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  • 1.
    Eriksson, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Roy, Tamal
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Sawadjoon, Supaporn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Bachmann, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Sköld, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Larhed, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Weis, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Selvaraju, Ramkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Synthesis and preclinical evaluation of the CRTH2 antagonist [11C]MK-7246 as a novel PET tracer and potential surrogate marker for pancreatic beta-cell mass2019In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 71, p. 1-10Article in journal (Refereed)
    Abstract [en]

    Introduction: MK-7246 is a potent and selective antagonist for chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). Within the pancreas CRTH2 is selectively expressed in pancreatic β-cells where it is believed to play a role in insulin release. Reduction in β-cell mass and insufficient insulin secretion in response to elevated blood glucose levels is a hallmark for type 1 and type 2 diabetes. Reported here is the synthesis of [11C]MK-7246 and initial preclinical evaluation towards CRTH2 imaging. The aim is to develop a method to quantify β-cell mass with PET and facilitate non-invasive studies of disease progression in individuals with type 2 diabetes.

    Methods: The precursor N-desmethyl-O-methyl MK-7246 was synthesized in seven steps and subjected to methylation with [11C]methyl iodide followed by hydrolysis to obtain [11C]MK-7246 labelled in the N-methyl position. Preclinical evaluation included in vitro radiography and immune-staining performed in human pancreatic biopsies. Biodistribution studies were performed in rat by PET-MRI and in pig by PET-CT imaging. The specific tracer uptake was examined in pig by scanning before and after administration of MK-7246 (1 mg/kg). Predicted dosimetry of [11C]MK-7246 in human males was estimated based on the biodistribution in rat.

    Results: [11C]MK-7246 was obtained with activities sufficient for the current investigations (270±120 MBq) and a radiochemical purity of 93±2%. The tracer displayed focal binding in areas with insulin positive islet of Langerhans in human pancreas sections. Baseline uptake in pig was significantly reduced in CRTH2-rich areas after administration of MK-7246; pancreas (66% reduction) and spleen (88% reduction). [11C]MK-7246 exhibited a safe human predicted dosimetry profile as extrapolated from the rat biodistribution data.

    Conclusions: Initial preclinical in vitro and in vivo evaluation of [11C]MK-7246 show binding and biodistribution properties suitable for PET imaging of CRTH2. Further studies are warranted to assess its potential in β-cell mass imaging and CRTH2 drug development.

  • 2.
    Galkin, Maxim V.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
    Sawadjoon, Supaporn
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
    Rohde, Volker
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
    Dawange, Monali
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
    Samec, Joseph S. M.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
    Mild Heterogeneous Palladium-Catalyzed Cleavage of beta-O-4 '-Ether Linkages of Lignin Model Compounds and Native Lignin in Air2014In: ChemCatChem, ISSN 1867-3880, E-ISSN 1867-3899, Vol. 6, no 1, p. 179-184Article in journal (Refereed)
    Abstract [en]

    A mild and robust heterogeneous palladium-catalyzed CO bond cleavage of 2-aryloxy-1-arylethanols using formic acid as reducing agent in air was developed. The cleaved products were isolated in 92-98% yield; and by slightly varying the reaction conditions, a ketone, an alcohol, or an alkane can be generated in near-quantitative yield. This reaction is applicable to cleaving the -O-4-ether bond found in lignin polymers of different origin. The reaction was performed on a lignin polymer model to generate either the monomeric aryl ketone or alkane in a quantitative yield. Moderate depolymerization was achieved with native lignin at similar reaction conditions. Mechanistic studies under kinetic control indicate that an initial palladium-catalyzed dehydrogenation of the alcohol is followed by insertion of palladium to an enol equivalent. A palladium-formato complex reductively cleaves the palladium-enolate complex to generate the ketone.

  • 3.
    Howard, Fredrick
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Sawadjoon, Supaporn
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Samec, Joseph S. M.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    A chemoselective route to either 4-methyl-2,4-diphenyl-2-pentene or 1,1,3-trimethyl-3-phenylindane from 2-phenylpropan-2-ol mediated by BiBr3: a mechanistic study2010In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 51, no 32, p. 4208-4210Article in journal (Refereed)
    Abstract [en]

    The reaction of 2-phenylpropan-2-ol mediated by BiBr3 can, through control of the temp., yield selectively either 4-methyl-2,4-diphenyl-2-pentene or 1,1,3-trimethyl-3-phenylindane. A reaction mechanism that proceeds via 1-methylstyrene is disclosed.

