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Sawadjoon, Supaporn
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Eriksson, J., Roy, T., Sawadjoon, S., Bachmann, K., Sköld, C., Larhed, M., . . . Odell, L. R. (2019). Synthesis and preclinical evaluation of the CRTH2 antagonist [11C]MK-7246 as a novel PET tracer and potential surrogate marker for pancreatic beta-cell mass. Nuclear Medicine and Biology, 71, 1-10
Öppna denna publikation i ny flik eller fönster >>Synthesis and preclinical evaluation of the CRTH2 antagonist [11C]MK-7246 as a novel PET tracer and potential surrogate marker for pancreatic beta-cell mass
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2019 (Engelska)Ingår i: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 71, s. 1-10Artikel i tidskrift (Refereegranskat) Published
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.

Nationell ämneskategori
Organisk kemi Läkemedelskemi
Identifikatorer
urn:nbn:se:uu:diva-381559 (URN)10.1016/j.nucmedbio.2019.04.002 (DOI)000475837000001 ()
Forskningsfinansiär
Vetenskapsrådet, 2018-05133Knut och Alice Wallenbergs StiftelseBarndiabetesfondenGöran Gustafssons stiftelse för naturvetenskaplig och medicinsk forskning (KVA)
Tillgänglig från: 2019-04-11 Skapad: 2019-04-11 Senast uppdaterad: 2019-09-13Bibliografiskt granskad
Sawadjoon, S., Orthaber, A., Sjöberg, P. J. R., Eriksson, L. & Samec, J. S. M. (2014). Equilibrium Study of Pd(dba)2 and P(OPh)3 in the Pd-Catalyzed Allylation of Aniline by Allyl Alcohol. Organometallics, 33(1), 249-253
Öppna denna publikation i ny flik eller fönster >>Equilibrium Study of Pd(dba)2 and P(OPh)3 in the Pd-Catalyzed Allylation of Aniline by Allyl Alcohol
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2014 (Engelska)Ingår i: Organometallics, ISSN 0276-7333, E-ISSN 1520-6041, Vol. 33, nr 1, s. 249-253Artikel i tidskrift (Refereegranskat) Published
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.

Nationell ämneskategori
Naturvetenskap
Identifikatorer
urn:nbn:se:uu:diva-218947 (URN)10.1021/om4009873 (DOI)000329879900029 ()
Tillgänglig från: 2014-02-27 Skapad: 2014-02-20 Senast uppdaterad: 2017-12-05Bibliografiskt granskad
Sawadjoon, S., Sjöberg, P. J., Orthaber, A., Matsson, O. & Samec, J. S. (2014). Mechanistic Insights into the Pd-Catalyzed Direct Amination of Allyl Alcohols: Evidence for an Outer-sphere Mechanism Involving a Palladium Hydride Intermediate. Chemistry - A European Journal, 20(6), 1520-1524
Öppna denna publikation i ny flik eller fönster >>Mechanistic Insights into the Pd-Catalyzed Direct Amination of Allyl Alcohols: Evidence for an Outer-sphere Mechanism Involving a Palladium Hydride Intermediate
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2014 (Engelska)Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 20, nr 6, s. 1520-1524Artikel i tidskrift (Refereegranskat) Published
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.

Nationell ämneskategori
Analytisk kemi Fysikalisk kemi
Identifikatorer
urn:nbn:se:uu:diva-215613 (URN)10.1002/chem.201303431 (DOI)000337300000008 ()24403056 (PubMedID)
Tillgänglig från: 2014-01-15 Skapad: 2014-01-15 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
Galkin, M. V., Sawadjoon, S., Rohde, V., Dawange, M. & Samec, J. S. M. (2014). Mild Heterogeneous Palladium-Catalyzed Cleavage of beta-O-4 '-Ether Linkages of Lignin Model Compounds and Native Lignin in Air. ChemCatChem, 6(1), 179-184
Öppna denna publikation i ny flik eller fönster >>Mild Heterogeneous Palladium-Catalyzed Cleavage of beta-O-4 '-Ether Linkages of Lignin Model Compounds and Native Lignin in Air
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2014 (Engelska)Ingår i: ChemCatChem, ISSN 1867-3880, E-ISSN 1867-3899, Vol. 6, nr 1, s. 179-184Artikel i tidskrift (Refereegranskat) Published
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.

