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Multicomponent Reactions in 11C/12C Chemistry: – Targeting the Angiotensin II Subtype 2 Receptor
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.ORCID iD: 0000-0002-9441-3767
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Section 1 of this thesis contains an introduction to method development in organic synthesis, multicomponent reactions, sulfonyl azides, tracer development in 11C chemistry and the biological target.

Section 2 describes the use of sulfonyl azides in carbonylative chemistry. Paper I covers development of a diazotransfer protocol. In total, 30 arylsulfonyl azides were synthesised from primary sulfonamides (20–90% yield). 15N mechanistic studies were carried out and in Paper II, the products were converted into sulfonamides, sulfonylureas and sulfonyl carbamates (19–90% yield). For ureas and carbamates, a two-chamber protocol was employed to release CO from Mo(CO)6. 15N mechanistic studies showed that the sulfonamides were formed by direct displacement of azide.

Section 3 covers imaging and biological studies of the angiotensin II receptor subtype 2 (AT2R). In Paper III, 12 11C-sulfonyl carbamates were prepared in isolated radiochemical yields of 3–51% via Rh(I)-mediated carbonylation. The first non-peptide AT2R agonist, C21, was labelled (isolated RCY 24±10%, SA 34–51 GBq/µmol). C21 was tested in a prostate cancer assay, followed by biodistribution and small-animal PET studies. In Paper IV, a 11C-labelled AT2R ligand prepared via Pd(0)-mediated aminocarbonylation was used for autoradiography, biodistribution and small-animal PET studies.  

Section 4 describes the development of a multicomponent method for the synthesis of 3,4-dihydroquinazolinones (Paper V). 31 3,4-dihydroquinazolinones were synthesized via a cyclic iminium ion.  

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 93 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 219
Keyword [en]
carbonylation, positron emission tomography, multicomponent reactions, AT2R, 3, 4-dihydroquinazolinone, sulfonyl azides
National Category
Organic Chemistry
Research subject
Pharmaceutical Science
Identifiers
URN: urn:nbn:se:uu:diva-295436ISBN: 978-91-554-9636-4OAI: oai:DiVA.org:uu-295436DiVA: diva2:941172
Public defence
2016-09-23, Hall B21, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2016-09-02 Created: 2016-06-07 Last updated: 2016-09-05
List of papers
1. Synthesis of sulfonyl azides via diazotransfer using an imidazole-1-sulfonyl azide salt: scope and ¹⁵N NMR labeling experiments
Open this publication in new window or tab >>Synthesis of sulfonyl azides via diazotransfer using an imidazole-1-sulfonyl azide salt: scope and ¹⁵N NMR labeling experiments
2014 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 79, no 11, 4826-4831 p.Article in journal (Refereed) Published
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

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2014
National Category
Organic Chemistry
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-232477 (URN)10.1021/jo500553q (DOI)000337073900006 ()
Available from: 2014-09-18 Created: 2014-09-18 Last updated: 2016-08-26Bibliographically approved
2. Sulfonyl Azides as Precursors in Ligand-free Palladium-Catalyzed Synthesis of Sulfonyl Carbamates and Sulfonyl Ureas and Synthesis of Sulfonamides
Open this publication in new window or tab >>Sulfonyl Azides as Precursors in Ligand-free Palladium-Catalyzed Synthesis of Sulfonyl Carbamates and Sulfonyl Ureas and Synthesis of Sulfonamides
2016 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 81, no 7, 2681-2691 p.Article in journal (Refereed) Published
Abstract [en]

An efficient synthesis of sulfonyl carbamates and sulfonyl ureas from sulfonyl azides employing a palladium-catalyzed carbonylation protocol has been developed. Using a two-chamber system, sulfonyl azides, PdCl2, and CO gas, released ex situ from Mo(CO)(6), were assembled to generate sulfonyl isocyanates in situ, and alcohols and aryl amines were exploited as nucleophiles to afford a broad range of sulfonyl carbamates and sulfonyl ureas. A protocol for the direct formation of substituted sulfonamides from sulfonyl azides and amines via nucleophilic substitution was also developed.

