
    Aarhus Univ, Carbon Dioxide Activat Ctr CADIAC, Interdisciplinary Nanosci Ctr iNANO, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark.;Aarhus Univ, Dept Chem, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark..
    Skrydstrup, Troels
    Aarhus Univ, Carbon Dioxide Activat Ctr CADIAC, Interdisciplinary Nanosci Ctr iNANO, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark.;Aarhus Univ, Dept Chem, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark..
    Johansson, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Palladium-Catalyzed Aminocarbonylation in Solid-Phase Peptide Synthesis: A Method for Capping, Cyclization, and Isotope Labeling2017Ingår i: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 19, nr 11, s. 2873-2876Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A new synthetic approach for introducing N-capping, groups onto peptides attached to a solid support, Combining aminocarbonylation under mild conditions Wing a palladacycle precatalyst and, solid-phase peptide synthesis is reported. The use of la silacarboxylic acid as an in situ CO-releasing molecule allowed the reaction to be performed single vial. The method also enables versatile substitution of side chains, side-chain to side-chain cyclizations, and selective aryl labeling of modified peptides.

  • 308.
    Skogh, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Lesniak, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Gaugaz, Fabienne Z.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Svensson, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lindeberg, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Fransson, Rebecca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Hallberg, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Sandström, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Importance of N-and C-terminal residues of substance P 1-7 for alleviating allodynia in mice after peripheral administration2017Ingår i: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 106, s. 345-351Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The heptapeptide SP1-7 (1, Arg(1)-Pro(2)-Lys(3)-Pro(4)-Gln(5)-Gln(6)-Phe(7)) is the major bioactive metabolite formed after proteolytic processing of the neuropeptide substance P (SP, Arg(1)-Pro(2)-Lys(3)-Pro(4)-GIn(5)-Gln(6)-Phe(7)-Phe(8)-Gly(9)-Leu(10)-Meti(11)-NH2). The heptapeptide 1 frequently exhibits opposite effects to those induced by SP, such as exerting antinociception, or attenuating thermal hyperalgesia and mechanical allodynia. The heptapeptide SP1-7 amide (2, Arg(1)-Pro(2)-Lys(3)-Pro(4)-Gln(5)-Gln(6)-Phe(7)-NH2 ) is often more efficacious than 1 in experimental pain models. We have now assessed the anti-allodynic outcome after systemic administration of 2 and a series of Ala substituted and truncated analogues of 2, in the spared nerve injury (SNI) mice model and the results obtained were correlated with in vitro plasma stability and permeability measurements. It is herein demonstrated that an intact Arg(1) in SP1-7 amide analogues is fundamental for retaining a potent in vivo effect, while Lys(3) of 2 is less important. A displacement with Ala(1) or truncation rendered the peptide analogues either inactive or with a significantly attenuated in vivo activity. Thus, the pentapeptide SP3-7 amide (7, t(1/2) = 11.1 min) proven to be the major metabolite of 2, demonstrated an in vivo effect itself although considerably less significant than 2 in the SNI model. Intraperitoneal administration of 2 in a low dose furnished the most powerful anti-allodynic effect in the SNI model of all the analogous evaluated, despite a fast proteolysis of 2 in plasma (t(1/2) = 6.4 min). It is concluded that not only the C-terminal residue, that we previously demonstrated, but also the N-terminal with its basic side chain, are important for achieving effective pain relief. This information is of value for the further design process aimed at identifying more drug-like SP1-7 amide related peptidomimetics with pronounced antiallodynic effects.

  • 309.
    Sköld, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Computational Modeling of the AT2 Receptor and AT2 Receptor Ligands: Investigating Ligand Binding, Structure–Activity Relationships, and Receptor-Bound Models2007Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Rational conversion of biologically active peptides to nonpeptide compounds with retained activity is an appealing approach in drug development. One important objective of the work presented in this thesis was to use computational modeling to aid in such a conversion of the peptide angiotensin II (Ang II, Asp-Arg-Val-Tyr-Ile-His-Pro-Phe). An equally important objective was to gain an understanding of the requirements for ligand binding to the Ang II receptors, with a focus on interactions with the AT2 receptor.

    The bioactive conformation of a peptide can provide important guidance in peptidomimetic design. By designing and introducing well-defined secondary structure mimetics into Ang II the bioactive conformation can be addressed. In this work, both γ- and β-turn mimetic scaffolds have been designed and characterized for incorporation into Ang II. Using conformational analysis and the pharmacophore recognition method DISCO, a model was derived of the binding mode of the pseudopeptide Ang II analogues. This model indicated that the positioning of the Arg side chain was important for AT2 receptor binding, which was also supported when the structure–activity relationship of Ang II was investigated by performing a glycine scan.

    To further examine ligand binding, a 3D model of the AT2 receptor was constructed employing homology modeling. Using this receptor model in a docking study of the ligands, binding modes were identified that were in agreement with data from point-mutation studies of the AT2 receptor.

    By investigating truncated Ang II analogues, small pseudopeptides were developed that were structurally similar to nonpeptide AT2 receptor ligands. For further guidance in ligand design of nonpeptide compounds, three-dimensional quantitative structure–activity relationship models for AT1 and AT2 receptor affinity as well as selectivity were derived.

    Delarbeten
    1. A Selective AT2 Receptor Ligand with a γ-Turn-Like Mimetic replacing the Amino Acid Residues 4-5 of Angiotensin II
    Öppna denna publikation i ny flik eller fönster >>A Selective AT2 Receptor Ligand with a γ-Turn-Like Mimetic replacing the Amino Acid Residues 4-5 of Angiotensin II
    Visa övriga...
    2004 (Engelska)Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 47, nr 4, s. 859-870Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Three angiotensin II (Ang II) analogues encompassing a benzodiazepine-based γ-turn-like scaffold have been synthesized. Evaluation of the compounds in a radioligand binding assay showed that they had no affinity to the rat liver AT1 receptor. However, one of the compounds displayed considerable affinity to the pig uterus AT2 receptor (Ki = 3.0 nM) while the other two lacked affinity to this receptor. It was hypothesized that the reason for the inactivity of one of these analogues to the AT2 receptor was that the guanidino group of the Arg2 residue and/or the N-terminal end of the pseudopeptide could not interact optimally with the receptor. To investigate this hypothesis, a conformational analysis was performed and a comparison was carried out with the monocyclic methylenedithioether analogue cyclo(S−CH2−S)[Cys3,5]Ang II which is known to bind with high affinity to the AT2 receptor (Ki = 0.62 nM). This comparison showed that, in the compounds with high AT2 receptor affinity, the guanidino group of the Arg2 residue and the N-terminal end could access common regions of space that were not accessible to the inactive compound. To examine the importance of the guanidino group for binding, the Arg side chain was removed by substituting Arg2 for Ala2 in the analogue having the high affinity. This analogue lacked affinity to AT2 receptors, which supports the role of the guanidino group in receptor binding.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-92323 (URN)10.1021/jm030921v (DOI)
    Tillgänglig från: 2004-11-10 Skapad: 2004-11-10 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    2. Synthesis and AT2 receptor-binding properties of angiotensin II analogues
    Öppna denna publikation i ny flik eller fönster >>Synthesis and AT2 receptor-binding properties of angiotensin II analogues
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    2004 (Engelska)Ingår i: Journal of Peptide Research, ISSN 1397-002X, E-ISSN 1399-3011, Vol. 64, nr 5, s. 194-201Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The present study investigates the importance of the amino acid side chains in the octapeptide angiotensin II (Ang II) for binding to the AT2 receptor. A Gly scan was performed where each amino acid in Ang II was substituted one-by-one with glycine. The resulting set of peptides was tested for affinity to the AT2 receptor (porcine myometrial membranes). For a comparison, the peptides were also tested for affinity to the AT1 receptor (rat liver membranes). Only the substitution of Arg2 reduced affinity to the AT2 receptor considerably (92-fold when compared with Ang II). For the other Gly-substituted analogues the affinity to the AT2 receptor was only moderately affected. To further investigate the role of the Arg2 side chain for receptor binding, we synthesized some N-terminally modified Ang II analogues. According to these studies a positive charge in the N-terminal end of angiotensin III [Ang II (2–8)] is not required for high AT2 receptor affinity but seems to be more important in Ang II. With respect to the AT1 receptor, [Gly2]Ang II and [Gly8]Ang II lacked binding affinity (Ki > 10 μm). Replacement of the Val3 or Ile5 residues with Gly produced only a slight decrease in affinity. Interestingly, substitution of Tyr4 or His6, which are known to be very important for AT1 receptor binding, resulted in only 48 and 14 times reduction in affinity, respectively.

    Nyckelord
    angiotensin II, angiotensin III, AT1 binding, AT2 binding, Gly scan, peptide synthesis, structure–activity relationship
    Nationell ämneskategori
    Kemi
    Identifikatorer
    urn:nbn:se:uu:diva-92324 (URN)10.1111/j.1399-3011.2004.00184.x (DOI)
    Tillgänglig från: 2004-11-10 Skapad: 2004-11-10 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    3. New selective AT2 receptor ligands encompassing a γ-turn mimetic replacing the amino acid residues 4-5 of angiotensin II act as agonists
    Öppna denna publikation i ny flik eller fönster >>New selective AT2 receptor ligands encompassing a γ-turn mimetic replacing the amino acid residues 4-5 of angiotensin II act as agonists
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    2005 (Engelska)Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 48, nr 12, s. 4009-4024Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    New benzodiazepine-based γ-turn mimetics with one or two amino acid side chains were synthesized. The γ-turn mimetics were incorporated into angiotensin II (Ang II) replacing the Val3-Tyr4-Ile5 or Tyr4-Ile5 peptide segments. All of the resulting pseudopeptides displayed high AT2/AT1 receptor selectivity and exhibited AT2 receptor affinity in the low nanomolar range. Molecular modeling was used to investigate whether the compounds binding to the AT2 receptor could position important structural elements in common areas. A previously described benzodiazepine-based γ-turn mimetic with high affinity for the AT2 receptor was also included in the modeling. It was found that the molecules, although being structurally quite different, could adopt the same binding mode/interaction pattern in agreement with the model hypothesis. The pseudopeptides selected for agonist studies were shown to act as AT2 receptor agonists being able to induce outgrowth of neurite cells, stimulate p42/p44mapk, and suppress proliferation of PC12 cells.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-95767 (URN)10.1021/jm0491492 (DOI)
    Tillgänglig från: 2007-04-17 Skapad: 2007-04-17 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    4. Angiotensin II Pseudopeptides Containing 1,3,5-Trisubstituted Benzene Scaffolds with High AT2 Receptor Affinity
    Öppna denna publikation i ny flik eller fönster >>Angiotensin II Pseudopeptides Containing 1,3,5-Trisubstituted Benzene Scaffolds with High AT2 Receptor Affinity
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    2005 (Engelska)Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 48, nr 21, s. 6620-6631Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Two 1,3,5-trisubstituted aromatic scaffolds intended to serve as γ-turn mimetics have been synthesized and incorporated in five pseudopeptide analogues of angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe), replacing Val-Tyr-Ile, Val-Tyr, or Tyr-Ile. All the tested compounds exhibited nanomolar affinity for the AT2 receptor with the best compound (3) having a Ki of 1.85 nM. Four pseudopeptides were AT2 selective, while one (5) also exhibited good affinity for the AT1 receptor (Ki = 30.3 nM). This pseudopeptide exerted full agonistic activity in an AT2 receptor induced neurite outgrowth assay but displayed no agonistic effect in an AT1 receptor functional assay. Molecular modeling, using the program DISCOtech, showed that the high-affinity ligands could interact similarly with the AT2 receptor as other ligands with high affinity for this receptor. A tentative agonist model is proposed for AT2 receptor activation by angiotensin II analogues. We conclude that the 1,3,5-trisubstituted benzene rings can be conveniently prepared and are suitable as γ-turn mimics.