  • 4.
    Sawadjoon, Supaporn
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
    Galkin, Maxim
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
    Dahlstrand, Christian
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Rohde, Volker
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Samec, Joseph S. M.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
    Selective palladium-catalyzed reductive cleavage of beta-O-4-glucolaryl ether linkages in lignin model compounds2013In: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 245, p. 15-ORGN-Article in journal (Other academic)
  • 5.
    Sawadjoon, Supaporn
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
    Lundstedt, Anna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Samec, Joseph
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
    Pd-Catalyzed Transfer Hydrogenolysis of Primary, Secondary, and Tertiary Benzylic Alcohols by Formic Acid: A Mechanistic Study2013In: ACS Catalysis, ISSN 2155-5435, Vol. 3, no 4, p. 635-642Article in journal (Refereed)
    Abstract [en]

    A palladium-catalyzed transfer hydrogenolysis of primary, secondary, and tertiary benzylic alcohols by formic acid has been developed and studied. The product hydrocarbons were obtained in excellent yields from bothsecondary and tertiary benzylic alcohols and in good yields for primary benzylicalcohols. The rate of disappearance of 1-phenylethanol (1) follows zero-order dependence in 1 and first-order dependence in formic acid and palladium. Catalytic amounts of base inhibit a competing disproportionation reaction ofalcohol to alkane and ketone, and an optimum was obtained when 5 equiv ofbase to palladium was used Deuterium kinetic isotope studies for the transferhydrogenolysis reveal individual isotope effects for the hydridic position (k(CHOH)/k(CDOH) = 2.26 +/- 0.24) and the protic position (k(CHOH)/k(CHOD) = 0.62 +/- 0.06) of the formic acid. Simultaneous deuteration in both positions offormic acid gave a combined isotope effect of (k(CHOH)/k(CDOD) = 1.41 +/- 0.11). We propose a mechanism involving the following steps: a competitive inhibition of the open palladium site by adsorption of the formate anion to generate formato-palladium species, followed by a reversible protonation and arate-limiting hydride transfer to obtain the active palladium with chemisorbed hydrogen that performs the hydrogenolysis of the alcohol in a fast reaction step.

  • 6.
    Sawadjoon, Supaporn
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Orthaber, Andreas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Inorganic Chemistry.
    Sjöberg, Per J. R.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Eriksson, Lars
    Samec, Joseph S. M.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Equilibrium Study of Pd(dba)2 and P(OPh)3 in the Pd-Catalyzed Allylation of Aniline by Allyl Alcohol2014In: Organometallics, ISSN 0276-7333, E-ISSN 1520-6041, Vol. 33, no 1, p. 249-253Article in journal (Refereed)
    Abstract [en]

    Reaction of Pd(dba)2 and P(OPh)3 shows a unique equilibrium where the Pd[P(OPh)3]3 complex is favored over both Pd(dba)[P(OPh)3]2 and Pd[P(OPh)3]4 complexes at room temperature. At a lower temperature, Pd[P(OPh)3]4 becomes the most abundant complex in solution. X-ray studies of Pd[P(OPh)3]3 and Pd(dba)[P(OPh)3]2 complexes show that both complexes have a trigonal geometry with a Pd–P distance of 2.25 Å due to the π-acidity of the phosphite ligand. In solution, pure Pd(dba)[P(OPh)3]2 complex equilibrates to the favored Pd[P(OPh)3]3 complex, which is the most stable complex of those studied, and also forms the most active catalytic species. This catalyst precursor dissociates one ligand to give the reactive Pd[P(OPh)3]2, which performs an oxidative addition of nonmanipulated allyl alcohol to generate the π-allyl-Pd[P(OPh)3]2 intermediate according to ESI-MS studies.

  • 7.
    Sawadjoon, Supaporn
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
    Samec, Joseph S. M.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
    Mechanistic studies and synthetic applications of palladium-catalyzed direct aminations of allylic alcohols2013In: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 245, p. 645-ORGN-Article in journal (Other academic)
  • 8.
    Sawadjoon, Supaporn
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
    Sjöberg, Per J R
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Orthaber, Andreas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Molecular Biomimetics.
    Matsson, Olle
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Samec, Joseph S M
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
    Mechanistic Insights into the Pd-Catalyzed Direct Amination of Allyl Alcohols: Evidence for an Outer-sphere Mechanism Involving a Palladium Hydride Intermediate2014In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 20, no 6, p. 1520-1524Article in journal (Refereed)
    Abstract [en]

    The mechanism of direct amination of allyl alcohol by a palladium triphenylphosphite complex has been explored. Labelling studies show that the reaction proceeds through a π-allylpalladium intermediate. A second-order dependence of reaction rate on allyl alcohol concentration was observed. Kinetic isotope effect studies and ESI-MS studies are in agreement with a reaction proceeding through a palladium hydride intermediate in which both O-H bond and C-O bond cleavages are involved in rate-determining steps. A stereochemical study supports an outer-sphere nucleophilic attack of the π-allylpalladium intermediate giving complete chiral transfer from starting material to product.

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