National Category
Natural Sciences
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-281023 (URN)10.1021/acs.joc.5b02755 (DOI)000373520200001 ()26967791 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationCarl Tryggers foundation
Available from: 2016-03-16 Created: 2016-03-16 Last updated: 2016-08-26Bibliographically approved
3. Synthesis of 11C-labelled Sulfonyl Carbamates via a Multicomponent Reaction Employing Sulfonyl Azides, Alcohols and [11C]CO
Open this publication in new window or tab >>Synthesis of 11C-labelled Sulfonyl Carbamates via a Multicomponent Reaction Employing Sulfonyl Azides, Alcohols and [11C]CO
Show others...
(English)Article in journal (Refereed) Submitted
Abstract [en]

Herein we describe the development of new methodologyfocusing on 11C-labelling of sulfonyl carbamates in a multicomponentreaction comprising a sulfonyl azide, an alkyl alcohol and [11C]CO. Anumber of 11C-labelled sulfonyl carbamates were synthesised andisolated, and the developed methodology was then applied in thepreparation of a biologically active molecule. The target compoundwas obtained in 18±8% isolated radiochemical yield and wasevaluated for binding properties in a tumor cell assay, as well asundergoing in vivo biodistribution and imaging studies. Thisrepresents the first successful radiolabelling of C21, a non-peptideangiotensin II receptor subtype 2 agonist currently in clinical trials.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-296406 (URN)
Available from: 2016-06-16 Created: 2016-06-16 Last updated: 2016-08-26Bibliographically approved
4. Synthesis and evaluation of a 11C-labelled angiotensin II AT2 receptor ligand
Open this publication in new window or tab >>Synthesis and evaluation of a 11C-labelled angiotensin II AT2 receptor ligand
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2010 (English)In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 53, no 10, 616-624 p.Article in journal (Refereed) Published
Abstract [en]

Three C-11-radiolabelled high-affinity nonpeptide AT(2) receptor-selective ligands were synthesized and one of these was evaluated as positron emission tomography (PET) tracer. The labelling reaction was performed via palladium(0)-mediated aminocarbonylation of the aryl iodide substrate using [C-11] carbon monoxide as the labelled precursor. As an example, starting with 10.0 GBq [C-11] carbon monoxide, 1.10 GBq of the product N-butoxycarbonyl-3-[4-(N-benzyl-[C-11] carbamoyl)phenyl]-5-isobutylthiophene-2-sulphonamide [C-11]4d was obtained in 36% decay-corrected radiochemical yield (from [C-11] carbon monoxide), 42 min from end of bombardment with a specific activity of 110 GBq.mu mol(-1). The N-isopropyl-[C-11] carbamoyl-analogue [C-11]4c (radiochemical purity >95%) was studied employing autoradiography, organ distribution, and small animal PET. In vitro autoradiography showed specific binding in the pancreas and kidney. Organ distribution in six rats revealed a high uptake in the liver, intestine, kidney, and adrenals. Small animal PET showed rapid and reversible uptake in the kidneys followed by accumulation in the urinary bladder suggesting fast renal excretion of the tracer. In addition, high accumulation was also seen in the liver. For future studies, more metabolically stable tracers will need to be developed. To the best of our knowledge, this is the first attempt of the use of PET imaging for the detection of expressed, fully functional AT(2) receptors in living subjects.

Keyword
angiotensin II, AT2, PET, 11C, aminocarbonylation, [11C]carbon monoxide
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-98914 (URN)10.1002/jlcr.1793 (DOI)000282667600004 ()
Available from: 2009-03-05 Created: 2009-03-05 Last updated: 2016-08-26Bibliographically approved
5. A microwave-assisted multicomponent synthesis of substituted 3,4-dihydroquinazolinones
Open this publication in new window or tab >>A microwave-assisted multicomponent synthesis of substituted 3,4-dihydroquinazolinones
Show others...
2015 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 13, no 7, 2044-2054 p.Article in journal (Refereed) Published
Abstract [en]

A microwave-assisted, multicomponent protocol for the synthesis of substituted 3,4-dihydroquinazolinones via a novel cascade imine/cyclization/aza-Henry reaction sequence is reported. Starting from o-formyl carbamates, a series of structurally diverse 3,4-dihydroquinazolinones was synthesized via a cyclic iminium ion intermediate in moderate to excellent yields. Notably, the reaction is fast, flexible, simple to perform and tolerates a variety of functional groups.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-245140 (URN)10.1039/c4ob02417f (DOI)000349401300016 ()25518892 (PubMedID)
Available from: 2015-02-25 Created: 2015-02-25 Last updated: 2016-08-26Bibliographically approved

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