    Nationell ämneskategori
    Naturvetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-95768 (URN)10.1021/jm050280z (DOI)
    Tillgänglig från: 2007-04-17 Skapad: 2007-04-17 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    5. Design, synthesis, and incorporation of a beta-turn mimetic in angiotensin II forming novel pseudopeptides with affinity for AT(1) and AT(2) receptors
    Öppna denna publikation i ny flik eller fönster >>Design, synthesis, and incorporation of a beta-turn mimetic in angiotensin II forming novel pseudopeptides with affinity for AT(1) and AT(2) receptors
    Visa övriga...
    2006 (Engelska)Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 49, nr 20, s. 6133-6137Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    A benzodiazepine-based beta-turn mimetic has been designed, synthesized, and incorporated into angiotensin II. Comparison of the mimetic with beta-turns in crystallized proteins showed that it most closely resembles a type II beta-turn. The compounds exhibited high to moderate binding affinity for the AT(2) receptor, and one also displayed high affinity for the AT(1) receptor. Molecular modeling showed that the high-affinity compounds could be incorporated into a previously derived model of AT(2) receptor ligands.

    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-95769 (URN)10.1021/jm051222g (DOI)000240826200029 ()17004728 (PubMedID)
    Tillgänglig från: 2007-04-17 Skapad: 2007-04-17 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
    6. Modeling binding modes of angiotensin II and pseudopeptide analogues to the AT2 receptor
    Öppna denna publikation i ny flik eller fönster >>Modeling binding modes of angiotensin II and pseudopeptide analogues to the AT2 receptor
    2008 (Engelska)Ingår i: Journal of Molecular Graphics and Modelling, ISSN 1093-3263, E-ISSN 1873-4243, Vol. 26, nr 6, s. 991-1003Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The 3D model of the AT(2) receptor has been built employing homology to the transmembrane domain of rhodopsin and a novel build-up procedure for restoring the extracellular loops. By docking a model peptide of angiotensin II in the AT(2) receptor model two plausible binding modes were identified. These binding modes were in agreement with most of the suggested ligand-receptor contact points reported in the literature. Eight active and one inactive pseuclopeptide angiotensin II analogue were also docked in the receptor and four of the active pseudopeptides were found to mimic the binding mode of angiotensin II. An alternative binding mode for the other four active pseudopeptides was found.

    Nyckelord
    AT(2) receptor, angiotensin II, homology modeling, docking, bioactive conformation
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-95770 (URN)10.1016/j.jmgm.2007.08.005 (DOI)000253068700012 ()17936050 (PubMedID)
    Tillgänglig från: 2007-04-17 Skapad: 2007-04-17 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
    7. Synthesis of a new class of druglike angiotensin II C-terminal mimics with affinity for the AT2 receptor
    Öppna denna publikation i ny flik eller fönster >>Synthesis of a new class of druglike angiotensin II C-terminal mimics with affinity for the AT2 receptor
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    2007 (Engelska)Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 50, nr 7, s. 1711-1715Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Four tripeptides corresponding to the C-terminal region of angiotensin II were synthesized. One of these peptides (Ac-His-Pro-Ile) showed moderate binding affinity for the AT2 receptor. Two aromatic histidine-related scaffolds were synthesized and introduced in the tripeptides to give eight new peptidomimetic structures. Three of the new peptide-derived druglike molecules exhibited selective, nanomolar affinity for the AT2 receptor. These ligands may become lead compounds in the future development of novel classes of selective AT2 receptor agonists.

    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-95771 (URN)10.1021/jm0613469 (DOI)000245259000033 ()17358051 (PubMedID)
    Tillgänglig från: 2007-04-17 Skapad: 2007-04-17 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
    8. Development of CoMFA models of affinity and selectivity to angiotensin II type-1 and type-2 receptors
    Öppna denna publikation i ny flik eller fönster >>Development of CoMFA models of affinity and selectivity to angiotensin II type-1 and type-2 receptors
    2007 (Engelska)Ingår i: Journal of Molecular Graphics and Modelling, ISSN 1093-3263, E-ISSN 1873-4243, Vol. 26, nr 1, s. 145-153Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The renin-angiotensin system (RAS) is of major importance in cardiovascular and renal regulation and has been an attractive target in drug discovery for a long time. The main receptors involved in the RAS are the Angiotensin type-1 (AT1) and type-2 (AT2) receptors, which are both activated by the endogenous octapeptide angiotensin II (AngII). This study describes the development of 3D-QSAR models for AT1 and AT2 receptor affinity and AT1/AT2 receptor selectivity using CoMFA. A data set of 244 compounds, based on the triazolinone and quinazolinone structural classes was compiled from the literature. Before CoMFA could be performed, an alignment rule for the two structural classes was defined using the pharmacophore-searching program DISCOtech. Models were validated using a test set obtained by dividing the data set into a training set and test set using hierarchical clustering, based on the CoMFA fields, AT1-, AT2-receptor affinities, and AT1/AT2 selectivity values. Predictive models with good statistics could be developed both for AT1 and AT2 receptor affinity as well as selectivity towards these receptors.

    Nyckelord
    Angiotensin, AT1, AT2, Selectivity, CoMFA, 3D-QSAR, DISCOtech, Training set selection
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-95772 (URN)10.1016/j.jmgm.2006.10.004 (DOI)000248646500014 ()17161636 (PubMedID)
    Tillgänglig från: 2007-04-17 Skapad: 2007-04-17 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
  • 310.
    Sköld, Christian
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Karlén, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Development of CoMFA models of affinity and selectivity to angiotensin II type-1 and type-2 receptors2007Ingår i: Journal of Molecular Graphics and Modelling, ISSN 1093-3263, E-ISSN 1873-4243, Vol. 26, nr 1, s. 145-153Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The renin-angiotensin system (RAS) is of major importance in cardiovascular and renal regulation and has been an attractive target in drug discovery for a long time. The main receptors involved in the RAS are the Angiotensin type-1 (AT1) and type-2 (AT2) receptors, which are both activated by the endogenous octapeptide angiotensin II (AngII). This study describes the development of 3D-QSAR models for AT1 and AT2 receptor affinity and AT1/AT2 receptor selectivity using CoMFA. A data set of 244 compounds, based on the triazolinone and quinazolinone structural classes was compiled from the literature. Before CoMFA could be performed, an alignment rule for the two structural classes was defined using the pharmacophore-searching program DISCOtech. Models were validated using a test set obtained by dividing the data set into a training set and test set using hierarchical clustering, based on the CoMFA fields, AT1-, AT2-receptor affinities, and AT1/AT2 selectivity values. Predictive models with good statistics could be developed both for AT1 and AT2 receptor affinity as well as selectivity towards these receptors.

  • 311.
    Sköld, Christian
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Kleimark, Jonatan
    Department of Chemistry, University of Gothenburg.
    Trejos, Alejandro
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Odell, Luke R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Nilsson Lill, Sten O.
    Department of Chemistry, University of Gothenburg.
    Norrby, Per-Ola
    Department of Chemistry, University of Gothenburg.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Transmetallation Versus β-Hydride Elimination: The Role of 1,4 Benzoquinone in Chelation-Controlled Arylation Reactions with Arylboronic Acids2012Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 18, nr 15, s. 4714-4722Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The formation of an atypical, saturated, diarylated, Heck/Suzuki, domino product produced under oxidative Heck reaction conditions, employing arylboronic acids and a chelating vinyl ether, has been investigated by DFT calculations. The calculations highlight the crucial role of 1,4-benzoquinone (BQ) in the reaction. In addition to its role as an oxidant of palladium, which is necessary to complete the catalytic cycle, this electron-deficient alkene opens up a low-energy reaction pathway from the post-insertion sigma-alkyl complex. The association of BQ lowers the free-energy barrier for transmetallation of the s-alkyl complex to create a pathway that is energetically lower than the oxidative Heck reaction pathway. Furthermore, the calculations showed that the reaction is made viable by BQ-mediated reductive elimination and leads to the saturated diarylated product.

  • 312.
    Sköld, Christian
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Nikiforovich, Gregory
    Karlén, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Modeling binding modes of angiotensin II and pseudopeptide analogues to the AT2 receptor2008Ingår i: Journal of Molecular Graphics and Modelling, ISSN 1093-3263, E-ISSN 1873-4243, Vol. 26, nr 6, s. 991-1003Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The 3D model of the AT(2) receptor has been built employing homology to the transmembrane domain of rhodopsin and a novel build-up procedure for restoring the extracellular loops. By docking a model peptide of angiotensin II in the AT(2) receptor model two plausible binding modes were identified. These binding modes were in agreement with most of the suggested ligand-receptor contact points reported in the literature. Eight active and one inactive pseuclopeptide angiotensin II analogue were also docked in the receptor and four of the active pseudopeptides were found to mimic the binding mode of angiotensin II. An alternative binding mode for the other four active pseudopeptides was found.

  • 313.
    Steckelings, U. Muscha
    et al.
    Center for Cardiovascular Research, Charité-Universitätsmedizin Berlin, Germany.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Widdop, Robert E.
    Department of Pharmacology, Monash University, Clayton, Australia.
    Jones, Emma S.
    Department of Pharmacology, Monash University, Clayton, Australia.
    Wallinder, Charlotta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Namsolleck, Pawel
    Center for Cardiovascular Research, Charité-Universitätsmedizin, Berlin, Germany.
    Dahlöf, Björn
    Sahlgrenska University Hospital/Östra, Sweden.
    Unger, Thomas
    Center for Cardiovascular Research, Charité-Universitätsmedizin Berlin, Germany.
    Non-peptide AT2-receptor agonists2011Ingår i: Current opinion in pharmacology (Print), ISSN 1471-4892, E-ISSN 1471-4973, Vol. 11, nr 2, s. 187-192Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The renin-angiotensin-system harbours two main receptor subtypes binding angiotensin II which are the AT1-receptor and the AT2-receptor. While the AT1-receptor has been a drug target in cardiovascular disease for many years, the AT2-receptor was only a subject of academic interest. This has changed with the design and synthesis of a first non-peptide, orally active AT2-receptor agonist, compound 21 (C21). First data using 021 revealed tissue protective effects and functional improvement after myocardial infarction and in hypertension-induced end organ damage, notably in a blood-pressure independent way. In all of these models, AT2-receptor mediated anti-inflammation seemed an important underlying mechanism. 021 is awaited to enter a phase I clinical study in 2011.

  • 314.
    Stevens, Marc
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sawant, Rajiv
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Odell, Luke
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Synthesis of sulfonyl azides via diazotransfer using an imidazole-1-sulfonyl azide salt: scope and ¹⁵N NMR labeling experiments2014Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 79, nr 11, s. 4826-4831Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Imidazole-1-sulfonyl azide hydrogen sulfate is presented as an efficient reagent for the synthesis of sulfonyl azides from primary sulfonamides. The described method is experimentally simple and high-yielding and does not require the addition of Cu salts. Furthermore, 15N NMR mechanistic studies show the reaction proceeds via a diazo transfer mechanism. Imidazole-1-sulfonyl azide hydrogen sulfate provides a considerable advantage over existing diazo transfer reagents in terms of impact stability, cost, and ease of use

  • 315.
    Stevens, Marc Y.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Chow, Shiao Y.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Estrada, Sergio
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Eriksson, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Asplund, Veronika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Antoni, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Åberg, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Odell, Luke R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Synthesis of C-11-labeled Sulfonyl Carbamates through a Multicomponent Reaction Employing Sulfonyl Azides, Alcohols, and [C-11]CO2016Ingår i: ChemistryOpen, ISSN 2191-1363, Vol. 5, nr 6, s. 566-573Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We describe the development of a new methodology focusing on C-11-labeling of sulfonyl carbamates in a multicomponent reaction comprised of a sulfonyl azide, an alkyl alcohol, and [C-11] CO. A number of C-11-labeled sulfonyl carbamates were synthesized and isolated, and the developed methodology was then applied in the preparation of a biologically active molecule. The target compound was obtained in 24 +/- 10% isolated radiochemical yield and was evaluated for binding properties in a tumor cell assay; in vivo biodistribution and imaging studies were also performed. This represents the first successful radiolabeling of a non-peptide angiotensin II receptor subtype 2 agonist, C21, currently in clinical trials for the treatment of idiopathic pulmonary fibrosis.