Nyckelord
heterogeneous catalysis, cleavage reactions, green chemistry, palladium, polymers, lignin
Nationell ämneskategori
Naturvetenskap
Identifikatorer
urn:nbn:se:uu:diva-220309 (URN)10.1002/cctc.201300540 (DOI)000330636800023 ()
Anmärkning

De två första författarna delar första författarskapet.

Tillgänglig från: 2014-03-17 Skapad: 2014-03-12 Senast uppdaterad: 2017-12-05Bibliografiskt granskad
Sawadjoon, S. & Samec, J. S. M. (2013). Mechanistic studies and synthetic applications of palladium-catalyzed direct aminations of allylic alcohols. Paper presented at 245th National Spring Meeting of the American-Chemical-Society (ACS), APR 07-11, 2013, New Orleans, LA, USA. Abstract of Papers of the American Chemical Society, 245, 645-ORGN
Öppna denna publikation i ny flik eller fönster >>Mechanistic studies and synthetic applications of palladium-catalyzed direct aminations of allylic alcohols
2013 (Engelska)Ingår i: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 245, s. 645-ORGN-Artikel i tidskrift, Meeting abstract (Övrigt vetenskapligt) Published
Nationell ämneskategori
Naturvetenskap
Identifikatorer
urn:nbn:se:uu:diva-210343 (URN)000324303603309 ()
Konferens
245th National Spring Meeting of the American-Chemical-Society (ACS), APR 07-11, 2013, New Orleans, LA, USA
Tillgänglig från: 2013-11-06 Skapad: 2013-11-05 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
Sawadjoon, S., Lundstedt, A. & Samec, J. (2013). Pd-Catalyzed Transfer Hydrogenolysis of Primary, Secondary, and Tertiary Benzylic Alcohols by Formic Acid: A Mechanistic Study. ACS Catalysis, 3(4), 635-642
Öppna denna publikation i ny flik eller fönster >>Pd-Catalyzed Transfer Hydrogenolysis of Primary, Secondary, and Tertiary Benzylic Alcohols by Formic Acid: A Mechanistic Study
2013 (Engelska)Ingår i: ACS Catalysis, ISSN 2155-5435, Vol. 3, nr 4, s. 635-642Artikel i tidskrift (Refereegranskat) Published
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.

Nationell ämneskategori
Naturvetenskap
Identifikatorer
urn:nbn:se:uu:diva-196658 (URN)10.1021/cs300785r (DOI)000317328000024 ()
Forskningsfinansiär
Energimyndigheten
Tillgänglig från: 2013-03-12 Skapad: 2013-03-12 Senast uppdaterad: 2014-01-23Bibliografiskt granskad
Sawadjoon, S., Galkin, M., Dahlstrand, C., Rohde, V. & Samec, J. S. M. (2013). Selective palladium-catalyzed reductive cleavage of beta-O-4-glucolaryl ether linkages in lignin model compounds. Paper presented at 245th National Spring Meeting of the American-Chemical-Society (ACS), APR 07-11, 2013, New Orleans, LA, USA. Abstract of Papers of the American Chemical Society, 245, 15-ORGN
Öppna denna publikation i ny flik eller fönster >>Selective palladium-catalyzed reductive cleavage of beta-O-4-glucolaryl ether linkages in lignin model compounds
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2013 (Engelska)Ingår i: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 245, s. 15-ORGN-Artikel i tidskrift, Meeting abstract (Övrigt vetenskapligt) Published
Nationell ämneskategori
Naturvetenskap
Identifikatorer
urn:nbn:se:uu:diva-210342 (URN)000324303602715 ()
Konferens
245th National Spring Meeting of the American-Chemical-Society (ACS), APR 07-11, 2013, New Orleans, LA, USA
Tillgänglig från: 2013-11-06 Skapad: 2013-11-05 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
Howard, F., Sawadjoon, S. & Samec, J. S. M. (2010). 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 study. Tetrahedron Letters, 51(32), 4208-4210
Öppna denna publikation i ny flik eller fönster >>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 study
2010 (Engelska)Ingår i: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 51, nr 32, s. 4208-4210Artikel i tidskrift (Refereegranskat) Published
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.

Nyckelord
phenylpropanol bismuth tribromide catalyst dimerization mechanism
Nationell ämneskategori
Kemi
Identifikatorer
urn:nbn:se:uu:diva-174510 (URN)10.1016/j.tetlet.2010.06.018 (DOI)000280345800014 ()
Anmärkning

CAPLUS AN 2010:873537(Journal)

Tillgänglig från: 2012-05-21 Skapad: 2012-05-21 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
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