  • 316.
    Stevens, Marc Y.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Rozycka-Sokolowska, Ewa
    Andersson, Gabriella
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Odell, Luke R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Marciniak, Bernard
    Joule, John A.
    Cyclic amidines as precursors for imidazoles2015Ingår i: ARKIVOC, ISSN 1551-7004, E-ISSN 1551-7012, s. 219-229Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The regioselective nucleophilic reactivity of cyclic amidines is considered in the context of their reactions with 2-haloketones to generate imidazoles. Since the tautomer with an endocyclic imine is favoured, reaction with the 2-haloketone electrophile proceeds via initial alkylation at the ring nitrogen. This was confirmed by repeating a suitable literature reaction and submitting the isolated product to single-crystal X-ray analysis.

  • 317.
    Stevens, Marc Y.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Sawant, Rajiv T.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Odell, Luke R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Synthesis of arylsulfonyl azides via diazotransfer using an imidazole-1-sulfonyl azide salt: Scope and N-15 NMR labeling experiments2014Ingår i: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 248Artikel i tidskrift (Övrigt vetenskapligt)
  • 318.
    Strand, Joanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Nordeman, Patrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Honarvar, Hadis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Altai, Mohamed
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Site-specific radioiodination of HER2-targeting affibody molecules using iodophenetylmaleimide decreases renal uptake of radioactivity2012Ingår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 39, nr S2, s. S419-S419Artikel i tidskrift (Övrigt vetenskapligt)
  • 319.
    Suresh, Surisetti
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Shyamraj, Dharavath
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Synthesis of antimalarial compounds fosmidomycin and FR900098 through N- or P-alkylation reactions2013Ingår i: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 69, nr 3, s. 1183-1188Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Two straightforward and convenient routes for the synthesis of the antimalarial agents FR900098 and fosmidomycin are described. In the key steps N- or P-alkylation reactions are used. The best overall yields of FR900098 and fosmidomycin in 15 mmol scale are 83% and 68%, respectively. These routes utilize readily available materials and avoid harsh conditions.

  • 320.
    Svennebring, Andreas
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Fast Microwave-Enhanced Intra-, Pseudo-intra- and Intermolecular Heck Reactions2006Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The Heck reaction is one of the most appreciated methods for carbon-carbon bond formation. Due to its mildness and ability to be tuned by additives, it often leaves few alternative competitive reactions. It has also proven easy to develop the reaction conditions in an environmentally benign direction. Through the introduction of palladium chelating groups in olefinic precursors for the Heck reaction, it has been possible to direct the substitution in the following Heck arylation in favor of the terminal position with good regioselectivity. In this thesis, the concept has been utilized to produce a small array of drug-like compounds at useful yields under fast microwave-enhanced conditions utilizing the thermostable Herrmanns palladacycle. During the last decade, this, together with other palladacycles has become commonly employed as precatalyst for the Heck reaction. However, there have been conflicting opinions regarding the mechanisms governing its catalytic effect. A PdII-PdIV catalytic cycle has been suggested to be operative, in contrast to the classical Pd0-PdII cycle. In order to clarify the presence of such a mechanism, a set of Heck reactions was performed with the advent of different palladium precatalysts (classical and palladacycles), which revealed that the regiochemicαal substitution pattern is highly conserved, regardless of which precatalyst was employed, and thus, the same mechanism seems to be operative. This is also supported by data from ESI-MS investigations where all the reactions investigated gave rise to the same set of oxidative addition complexes. A crafted route to 3-aryl-1,2-cyclohexandiones has been developed in which 1,2-cyclohexandione is produced is situ from 2,3-epoxycyclohexanone, followed by Heck arylation. A diverse array of aryl bromides encompassing electron-rich, electron-poor, neutral and sterically hindered repressentatives has been successfully utilized to produce the corresponding products at useful yields.The intramolecular Heck reaction offers a route to quaternary carbonic centersand is being increasingly exploited in synthetic endeavors. However, the use of electron-rich olefinic precursors is only reported in a few cases. The implementation of one capto-dative and five electron-rich olefins has therefore been successfully subjected to Heck reaction conditions rendering the corresponding spiro compounds.

    Delarbeten
    1. Microwave-Promoted and Chelation-Controlled Double Arylation of Terminal Olefinic Carbon of Vinyl Ethers.
    Öppna denna publikation i ny flik eller fönster >>Microwave-Promoted and Chelation-Controlled Double Arylation of Terminal Olefinic Carbon of Vinyl Ethers.
    2004 (Engelska)Ingår i: The Journal of Organic Chemistry, ISSN 0022-3263, Vol. 69, nr 10, s. 3345-3349Artikel i tidskrift (Refereegranskat) Published
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-95220 (URN)
    Tillgänglig från: 2006-11-23 Skapad: 2006-11-23 Senast uppdaterad: 2013-07-04Bibliografiskt granskad
    2. A mechanistic study on modern palladium catalyst precursors as new gateways to Pd(0) in cationic Heck reactions
    Öppna denna publikation i ny flik eller fönster >>A mechanistic study on modern palladium catalyst precursors as new gateways to Pd(0) in cationic Heck reactions
    2008 (Engelska)Ingår i: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 64, nr 8, s. 1808-1812Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Electrospray ionization mass spectrometry (ESI-MS) was used as a means to directly identify catalytic cationic organopalladium species in ligand-controlled Heck reactions involving electron-rich olefins and different Pd-sources. In these high-temperature Heck arylations, the oxidative addition intermediates were observed as bidentate ligand chelated cationic aryl palladium species, suggesting that the used ligand attaches to the metal center at the very beginning of the catalytic cycle. This was also in agreement with the obtained regioisomeric profile of the isolated products. The investigation supports the standard Pd(0)/Pd(II) Heck mechanism and provides further insight regarding the conceivable composition of fundamental Pd(II) intermediates in an ongoing Heck reaction.

    Nyckelord
    ESI-MS, Heck, palladium, microwave
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-95221 (URN)10.1016/j.tet.2007.11.111 (DOI)000253620600028 ()
    Tillgänglig från: 2006-11-23 Skapad: 2006-11-23 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
    3. A One-Pot Isomerization-Arylation of 2,3-Epoxycyclohexanone under Controlled Microwave Heating
    Öppna denna publikation i ny flik eller fönster >>A One-Pot Isomerization-Arylation of 2,3-Epoxycyclohexanone under Controlled Microwave Heating
    Visa övriga...
    2005 (Engelska)Ingår i: The Journal of Organic Chemistry, ISSN 0022-3263, Vol. 70, nr 12, s. 4720-4725Artikel i tidskrift (Refereegranskat) Published
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-95222 (URN)
    Tillgänglig från: 2006-11-23 Skapad: 2006-11-23 Senast uppdaterad: 2013-07-04Bibliografiskt granskad
    4. Microwave-accelerated spiro-cyclizations of o-halobenzyl cyclohexenyl ethers by palladium(0) catalysis
    Öppna denna publikation i ny flik eller fönster >>Microwave-accelerated spiro-cyclizations of o-halobenzyl cyclohexenyl ethers by palladium(0) catalysis
    2007 (Engelska)Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 72, nr 15, s. 5851-5854Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    A number of new spiro[cyclohexane-1,1'-isobenzofuran]-based compounds was synthesized by palladium(0)-catalyzed 5-exo cyclization of a series of cyclohexenyl o-halobenzyl ethers. Controlled microwave heating was found to promote both product yield and reaction rate without compromising the selectivity. Heck cyclization of aryl iodide 6, 2-(2-iodobenzyloxy)cyclohex-2-enyl acetate, proceeded selectively without involvement of the allylic acetate functionality.

    Nyckelord
    Cyclization, Ethers, Microwaves, Palladium/*chemistry
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-95223 (URN)10.1021/jo0708487 (DOI)000247992800053 ()
    Tillgänglig från: 2006-11-23 Skapad: 2006-11-23 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
  • 321.
    Svennebring, Andreas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Garg, Neeraj
    Nilsson, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. ORGFARM.
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    A One-Pot Isomerization-Arylation of 2,3-Epoxycyclohexanone under Controlled Microwave Heating2005Ingår i: The Journal of Organic Chemistry, ISSN 0022-3263, Vol. 70, nr 12, s. 4720-4725Artikel i tidskrift (Refereegranskat)
  • 322.
    Svennebring, Andreas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Nilsson, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Microwave-accelerated spiro-cyclizations of o-halobenzyl cyclohexenyl ethers by palladium(0) catalysis2007Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 72, nr 15, s. 5851-5854Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A number of new spiro[cyclohexane-1,1'-isobenzofuran]-based compounds was synthesized by palladium(0)-catalyzed 5-exo cyclization of a series of cyclohexenyl o-halobenzyl ethers. Controlled microwave heating was found to promote both product yield and reaction rate without compromising the selectivity. Heck cyclization of aryl iodide 6, 2-(2-iodobenzyloxy)cyclohex-2-enyl acetate, proceeded selectively without involvement of the allylic acetate functionality.

  • 323.
    Svennebring, Andreas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Nilsson, Peter
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Microwave-Promoted and Chelation-Controlled Double Arylation of Terminal Olefinic Carbon of Vinyl Ethers.2004Ingår i: The Journal of Organic Chemistry, ISSN 0022-3263, Vol. 69, nr 10, s. 3345-3349Artikel i tidskrift (Refereegranskat)
  • 324.
    Svennebring, Andreas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sjöberg, Per
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Analytisk kemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Nilsson, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. ORGFARM.
    A mechanistic study on modern palladium catalyst precursors as new gateways to Pd(0) in cationic Heck reactions2008Ingår i: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 64, nr 8, s. 1808-1812Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Electrospray ionization mass spectrometry (ESI-MS) was used as a means to directly identify catalytic cationic organopalladium species in ligand-controlled Heck reactions involving electron-rich olefins and different Pd-sources. In these high-temperature Heck arylations, the oxidative addition intermediates were observed as bidentate ligand chelated cationic aryl palladium species, suggesting that the used ligand attaches to the metal center at the very beginning of the catalytic cycle. This was also in agreement with the obtained regioisomeric profile of the isolated products. The investigation supports the standard Pd(0)/Pd(II) Heck mechanism and provides further insight regarding the conceivable composition of fundamental Pd(II) intermediates in an ongoing Heck reaction.

  • 325.
    Svensson, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Computational Methods in Medicinal Chemistry: Mechanistic Investigations and Virtual Screening Development2015Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Computational methods have become an integral part of drug development and can help bring new and better drugs to the market faster. The process of predicting the biological activity of large compound collections is known as virtual screening, and has been instrumental in the development of several drugs today in the market. Computational methods can also be used to elucidate the energies associated with chemical reactivity and predict how to improve a synthetic protocol. These two applications of computational medicinal chemistry is the focus of this thesis.

    In the first part of this work, quantum mechanics has been used to probe the energy surface of palladium(II)-catalyzed decarboxylative reactions in order to gain a better understating of these systems (paper I-III). These studies have mapped the reaction pathways and been able to make accurate predictions that were verified experimentally.

    The other focus of this work has been to develop virtual screening methodology. Our first study in the area (paper IV) investigated if the results from several virtual screening methods could be combined using data fusion techniques in order to get a more consistent result and better performance. The study showed that the results obtained from data fusion were more consistent than the results from any single method. The data fusion methods also for several target had a better performance than any of the included single methods.

    Next, we developed a dataset suitable for evaluating the performance of virtual screening methods when applied to large compound collection as a replacement or complement for high throughput screening (paper V). This is the first benchmark dataset of its kind.

    Finally, a method for using computationally derived reaction coordinates as basis for virtual screening was developed. The aim was to find inhibitors that resemble key steps in the mechanism (paper VI). This initial proof of concept study managed to locate several known and one previously not reported reaction mimetics against insulin regulated amino peptidase.

    Delarbeten
    1. Theoretical and Experimental Investigation of Palladium(II)-Catalyzed Decarboxylative Addition of Arenecarboxylic Acid to Nitrile
    Öppna denna publikation i ny flik eller fönster >>Theoretical and Experimental Investigation of Palladium(II)-Catalyzed Decarboxylative Addition of Arenecarboxylic Acid to Nitrile
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    2013 (Engelska)Ingår i: Organometallics, ISSN 0276-7333, E-ISSN 1520-6041, Vol. 32, nr 2, s. 490-497Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The reaction mechanism of palladium(II)-catalyzed decarboxylative addition of 2,6-dimethoxybenzoic acid to acetonitrile was investigated by means of density functional theory (DFT) calculations. Calculations of the free energy profile for decarboxylation and carbopalladation indicated carbopalladation as the rate-determining step of the reaction. Investigation of the free energy profile for a series of experimentally evaluated nitrogen-based bidentate palladium ligands revealed that higher energy is required for decarboxylation and carbopalladation employing the experimentally least efficient ligand. The DFT investigation also showed that the relative free energies of the transition states were lowered in polar solvent, and preparative experiments confirmed that a nonoptimal ligand could be greatly improved by addition of water to the reaction system.

    Nationell ämneskategori
    Medicin och hälsovetenskap Kemi
    Identifikatorer
    urn:nbn:se:uu:diva-196041 (URN)10.1021/om3009525 (DOI)000314332100017 ()
    Tillgänglig från: 2013-03-04 Skapad: 2013-03-04 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
    2. Decarboxylative Palladium(II)-Catalyzed Synthesis of Aryl Amidines from Aryl Carboxylic Acids: Development and Mechanistic Investigation
    Öppna denna publikation i ny flik eller fönster >>Decarboxylative Palladium(II)-Catalyzed Synthesis of Aryl Amidines from Aryl Carboxylic Acids: Development and Mechanistic Investigation
    Visa övriga...
    2013 (Engelska)Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 19, nr 41, s. 13803-13810Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    A fast and convenient synthesis of aryl amidines starting from carboxylic acids and cyanamides is reported. The reaction was achieved by palladium(II)-catalysis in a one-step microwave protocol using [Pd(O2CCF3)(2)], 6-methyl-2,2-bipyridyl and trifluoroacetic acid (TFA) in N-methylpyrrolidinone (NMP), providing the corresponding aryl amidines in moderate to excellent yields. The protocol is very robust with regards to the cyanamide coupling partner but requires electron-rich ortho-substituted aryl carboxylic acids. Mechanistic insight was provided by a DFT investigation and direct ESI-MS studies of the reaction. The results of the DFT study correlated well with the experimental findings and, together with the ESI-MS study, support the suggested mechanism. Furthermore, a scale-out (scale-up) was performed with a non-resonant microwave continuous-flow system, achieving a maximum throughput of 11mmolh(-1) by using a glass reactor with an inner diameter of 3mm at a flow rate of 1mLmin(-1).

    Nyckelord
    decarboxylation, density functional calculations, mass spectrometry, microwave chemistry, palladium
    Nationell ämneskategori
    Naturvetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-210180 (URN)10.1002/chem.201301809 (DOI)000325135800026 ()
    Tillgänglig från: 2013-11-04 Skapad: 2013-11-04 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
    3. Mechanistic Investigation of Palladium(II)-Catalyzed Decarboxylative Synthesis of Electron Rich Styrenes and 1,1-Diarylethenes
    Öppna denna publikation i ny flik eller fönster >>Mechanistic Investigation of Palladium(II)-Catalyzed Decarboxylative Synthesis of Electron Rich Styrenes and 1,1-Diarylethenes
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    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nyckelord
    palladium, DFT, mechanism, styrene
    Nationell ämneskategori
    Organisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-259441 (URN)
    Tillgänglig från: 2015-08-04 Skapad: 2015-08-04 Senast uppdaterad: 2015-10-01
    4. Virtual Screening Data Fusion Using Both Structure- and Ligand-Based Methods
    Öppna denna publikation i ny flik eller fönster >>Virtual Screening Data Fusion Using Both Structure- and Ligand-Based Methods
    2012 (Engelska)Ingår i: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 52, nr 1, s. 225-232Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Virtual screening is widely applied in drug discovery, and significant effort has been put into improving current methods. In this study, we have evaluated the performance of compound ranking in virtual screening using five different data fusion algorithms on a total of 16 data sets. The data were generated by docking, pharmacophore search, shape similarity, and electrostatic similarity, spanning both structure- and ligand-based methods. The algorithms used for data fusion were sum rank, rank vote, sum score, Pareto ranking, and parallel selection. None of the fusion methods require any prior knowledge or input other than the results from the single methods and, thus, are readily applicable. The results show that compound ranking using data fusion improves the performance and consistency of virtual screening compared to the single methods alone. The best performing data fusion algorithm was parallel selection, but both rank voting and Pareto ranking also have good performance.

    Nationell ämneskategori
    Läkemedelskemi
    Identifikatorer
    urn:nbn:se:uu:diva-169381 (URN)10.1021/ci2004835 (DOI)000299351600021 ()
    Tillgänglig från: 2012-02-28 Skapad: 2012-02-28 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
    5. Toward a Benchmarking Data Set Able to Evaluate Ligand- and Structure-based Virtual Screening Using Public HTS Data
    Öppna denna publikation i ny flik eller fönster >>Toward a Benchmarking Data Set Able to Evaluate Ligand- and Structure-based Virtual Screening Using Public HTS Data
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    2015 (Engelska)Ingår i: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 55, nr 2, s. 343-353Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Virtual screening has the potential to accelerate and reduce costs of probe development and drug discovery. To develop and benchmark virtual screening methods, validation data sets are commonly used. Over the years, such data sets have been constructed to overcome the problems of analogue bias and artificial enrichment. With the rapid growth of public domain databases containing high-throughput screening data, such as the PubChem BioAssay database, there is an increased possibility to use such data for validation. In this study, we identify PubChem data sets suitable for validation of both structure- and ligand-based virtual screening methods. To achieve this, high-throughput screening data for which a crystal structure of the bioassay target was available in the PDB were identified. Thereafter, the data sets were inspected to identify structures and data suitable for use in validation studies. In this work, we present seven data sets (MMP13, DUSP3, PTPN22, EPHX2, CTDSP1, MAPK10, and CDK5) compiled using this method. In the seven data sets, the number of active compounds varies between 19 and 369 and the number of inactive compounds between 59 405 and 337 634. This gives a higher ratio of the number of inactive to active compounds than what is found in most benchmark data sets. We have also evaluated the screening performance using docking and 3D shape similarity with default settings. To characterize the data sets, we used physicochemical similarity and 2D fingerprint searches. We envision that these data sets can be a useful complement to current data sets used for method evaluation.

    Ort, förlag, år, upplaga, sidor
    American Chemical Society (ACS), 2015
    Nationell ämneskategori
    Strukturbiologi Farmaceutisk synteskemi
    Forskningsämne
    Kemi med inriktning mot bioorganisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-248018 (URN)10.1021/ci5005465 (DOI)000349943100014 ()25564966 (PubMedID)
    Tillgänglig från: 2015-03-26 Skapad: 2015-03-26 Senast uppdaterad: 2018-03-05Bibliografiskt granskad
    6. Virtual Screening for Transition State Analogue Inhibitors of IRAP Based on Quantum Mechanically Derived Reaction Coordinates
    Öppna denna publikation i ny flik eller fönster >>Virtual Screening for Transition State Analogue Inhibitors of IRAP Based on Quantum Mechanically Derived Reaction Coordinates
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    2015 (Engelska)Ingår i: Journal of Chemical Information and Modeling, ISSN 1549-960X, Vol. 55, nr 9, s. 1984-1993Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Transition state- and high energy intermediate mimetics have the potential to be very potent enzyme inhibitors. In this study a model of peptide hydrolysis in the active site of insulin-regulated aminopeptidase (IRAP) was developed using density functional theory calculations and the cluster approach. The 3D structure models of the reaction coordinates were used for virtual screening to obtain new chemical starting points for IRAP inhibitors. This mechanism-based virtual screening process managed to identify several known peptidase inhibitors from a library of over five million compounds and biological testing identified one compound not previously reported as an IRAP inhibitor. This novel methodology for virtual screening is a promising approach to identify new inhibitors mimicking key transition states or intermediates of an enzymatic reaction.

    Ort, förlag, år, upplaga, sidor
    American Chemical Society (ACS), 2015
    Nationell ämneskategori
    Läkemedelskemi
    Identifikatorer
    urn:nbn:se:uu:diva-259442 (URN)10.1021/acs.jcim.5b00359 (DOI)000362056900018 ()26252078 (PubMedID)
    Forskningsfinansiär
    Carl Tryggers stiftelse för vetenskaplig forskning Vetenskapsrådet
    Tillgänglig från: 2015-08-05 Skapad: 2015-08-04 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
  • 326.
    Svensson, Fredrik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Engen, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Lundbäck, Thomas
    Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Chem Biol Consortium Sweden,Sci Life Lab, SE-17165 Solna, Sweden.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sköld, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Virtual Screening for Transition State Analogue Inhibitors of IRAP Based on Quantum Mechanically Derived Reaction Coordinates2015Ingår i: Journal of Chemical Information and Modeling, ISSN 1549-960X, Vol. 55, nr 9, s. 1984-1993Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Transition state- and high energy intermediate mimetics have the potential to be very potent enzyme inhibitors. In this study a model of peptide hydrolysis in the active site of insulin-regulated aminopeptidase (IRAP) was developed using density functional theory calculations and the cluster approach. The 3D structure models of the reaction coordinates were used for virtual screening to obtain new chemical starting points for IRAP inhibitors. This mechanism-based virtual screening process managed to identify several known peptidase inhibitors from a library of over five million compounds and biological testing identified one compound not previously reported as an IRAP inhibitor. This novel methodology for virtual screening is a promising approach to identify new inhibitors mimicking key transition states or intermediates of an enzymatic reaction.

  • 327.
    Svensson, Fredrik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Fardost, Ashkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Skillinghaug, Bobo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Wakchaure, Prasad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Wejdemar, Matyas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sköld, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Mechanistic Investigation of Palladium(II)-Catalyzed Decarboxylative Synthesis of Electron Rich Styrenes and 1,1-DiarylethenesManuskript (preprint) (Övrigt vetenskapligt)
  • 328.
    Svensson, Fredrik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Karlén, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sköld, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Virtual Screening Data Fusion Using Both Structure- and Ligand-Based Methods2012Ingår i: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 52, nr 1, s. 225-232Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Virtual screening is widely applied in drug discovery, and significant effort has been put into improving current methods. In this study, we have evaluated the performance of compound ranking in virtual screening using five different data fusion algorithms on a total of 16 data sets. The data were generated by docking, pharmacophore search, shape similarity, and electrostatic similarity, spanning both structure- and ligand-based methods. The algorithms used for data fusion were sum rank, rank vote, sum score, Pareto ranking, and parallel selection. None of the fusion methods require any prior knowledge or input other than the results from the single methods and, thus, are readily applicable. The results show that compound ranking using data fusion improves the performance and consistency of virtual screening compared to the single methods alone. The best performing data fusion algorithm was parallel selection, but both rank voting and Pareto ranking also have good performance.

  • 329.
    Svensson, Fredrik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Mane, Rajendra S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sävmarker, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sköld, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Theoretical and Experimental Investigation of Palladium(II)-Catalyzed Decarboxylative Addition of Arenecarboxylic Acid to Nitrile2013Ingår i: Organometallics, ISSN 0276-7333, E-ISSN 1520-6041, Vol. 32, nr 2, s. 490-497Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The reaction mechanism of palladium(II)-catalyzed decarboxylative addition of 2,6-dimethoxybenzoic acid to acetonitrile was investigated by means of density functional theory (DFT) calculations. Calculations of the free energy profile for decarboxylation and carbopalladation indicated carbopalladation as the rate-determining step of the reaction. Investigation of the free energy profile for a series of experimentally evaluated nitrogen-based bidentate palladium ligands revealed that higher energy is required for decarboxylation and carbopalladation employing the experimentally least efficient ligand. The DFT investigation also showed that the relative free energies of the transition states were lowered in polar solvent, and preparative experiments confirmed that a nonoptimal ligand could be greatly improved by addition of water to the reaction system.

  • 330.
    Sävmarker, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Palladium-Catalyzed Carbonylation and Arylation Reactions2012Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Palladium-catalyzed reactions have found widespread use in contemporary organic chemistry due to their impressive range of functional group tolerance and high chemo- and regioselectivity. The pioneering contributions to the development of the Pd-catalyzed C-C bond forming cross-coupling reaction were rewarded with the Nobel Prize in Chemistry in 2010. Today, this is a rapidly growing field, and the development of novel methods, as well as the theoretical understanding of the various processes involved are of immense importance for continued progress in this field.

    The aim of the work presented in this thesis was to develop novel palladium(0)- and palladium(II)-catalyzed reactions. The work involved in achieving this aim led to the development of a Mo(CO)6-mediated carbonylative Stille cross coupling reaction for the preparation of various deoxybenzoins. The protocol utilized convenient gas-free conditions to facilitate the carbonylative coupling of benzyl bromides and chlorides with aryl and heteroaryl stannanes. Mo(CO)6-assisted conditions were then used in the development of a general protocol suitable for the aminocarbonylation of aryl triflates. Both electron-poor and electron-rich triflates were coupled with primary, secondary and aryl amines. In addition, DMAP was found to be a beneficial additive when using sterically hindered or poorly nucleophilic amines.

    An efficient and convenient method for the synthesis of styrenes from arylboranes was developed, employing the relatively inexpensive vinyl acetate as the ethene source under Pd(II)-catalyzed conditions. The reaction mechanism was studied using ESI-MS, and a plausible catalytic cycle was proposed.

    A method for the oxidative Heck reaction employing aryltrifluoroborates and aryl MIDA boronates was also developed. Electron-rich and electron-poor olefins were regioselectively arylated under microwave-assisted conditions. Various arylboron species were identified in an ongoing reaction using ESI-MS.   

    Further investigations led to the development of a direct method for the synthesis of arylamidines from aryltrifluoroborates and cyanamides. Under Pd(II)-catalyzed conditions it was possible to insert the aryl into primary, secondary and tertiary cyanamides.

    Finally, a desulfitative method for the synthesis of aryl ketones was developed. A variety of aryl sulfinates were effectively inserted into alkyl- and aryl nitriles. The mechanism was further investigated using ESI-MS and a plausible catalytic cycle was proposed.

    Delarbeten
    1. Deoxybenzoins from Stille carbonylative cross-couplings using molybdenum hexacarbonyl
    Öppna denna publikation i ny flik eller fönster >>Deoxybenzoins from Stille carbonylative cross-couplings using molybdenum hexacarbonyl
    2010 (Engelska)Ingår i: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 51, nr 52, s. 6886-6889Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Stille-type carbonylative cross-couplings, employing palladium catalysis and Mo(CO)6 as the carbon monoxide carrier, were used for the preparation of deoxybenzoins. Straightforward transformations were conveniently performed in closed vessels at 100 C, providing the products in good yields. Benzyl bromides and chlorides were used as coupling partners with aryl and heteroaryl stannanes. This mild three-component carbonylation employs the destabilizing agent DBU to promote smooth release of carbon monoxide from Mo(CO)6, which made this protocol operationally simple and minimized the formation of Stille diarylmethane products.

    Nyckelord
    Stille, molybdenum hexacarbonyl, deoxybenzoins, palladium
    Nationell ämneskategori
    Organisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-167715 (URN)10.1016/j.tetlet.2010.10.115 (DOI)000285670400023 ()
    Tillgänglig från: 2012-01-31 Skapad: 2012-01-31 Senast uppdaterad: 2017-12-08Bibliografiskt granskad
    2. Microwave-promoted aminocarbonylation of aryl triflates using Mo(CO)(6) as a solid CO source
    Öppna denna publikation i ny flik eller fönster >>Microwave-promoted aminocarbonylation of aryl triflates using Mo(CO)(6) as a solid CO source
    2008 (Engelska)Ingår i: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 49, nr 42, s. 6115-6118Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Palladium-catalyzed carbonylations of aryl triflates with a range of nucleophiles using Mo(CO)(6) as a solid CO source were explored. The reactions proceeded smoothly providing moderate to good yields of the corresponding aryl amides, esters, or acylsulfonamides after only 20 min of microwave irradiation. The acyl transfer reagent 4-dimethylaminopyridine was found to promote some of the more difficult transformations. (C) 2008 Elsevier Ltd. All rights reserved.

    Nyckelord
    carbonylation, microwave, palladium, aryl triflate, DMAP
    Nationell ämneskategori
    Kemi
    Identifikatorer
    urn:nbn:se:uu:diva-104379 (URN)10.1016/j.tetlet.2008.08.014 (DOI)000259883800024 ()0040-4039 (ISBN)
    Tillgänglig från: 2009-05-28 Skapad: 2009-05-28 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    3. Synthesis of styrenes by palladium(II)-catalyzed vinylation of arylboronic acids and aryltrifluoroborates by using vinyl acetate
    Öppna denna publikation i ny flik eller fönster >>Synthesis of styrenes by palladium(II)-catalyzed vinylation of arylboronic acids and aryltrifluoroborates by using vinyl acetate
    Visa övriga...
    2009 (Engelska)Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 15, nr 18, s. 4630-4636Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Reactions of aromatic and heteroaromatic boronic acids or aryltrifluoroborate salts with vinyl acetate in the presence of a palladium(II) catalyst give the corresponding styrenes in good yields. This Heck reaction proceeds with microwave heating in less than 30 min at 140 degrees C in the absence of base and tolerates a variety of substituents. No palladium reoxidant is needed and the vinylation is performed under non-inert conditions. Mass spectrometry (electrospray ionization mass spectrometry (ESIMS) and tandem mass spectrometry   (MS/MS)) was used to identify cationic palladium-containing complexes in ongoing reactions. The key intermediates that have been detected, together with experiments that used deuterated vinyl acetate, support the existence of catalytically active palladium hydride species, and that it is the arylation of ethylene, not vinyl acetate, which   generates the styrene product. The mechanism of the reaction is discussed in terms of the palladium(II) intermediates mentioned above.

    Nyckelord
    Heck reaction, mass spectrometry, mechanistic studies, palladium, styrene
    Nationell ämneskategori
    Kemi
    Identifikatorer
    urn:nbn:se:uu:diva-102918 (URN)10.1002/chem.200802744 (DOI)000265955200018 ()19274694 (PubMedID)
    Tillgänglig från: 2009-05-13 Skapad: 2009-05-12 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    4. Oxidative Heck Reactions Using Aryltrifluoroborates and Aryl N-Methyliminodiacetic Acid (MIDA) Boronates
    Öppna denna publikation i ny flik eller fönster >>Oxidative Heck Reactions Using Aryltrifluoroborates and Aryl N-Methyliminodiacetic Acid (MIDA) Boronates
    Visa övriga...
    2012 (Engelska)Ingår i: ChemistryOpen, ISSN 2191-1363, Vol. 1, nr 3, s. 140-146Artikel i tidskrift (Refereegranskat) Published
    Ort, förlag, år, upplaga, sidor
    Weinheim: Wiley-VCH Verlagsgesellschaft, 2012
    Nyckelord
    Heck reactions, N-methyliminodiacetic acid (MIDA), oxidative reactions, palladium complexes, trifluoroborate
    Nationell ämneskategori
    Organisk kemi
    Forskningsämne
    Kemi med inriktning mot organisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-167718 (URN)10.1002/open.201200007 (DOI)000328607400004 ()
    Forskningsfinansiär
    Vetenskapsrådet
    Tillgänglig från: 2012-01-31 Skapad: 2012-01-31 Senast uppdaterad: 2017-12-08Bibliografiskt granskad
    5. Direct Palladium(II)-Catalyzed Synthesis of Arylamidines from Aryltrifluoroborates
    Öppna denna publikation i ny flik eller fönster >>Direct Palladium(II)-Catalyzed Synthesis of Arylamidines from Aryltrifluoroborates
    Visa övriga...
    2012 (Engelska)Ingår i: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 14, nr 9, s. 2394-2397Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    A fast and convenient synthesis of arylamidines starting from readily available potassium aryltrifluoroborates and cyanamides is reported. The coupling was achieved by Pd(II)-catalysis in a one step 20 min microwave protocol using Pd(O2CCF3), 6-methyl-2,2'-bipyridyl, TFA, and MeOH, providing the corresponding arylamidines in moderate to excellent yields.

    Nationell ämneskategori
    Organisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-167719 (URN)10.1021/ol300813c (DOI)000303492200052 ()
    Tillgänglig från: 2012-01-31 Skapad: 2012-01-31 Senast uppdaterad: 2017-12-08Bibliografiskt granskad
    6. Microwave-Assisted Palladium(II)-Catalyzed Synthesis of Aryl Ketones from Aryl Sulfinates and Direct ESI-MS Studies Thereof
    Öppna denna publikation i ny flik eller fönster >>Microwave-Assisted Palladium(II)-Catalyzed Synthesis of Aryl Ketones from Aryl Sulfinates and Direct ESI-MS Studies Thereof
    2011 (Engelska)Ingår i: ACS Catalysis, ISSN 2155-5435, Vol. 1, nr 11, s. 1455-1459Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    A fast palladium(II)-catalyzed and microwave-promoted procedure using 6-methyl-2,2'-bipyridyl as ligand to synthesize aryl ketones from aryl sulfinates and nitriles is described. More importantly, the first detailed investigation of the reaction mechanism using direct ESI-MS studies is reported.

    Nyckelord
    palladium, catalysis, desulfination, aryl sulfinates, aryl ketones, nitriles, ESI-MS, microwave
    Nationell ämneskategori
    Kemi
    Identifikatorer
    urn:nbn:se:uu:diva-162466 (URN)10.1021/cs200428u (DOI)000296598000002 ()
    Tillgänglig från: 2011-11-30 Skapad: 2011-11-30 Senast uppdaterad: 2012-06-01Bibliografiskt granskad
  • 331.
    Sävmarker, Jonas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Lindh, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Nilsson, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Deoxybenzoins from Stille carbonylative cross-couplings using molybdenum hexacarbonyl2010Ingår i: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 51, nr 52, s. 6886-6889Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Stille-type carbonylative cross-couplings, employing palladium catalysis and Mo(CO)6 as the carbon monoxide carrier, were used for the preparation of deoxybenzoins. Straightforward transformations were conveniently performed in closed vessels at 100 C, providing the products in good yields. Benzyl bromides and chlorides were used as coupling partners with aryl and heteroaryl stannanes. This mild three-component carbonylation employs the destabilizing agent DBU to promote smooth release of carbon monoxide from Mo(CO)6, which made this protocol operationally simple and minimized the formation of Stille diarylmethane products.

  • 332.
    Sävmarker, Jonas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Lindh, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Nilsson, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. ORGFARM.
    Sjöberg, Per
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Oxidative Heck Reactions Using Aryltrifluoroborates and Aryl N-Methyliminodiacetic Acid (MIDA) Boronates2012Ingår i: ChemistryOpen, ISSN 2191-1363, Vol. 1, nr 3, s. 140-146Artikel i tidskrift (Refereegranskat)
  • 333.
    Sävmarker, Jonas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Rydfjord, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Gising, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Odell, Luke R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Direct Palladium(II)-Catalyzed Synthesis of Arylamidines from Aryltrifluoroborates2012Ingår i: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 14, nr 9, s. 2394-2397Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A fast and convenient synthesis of arylamidines starting from readily available potassium aryltrifluoroborates and cyanamides is reported. The coupling was achieved by Pd(II)-catalysis in a one step 20 min microwave protocol using Pd(O2CCF3), 6-methyl-2,2'-bipyridyl, TFA, and MeOH, providing the corresponding arylamidines in moderate to excellent yields.

  • 334.
    Tanner, David
    et al.
    Uppsala universitet.
    Birgersson, Carin
    Uppsala universitet.
    Gogoll, Adolf
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Luthman, Kristina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    On the Use of C2-Symmetric Aziridines as Chiral Auxiliaries1994Ingår i: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 50, nr 32, s. 9797-9824Artikel i tidskrift (Refereegranskat)
  • 335.
    Tehler, Ulrika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Fagerberg, Jonas H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Svensson, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Artursson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Bergstrom, Christel A. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Optimizing Solubility and Permeability of a Biopharmaceutics Classification System (BCS) Class 4 Antibiotic Drug Using Lipophilic Fragments Disturbing the Crystal Lattice2013Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 56, nr 6, s. 2690-2694Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Esterification was used to simultaneously increase solubility and permeability of ciprofloxacin, a biopharmaceutics classification system (BCS) class 4 drug (low solubility/low permeability) with solid-state limited solubility. Molecular flexibility was increased to disturb the crystal lattice, lower the melting point, and thereby improve the solubility, whereas lipophilicity was increased to enhance the intestinal permeability. These structural changes resulted in BCS class 1 analogues (high solubility/high permeability) emphasizing that simple medicinal chemistry may improve both these properties.

  • 336. Tian, Z. Ryan
    et al.
    Sharma, Aruna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Nozari, Ala
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Subramaniam, Raman
    Lundstedt, Torbjörn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sharma, Hari Shanker
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Nanowired Drug Delivery to Enhance Neuroprotection in Spinal Cord Injury2012Ingår i: CNS & Neurological Disorders - Drug Targets, ISSN 1871-5273, Vol. 11, nr 1, s. 86-95Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Spinal cord injury (SCI) is a serious clinical situation for which no suitable drug therapy exists. SCI often results in paraplegia or quadriplegia and, apart from the personal trauma leads to huge costs to society for rehabilitation or day-to-day life support. Sensory motor dysfunction following SCI is mainly a consequence of the slowly progressing cord pathology after primary injury that worsens over tine. Thus, almost all sensory and motor nerve control and pathways passing through spinal cord and reflexes are compromised in SCI patients. As a result their peripheral nervous system, autonomic nervous function and central nervous system regulations are adversely affected. Experiments carried out in our laboratory show that various therapeutic agents, if given within 10 to 30 minutes after primary SCI could correct morphological changes to a certain extent. In these rat models of SCI reduction in cord pathology, e.g., blood-spinal cord barrier (BSCB) breakdown, edema formation and cell injury by the neuroprotective agents that also limited sensory motor dysfunction and improved functional behavior. However, these drugs if given beyond 30 minutes after SCI showed a markedly reduced neuroprotective efficacy. Thus, new strategies are needed to enhance neuroprotection in SCI to prevent structural and functional changes over longer periods of time. To that end our laboratory has initiated a series of investigations in which nanowired delivery of various neurotherapeutic agents are applied after different time periods of SCI, that resulted in a much better outcome than with the parent compounds under identical conditions. The superior neuroprotective activity of nanowired compound delivery could be due to a reduced metabolism of active compounds in the central nervous system (CNS) or by sustained release of the drug for longer times. In addition, nanowired drugs may penetrate the CNS faster and could reach widespread areas once entering the spinal cord. Thus, nanowired drug delivery to treat SCI may have potential therapeutic value. These aspects of nanowired drug delivery to enhance neuroprotection in SCI are discussed in this review based on our own investigations.

  • 337.
    Torell, Frida
    et al.
    Umea Univ, Dept Chem, Computat Life Sci Cluster CLiC, Umea, Sweden.;Karlsruhe Inst Technol, Karlsruhe, Germany..
    Bennett, Kate
    AcureOmics AB, Umea, Sweden..
    Raennar, Stefan
    AcureOmics AB, Umea, Sweden..
    Lundstedt-Enkel, Katrin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi. AcureOmics AB, Umea, Sweden..
    Lundstedt, Torbjörn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi. AcureOmics AB, Umea, Sweden..
    Trygg, Johan
    Umea Univ, Dept Chem, Computat Life Sci Cluster CLiC, Umea, Sweden..
    The effects of thawing on the plasma metabolome: evaluating differences between thawed plasma and multi-organ samples2017Ingår i: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 13, nr 6, artikel-id 66Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction Post-collection handling, storage and transportation can affect the quality of blood samples. Pre-analytical biases can easily be introduced and can jeopardize accurate profiling of the plasma metabolome. Consequently, a mouse study must be carefully planned in order to avoid any kind of bias that can be introduced, in order not to compromise the outcome of the study. The storage and shipment of the samples should be made in such a way that the freeze-thaw cycles are kept to a minimum. In order to keep the latent effects on the stability of the blood metabolome to a minimum it is essential to study the effect that the post-collection and pre-analytical error have on the metabolome.

    Objectives The aim of this study was to investigate the effects of thawing on the metabolic profiles of different sample types.

    Methods In the present study, a metabolomics approach was utilized to obtain a thawing profile of plasma samples obtained on three different days of experiment. The plasma samples were collected from the tail on day 1 and 3, while retro-orbital sampling was used on day 5. The samples were analysed using gas chromatography time-of-flight mass spectrometry (GC TOF-MS).

    Results The thawed plasma samples were found to be characterized by higher levels of amino acids, fatty acids, glycerol metabolites and purine and pyrimidine metabolites as a result of protein degradation, cell degradation and increased phospholipase activity. The consensus profile was thereafter compared to the previously published study comparing thawing profiles of tissue samples from gut, kidney, liver, muscle and pancreas.

    Conclusions The comparison between thawed organ samples and thawed plasma samples indicate that the organ samples are more sensitive to thawing, however thawing still affected all investigated sample types.

  • 338.
    Trejos, Alejandro
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Palladium-Catalysed Couplings in Organic Synthesis: Exploring Catalyst-Presenting Strategies and Medicinal Chemistry Applications2012Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Palladium-catalysed coupling reactions have been embraced by synthetic chemists as one of the preferred means for smooth formation of new carbon-carbon bonds: a truly ubiquitous methodology of synthesizing complex molecules.

    This thesis describes the study of a series of palladium(0)-catalysed C2-arylations of a 1-cyclopentenyl ether, equipped with a chiral (S)-N-methyl-pyrrolidine auxiliary. The investigated olefin was demonstrated to undergo Si-face insertion, providing (R)-configuration of the arylated C2-carbon.

    In addition, the mild and novel palladium(II)-catalysed dominoHeck/Suzuki β,α-diarylation-reduction of a dimethylaminoethyl-substituted chelating vinyl ether was developed using arylboronic acids as arylating agents in combination with 1,4-benzoquinone (BQ). Further, highly regioselective palladium(II)-catalysed α-and β-monoarylation of the chelating vinyl ether was achieved using either a bidentate ligand or by employing ligand-less conditions. These studies demonstrate that the choice of ligands has a profound effect on the reaction outcome, as productive β,α-diarylation could only be obtained by suppressing the competing β-hydride elimination using BQ as the stabilising ligand and terminal reoxidant.

    The pivotal role of BQ in the reaction was studied using computer-aided density functional theory calculations. The calculations highlight the crucial role of BQ as a Pd(II)-ligand. In addition of serving as an oxidant of palladium, the calculations support the view that the coordination of BQ to the Pd(II)-centre in the key σ-alkyl complex leads to a low-energy pathway, aided by a strong η2 Pd-BQ donation-back-donation interaction.

    Furthermore, an investigation of the scope and limitations of novel stereoselective and BQ-mediated palladium(II)-catalysed domino Heck/Suzuki β,α-diarylation reactions, involving metal coordinating cyclic methylamino vinyl ethers and a number of electronically diverse arylboronic acids, conducted.

    In addition, a set of 4-quinolone-3-carboxylic acids, structurally related to elvitegravir and bearing different substituents on the condensed benzene ring, was designed and synthesized as potential HIV-1 integrase inhibitors.

    Finally, in an effort to identify a new class of HIV-1 protease inhibitors, four different stereopure β-hydroxy γ-lactam-containing inhibitors were synthesized, biologically evaluated, and co-crystallized with the enzyme.

    Delarbeten
    1. Stereoselective Heck arylation of a functionalized cyclopentenyl ether using (S)-N-methyl-pyrrolidine as the stereochemical controller
    Öppna denna publikation i ny flik eller fönster >>Stereoselective Heck arylation of a functionalized cyclopentenyl ether using (S)-N-methyl-pyrrolidine as the stereochemical controller
    Visa övriga...
    2008 (Engelska)Ingår i: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 64, nr 37, s. 8746-8751Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The study of a series of palladium(0)-catalyzed C2-arylations of a 1-cyclopentenyl ether equipped with a chiral (S)-N-methyl-pyrrolidine auxiliary is reported. Stereoselective Heck monoarylations were performed using aryl iodides under classical heating conditions for 1.7-3.0 h at 80 degrees C and in one case using 30 min of microwave irradiation at 110 degrees C. To further explore the scope and nature of this stereoselective methodology, aryl bromides were also utilized as arylating agents, using 20 min of microwave processing at 120-130 degrees C. High to excellent diastereopurities (90-98% de) were obtained according to H-1 NMR and GC-MS analyses. The prolinol fragment apparently controlled the chastereoselectivity of the Heck reaction by presenting the arylpalladium species from the preferred side of the double bond. By X-ray structure diffraction analysis of an N-quaternized Heck product, the absolute configuration of the new stereocenter was established as (R), Supporting a Si-face migratory insertion.

    Nyckelord
    Heck reaction, microwave, vinyl ether, palladium catalysis; stereoselective
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-104394 (URN)10.1016/j.tet.2008.06.099 (DOI)000258841100022 ()0040-4020 (ISBN)
    Tillgänglig från: 2009-05-28 Skapad: 2009-05-28 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
    2. Palladium(II)-catalyzed coupling reactions with a chelating vinyl ether and arylboronic acids: a new Heck/Suzuki domino diarylation reaction
    Öppna denna publikation i ny flik eller fönster >>Palladium(II)-catalyzed coupling reactions with a chelating vinyl ether and arylboronic acids: a new Heck/Suzuki domino diarylation reaction
    2009 (Engelska)Ingår i: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 48, s. 7587-7589Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    A mild and novel palladium(II)-catalyzed domino Heck/Suzuki alpha,beta-diarylation-reduction of a dimethylaminoethyl substituted chelating vinyl ether was developed by using electron-rich arylboronic acids in combination with p-benzoquinone. Based on the preparative results, a catalytic cycle is proposed. Further, highly regioselective palladium(II)-catalyzed alpha- or beta-monoarylation of the chelating vinyl ether was achieved using either a bidentate ligand or by employing ligand-less conditions.

    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Forskningsämne
    Organisk farmaceutisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-124718 (URN)10.1039/b918358b (DOI)000272238900039 ()20024288 (PubMedID)
    Tillgänglig från: 2010-05-05 Skapad: 2010-05-05 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
    3. Chelation-Mediated Palladium(II)-Catalyzed Domino Heck-Mizoroki/Suzuki-Miyaura Reactions Using Arylboronic Acids: Increasing Scope and Mechanistic Understanding
    Öppna denna publikation i ny flik eller fönster >>Chelation-Mediated Palladium(II)-Catalyzed Domino Heck-Mizoroki/Suzuki-Miyaura Reactions Using Arylboronic Acids: Increasing Scope and Mechanistic Understanding
    2011 (Engelska)Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 76, nr 8, s. 2433-2438Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    A palladium(II)-catalyzed Heck-Mizoroki/Suzuki-Miyaura domino reaction involving metal coordinating dimethylaminoethyl vinyl ethers and a number of electron-rich and electron-deficient arylboronic acids has been developed. Through variation of the temperature and the concentration of the p-benzoquinone (p-Bq) ligand/reoxidant, conditions for the robust and convenient one-pot generation of diarylated-saturated ethers were identified. With the aid of coordination of the dimethylamino group to the arylpalladium intermediate, the otherwise predominant formation of the beta-arylated olefin could be reversed. A reaction route involving a chelation-controlled carbopalladation, providing a p-Bq stabilized six-membered palladacycle, followed by transmetalation and reductive elimination is suggested to explain the selective formation of saturated diarylated ether products.

    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-152784 (URN)10.1021/jo1018188 (DOI)000289187300004 ()21417443 (PubMedID)
    Tillgänglig från: 2011-05-02 Skapad: 2011-05-02 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
    4. Development of Stereocontrolled Palladium(II)-Catalyzed Domino Heck/Suzuki β, α-Diarylation Reactions with Chelating Vinyl Ethers and Arylboronic Acids
    Öppna denna publikation i ny flik eller fönster >>Development of Stereocontrolled Palladium(II)-Catalyzed Domino Heck/Suzuki β, α-Diarylation Reactions with Chelating Vinyl Ethers and Arylboronic Acids
    2012 (Engelska)Ingår i: ChemistryOpen, ISSN 2191-1363, Vol. 1, nr 1, s. 49-56Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    A stereoselective and 1,4-benzoquinone-mediated palladium(II)-catalyzed Heck/Suzuki domino reaction involving metal coordinating cyclic methylamino vinyl ethers and a number of electronically diverse arylboronic acids has been developed and studied. Diastereomeric ratios up to 39:1 and 78% isolated yields were obtained. The stereoselectivity of the reaction was found to be highly dependent on the nature of the arylboronic acid and the amount of water present in the reaction mixture. Thus, a domino b,a-diarylation–reduction of chelating vinyl ethers can now be accomplished and stereochemically controlled, given that optimized conditions and an appropriate chiral auxiliary are used. To the best of our knowledge, this represents the first example of a stereoselective, oxidative Heck/Suzuki domino reaction in the literature.

    Ort, förlag, år, upplaga, sidor
    Wiley-VCH Verlagsgesellschaft, 2012
    Nyckelord
    chirality, domino reactions, palladium, stereoselective catalysis, water effects
    Nationell ämneskategori
    Organisk kemi
    Forskningsämne
    Kemi med inriktning mot organisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-172735 (URN)10.1002/open.201100010 (DOI)000328606600008 ()
    Tillgänglig från: 2012-04-13 Skapad: 2012-04-13 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
    5. Transmetallation Versus β-Hydride Elimination: The Role of 1,4 Benzoquinone in Chelation-Controlled Arylation Reactions with Arylboronic Acids
    Öppna denna publikation i ny flik eller fönster >>Transmetallation Versus β-Hydride Elimination: The Role of 1,4 Benzoquinone in Chelation-Controlled Arylation Reactions with Arylboronic Acids
    Visa övriga...
    2012 (Engelska)Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 18, nr 15, s. 4714-4722Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The formation of an atypical, saturated, diarylated, Heck/Suzuki, domino product produced under oxidative Heck reaction conditions, employing arylboronic acids and a chelating vinyl ether, has been investigated by DFT calculations. The calculations highlight the crucial role of 1,4-benzoquinone (BQ) in the reaction. In addition to its role as an oxidant of palladium, which is necessary to complete the catalytic cycle, this electron-deficient alkene opens up a low-energy reaction pathway from the post-insertion sigma-alkyl complex. The association of BQ lowers the free-energy barrier for transmetallation of the s-alkyl complex to create a pathway that is energetically lower than the oxidative Heck reaction pathway. Furthermore, the calculations showed that the reaction is made viable by BQ-mediated reductive elimination and leads to the saturated diarylated product.

    Ort, förlag, år, upplaga, sidor
    Wiley-VCH Verlagsgesellschaft, 2012
    Nationell ämneskategori
    Organisk kemi Teoretisk kemi
    Forskningsämne
    Kemi
    Identifikatorer
    urn:nbn:se:uu:diva-172740 (URN)10.1002/chem.201102678 (DOI)000302162500033 ()
    Tillgänglig från: 2012-04-13 Skapad: 2012-04-13 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
    6. Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors
    Öppna denna publikation i ny flik eller fönster >>Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors
    Visa övriga...
    2012 (Engelska)Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55, nr 6, s. 2724-2736Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    In an effort to identify a new class of druglike HIV-1 protease inhibitors, four different stereopure beta-hydroxy gamma-lactam-containing inhibitors have been synthesized, biologically evaluated, and cocrystallized. The impact of the tether length of the central spacer (two or three carbons) was also investigated. A compound with a shorter tether and (3R,4S) absolute configuration exhibited high activity with a K-i of 2.1 nM and an EC50 of 0.64 mu M. Further optimization by decoration of the P1' side chain furnished an even more potent HIV-1 protease inhibitor (K-i = 0.8 nM, EC50 = 0.04 mu M). According to X-ray analysis, the new class of inhibitors did not fully succeed in forming two symmetric hydrogen bonds to the catalytic aspartates. The crystal structures of the complexes further explain the difference in potency between the shorter inhibitors (two-carbon spacer) and the longer inhibitors (three-carbon spacer).

    Nyckelord
    HIV, AIDS, protease inhibitor, aspartic protease, lactam, tertiary alcohol, X-ray
    Nationell ämneskategori
    Läkemedelskemi
    Forskningsämne
    Läkemedelskemi
    Identifikatorer
    urn:nbn:se:uu:diva-160186 (URN)10.1021/jm201620t (DOI)000301767000017 ()
    Tillgänglig från: 2011-10-17 Skapad: 2011-10-17 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
    7. Investigations on the 4-quinolone-3-carboxylic acid motif. 1. Synthesis and structure-activity relationship of a class of human immunodeficiency virus type 1 integrase inhibitors
    Öppna denna publikation i ny flik eller fönster >>Investigations on the 4-quinolone-3-carboxylic acid motif. 1. Synthesis and structure-activity relationship of a class of human immunodeficiency virus type 1 integrase inhibitors
    Visa övriga...
    2008 (Engelska)Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 51, nr 16, s. 5125-9Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    A set of 4-quinolone-3-carboxylic acids bearing different substituents on the condensed benzene ring was designed and synthesized as potential HIV-1 integrase inhibitors structurally related to elvitegravir. Some of the new compounds proved to be able to inhibit the strand transfer step of the virus integration process in the micromolar range. Docking studies and quantum mechanics calculations were used to rationalize these data.

    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-99766 (URN)10.1021/jm8003784 (DOI)000258637400032 ()18665580 (PubMedID)
    Tillgänglig från: 2009-03-19 Skapad: 2009-03-19 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
  • 339.
    Trejos, Alejandro
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Fardost, Ashkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Yahiaoui, Samir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Palladium(II)-catalyzed coupling reactions with a chelating vinyl ether and arylboronic acids: a new Heck/Suzuki domino diarylation reaction2009Ingår i: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 48, s. 7587-7589Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A mild and novel palladium(II)-catalyzed domino Heck/Suzuki alpha,beta-diarylation-reduction of a dimethylaminoethyl substituted chelating vinyl ether was developed by using electron-rich arylboronic acids in combination with p-benzoquinone. Based on the preparative results, a catalytic cycle is proposed. Further, highly regioselective palladium(II)-catalyzed alpha- or beta-monoarylation of the chelating vinyl ether was achieved using either a bidentate ligand or by employing ligand-less conditions.

  • 340.
    Trejos, Alejandro
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Odell, Luke R
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Alkenes with Metal-Directing Groups as Reaction Components2013Ingår i: Science of Synthesis: Cross-Coupling and Heck-Type Reactions, Volume 3, Metal-Catalyzed Heck-Type Reactions and C-C Cross Coupling via C–H Activation / [ed] Mats Larhed, Stuttgart: Georg Thieme Verlag KG, 2013, s. 345-390Kapitel i bok, del av antologi (Refereegranskat)
  • 341.
    Trejos, Alejandro
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Odell, Luke R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Development of Stereocontrolled Palladium(II)-Catalyzed Domino Heck/Suzuki β, α-Diarylation Reactions with Chelating Vinyl Ethers and Arylboronic Acids2012Ingår i: ChemistryOpen, ISSN 2191-1363, Vol. 1, nr 1, s. 49-56Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A stereoselective and 1,4-benzoquinone-mediated palladium(II)-catalyzed Heck/Suzuki domino reaction involving metal coordinating cyclic methylamino vinyl ethers and a number of electronically diverse arylboronic acids has been developed and studied. Diastereomeric ratios up to 39:1 and 78% isolated yields were obtained. The stereoselectivity of the reaction was found to be highly dependent on the nature of the arylboronic acid and the amount of water present in the reaction mixture. Thus, a domino b,a-diarylation–reduction of chelating vinyl ethers can now be accomplished and stereochemically controlled, given that optimized conditions and an appropriate chiral auxiliary are used. To the best of our knowledge, this represents the first example of a stereoselective, oxidative Heck/Suzuki domino reaction in the literature.

  • 342.
    Trejos, Alejandro
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sävmarker, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Schlummer, Stefanie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Datta, Gopal K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Nilsson, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Stereoselective Heck arylation of a functionalized cyclopentenyl ether using (S)-N-methyl-pyrrolidine as the stereochemical controller2008Ingår i: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 64, nr 37, s. 8746-8751Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The study of a series of palladium(0)-catalyzed C2-arylations of a 1-cyclopentenyl ether equipped with a chiral (S)-N-methyl-pyrrolidine auxiliary is reported. Stereoselective Heck monoarylations were performed using aryl iodides under classical heating conditions for 1.7-3.0 h at 80 degrees C and in one case using 30 min of microwave irradiation at 110 degrees C. To further explore the scope and nature of this stereoselective methodology, aryl bromides were also utilized as arylating agents, using 20 min of microwave processing at 120-130 degrees C. High to excellent diastereopurities (90-98% de) were obtained according to H-1 NMR and GC-MS analyses. The prolinol fragment apparently controlled the chastereoselectivity of the Heck reaction by presenting the arylpalladium species from the preferred side of the double bond. By X-ray structure diffraction analysis of an N-quaternized Heck product, the absolute configuration of the new stereocenter was established as (R), Supporting a Si-face migratory insertion.

  • 343. Valero-Esquitino, Verónica
    et al.
    Lucht, Kristin
    Namsolleck, Pawel
    Monnet-Tschudi, Florianne
    Stubbe, Tobias
    Lucht, Franziska
    Liu, Meng
    Ebner, Friederike
    Brandt, Christine
    Danyel, Leon A
    Villela, Daniel C
    Paulis, Ludovit
    Thoene-Reineke, Christa
    Dahlöf, Björn
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Unger, Thomas
    Sumners, Colin
    Steckelings, U Muscha
    Direct angiotensin type 2 receptor (AT2R) stimulation attenuates T-cell and microglia activation and prevents demyelination in experimental autoimmune encephalomyelitis in mice2015Ingår i: Clinical Science, ISSN 0143-5221, E-ISSN 1470-8736, Vol. 128, nr 2, s. 95-109Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In the present study, we evaluated stimulation of the angiotensin type 2 receptor (AT2R) by the selective non-peptide agonist Compound 21 (C21) as a novel therapeutic concept for the treatment of multiple sclerosis using the model of experimental autoimmune encephalomyelitis (EAE) in mice. C57BL-6 mice were immunized with myelin-oligodendrocyte peptide and treated for 4 weeks with C21 (0.3 mg/kg/day i.p.). Potential effects on myelination, microglia and T-cell composition were estimated by immunostaining and FACS analyses of lumbar spinal cords. The in vivo study was complemented by experiments in aggregating brain cell cultures and microglia in vitro. In the EAE model, treatment with C21 ameliorated microglia activation and decreased the number of total T-cells and CD4+ T-cells in the spinal cord. Fluorescent myelin staining of spinal cords further revealed a significant reduction in EAE-induced demyelinated areas in lumbar spinal cord tissue after AT2R stimulation. C21-treated mice had a significantly better neurological score than vehicle-treated controls. In aggregating brain cell cultures challenged with lipopolysaccharide (LPS) plus interferon-γ (IFNγ), AT2R stimulation prevented demyelination, accelerated re-myelination and reduced the number of microglia. Cytokine synthesis and nitric oxide production by microglia in vitro were significantly reduced after C21 treatment. These results suggest that AT2R stimulation protects the myelin sheaths in autoimmune central nervous system inflammation by inhibiting the T-cell response and microglia activation. Our findings identify the AT2R as a potential new pharmacological target for demyelinating diseases such as multiple sclerosis.

  • 344.
    Vallin, Karl S. A.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Emilsson, Per
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Hallberg, Anders
    High-Speed Heck Reactions in Ionic Liquid with Controlled Microwave Heating2002Ingår i: J. Org. Chem., Vol. 67, nr 17, s. 6243-6246Artikel i tidskrift (Refereegranskat)
  • 345.
    Vallin, Karl S. A.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Hallberg, Anders
    Aqueous DMF-Potassium Carbonate as a Substitute for Thallium and Silver Additives in the Palladium-Catalyzed Conversion of Aryl Bromides to Acetyl Arenes2001Ingår i: J. Org. Chem., Vol. 66, nr 12, s. 4340-4343Artikel i tidskrift (Refereegranskat)
  • 346.
    Vallin, Karl S. A.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Johansson, Katarina
    Hallberg, Anders
    Highly Selective Palladium-Catalyzed Synthesis of Protected a,ß-Unsaturated Methyl Ketones and 2-Alkoxy-1,3-Butadienes: High-Speed Chemistry by Microwave Flash Heating2000Ingår i: J. Org. Chem., Vol. 65, nr 15, s. 4537-4542Artikel i tidskrift (Refereegranskat)
  • 347.
    Vallin, Karl S. A.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Zhang, Qisheng
    Larhed, Mats
    Curran, Dennis P.
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    New Regioselective Heck-Vinylation with Enamides. Synthesis and Investigation of Fluorous Tagged Bidentate Ligands for Fast SeparationIngår i: J. Org. Chem.Artikel i tidskrift (Refereegranskat)
  • 348.
    Varasteh, Zohreh
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Rosenström, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Velikyan, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Rosestedt, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Lindeberg, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Larhed, Mats
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    The effect of macrocyclic chelators on the targeting properties of the 68Ga-labeled gastrin releasing peptide receptor antagonist PEG2-RM262015Ingår i: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 42, nr 5, s. 446-454Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction

    Overexpression of gastrin-releasing peptide receptors (GRPR) has been reported in several cancers. Bombesin (BN) analogs are short peptides with a high affinity for GRPR. Different BN analogs were evaluated for radionuclide imaging and therapy of GRPR-expressing tumors. We have previously investigated an antagonistic analog of BN (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2, RM26) conjugated to NOTA via a PEG2 spacer (NOTA-PEG2-RM26) labeled with 68Ga, 111In and Al18F. 68Ga-labeled NOTA-PEG2-RM26 showed high tumor-to-organ ratios.

    Methods

    The influence of different macrocyclic chelators (NOTA, NODAGA, DOTA and DOTAGA) on the targeting properties of 68Ga-labeled PEG2-RM26 was studied in vitro and in vivo.

    Results

    All conjugates were labeled with generator-produced 68Ga with high yields and demonstrated high stability and specific binding to GRPR. The IC50 values of natGa-X-PEG2-RM26 (X = NOTA, DOTA, NODAGA, DOTAGA) were 2.3 ± 0.2, 3.0 ± 0.3, 2.9 ± 0.3 and 10.0 ± 0.6 nM, respectively. The internalization of the conjugates by PC-3 cells was low. However, the DOTA-conjugated analog demonstrated a higher internalization rate compared to other analogs. GRPR-specific uptake was found in receptor-positive normal tissues and PC-3 xenografts for all conjugates. The biodistribution of the conjugates was influenced by the choice of the chelator moiety. Although all radiotracers cleared rapidly from the blood, [68Ga]Ga-NOTA-PEG2-RM26 showed significantly lower uptake in lung, muscle and bone compared to the other analogs. The uptake in tumors (5.40 ± 1.04 %ID/g at 2 h p.i.) and the tumor-to-organ ratios (25 ± 3, 157 ± 23 and 39 ± 4 for blood, muscle and bone, respectively) were significantly higher for the NOTA-conjugate than the other analogs.

    Conclusions

    Chelators had a clear influence on the biodistribution and targeting properties of 68Ga-labeled antagonistic BN analogs. Positively charged [68Ga]Ga-NOTA-PEG2-RM26 provided a low kidney radioactivity uptake, high affinity, high tumor uptake and high image contrast.

  • 349.
    Varasteh, Zohreh
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Rosenström, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Velikyan, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Altai, Mohamed
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Honarvar, Hadis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Rosestedt, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Lindeberg, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    The Effect of Mini-PEG-Based Spacer Length on Binding and Pharmacokinetic Properties of a Ga-68-Labeled NOTA-Conjugated Antagonistic Analog of Bombesin2014Ingår i: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 19, nr 7, s. 10455-10472Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The overexpression of gastrin-releasing peptide receptor (GRPR) in cancer can be used for peptide-receptor mediated radionuclide imaging and therapy. We have previously shown that an antagonist analog of bombesin RM26 conjugated to 1,4,7-triazacyclononane-N, N', N ''-triacetic acid (NOTA) via a diethyleneglycol (PEG(2)) spacer (NOTA-PEG(2)-RM26) and labeled with Ga-68 can be used for imaging of GRPR-expressing tumors. In this study, we evaluated if a variation of mini-PEG spacer length can be used for optimization of targeting properties of the NOTA-conjugated RM26. A series of analogs with different PEG-length (n = 2, 3, 4, 6) was synthesized, radiolabeled and evaluated in vitro and in vivo. The IC50 values of Ga-nat-NOTA-PEG(n)-RM26 (n = 2, 3, 4, 6) were 3.1 +/- 0.2, 3.9 +/- 0.3, 5.4 +/- 0.4 and 5.8 +/- 0.3 nM, respectively. In normal mice all conjugates demonstrated similar biodistribution pattern, however Ga-68-NOTA-PEG(3)-RM26 showed lower liver uptake. Biodistribution of Ga-68-NOTA-PEG(3)-RM26 was evaluated in nude mice bearing PC-3 (prostate cancer) and BT-474 (breast cancer) xenografts. High uptake in tumors (4.6 +/- 0.6% ID/g and 2.8 +/- 0.4% ID/g for PC-3 and BT-474 xenografts, respectively) and high tumor-to-background ratios (tumor/ blood of 44 +/- 12 and 42 +/- 5 for PC-3 and BT-474 xenografts, respectively) were found already at 2 h p.i. of Ga-68-NOTA-PEG(3)-RM26. Results of this study suggest that variation in the length of the PEG spacer can be used for optimization of targeting properties of peptide-chelator conjugates. However, the influence of the mini-PEG length on biodistribution is minor when di-, tri-, tetra- and hexaethylene glycol are compared.

  • 350.
    Varasteh, Zohreh
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Velikyan, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Lindeberg, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sandström, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Selvaraju, Ram Kumar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Malmberg, Jennie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Synthesis and Characterization of a High-Affinity NOTA-Conjugated Bombesin Antagonist for GRPR-Targeted Tumor Imaging2013Ingår i: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 24, nr 7, s. 1144-1153Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The gastrin-releasing peptide receptor (GRPR/BB2) is a molecular target for the visualization of prostate cancer. This work focused on the development of high-affinity, hydrophilic, antagonistic, bombesin-based imaging agents for PET and SPECT. The bombesin antagonist analog D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 ([D-Phe(6),Sta(13),Leu(14)]-bombesin[6-14]) was synthesized and conjugated to 1,4,7-triazacyclononane-N,N',N ''-triacetic acid (NOTA) via a diethylene glycol (PEG(2)) linker. The resulting conjugate, NOTA-PEG(2)-[D-Phe(6),Sta(13),Leu(14)]bombesin[6-14] (NOTA-P2-RM26), was labeled with Ga-68 (T-1/2 = 68 min, positron emitter) and In-111 (T-1/2 = 2.8 days, gamma emitter). The labeling stability, specificity, inhibition efficiency (IC50), and dissociation constant (K-D) of both labeled compounds as well as their cellular retention and internalization were investigated. The pharmacokinetics of the dual isotope) (In-111/Ga-68)-labeled peptide in both normal NMRI mice and PC-3 tumor-bearing Balb/c nu/nu mice was also studied. NOTA-P2-RM26 was labeled with In-111 and Ga-68 at a radiochemical yield of >98%. Both conjugates were shown to have high specificity and binding affinity for GRPR. The K-D value was determined to be 23 +/- 13 pM for the In-111-labeled compound in a saturation binding experiment. In addition, In-nat- and Ga-nat-NOTA-P2-RM26 showed low nanomolar binding inhibition concentrations (IC50 = 1.24 +/- 0.29 nM and 0.91 +/- 0.19 nM, respectively) in a competitive binding assay. The internalization rate of the radiolabeled conjugates was slow. The radiometal-labeled tracers demonstrated rapid blood clearance via the kidney and GRPR-specific uptake in the pancreas in normal mice. Tumor targeting and biodistribution studies in mice bearing PC-3 xenografts displayed high and specific uptake in tumors (8.1 +/- 0.4%ID/g for Ga-68 and 5.7 +/- 0.3%ID/g for In-111) and high tumor-to-background ratios (tumor/blood: 12 +/- 1 for Ga-68 and 10 +/- 1 for In-111) after only 1 h pi of 45 pmol of peptide. The xenografts were visualized by gamma and microPET cameras shortly after injection. In conclusion, the antagonistic bombesin analog NOTA-PEG(2)-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (NOTA-P2-RM26) is a promisindg candidate for prostate cancer imaging using PET and SPECT/CT.

45678 301 - 350 av 398
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