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Design and Synthesis of Amine Building Blocks and Protease Inhibitors
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Responsible organisation
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The first part of this thesis addresses the design and synthesis of amine building blocks accomplished by applying two different synthetic procedures, both of which were developed using solid-phase chemistry. Chapter 1 presents the first of these methods, entailing a practical solid-phase parallel synthesis route to N-monoalkylated aminopiperidines and aminopyrrolidines achieved by selective reductive alkylation of primary and/or secondary amines. Solid-phase NMR spectroscopy was used to monitor the reactions for which a new pulse sequence was developed. The second method, reported in Chapter 2, involves a novel approach to the synthesis of secondary amines starting from reactive alkyl halides and azides. The convenient solid-phase protocol that was devised made use of the Staudinger reaction in order to accomplish highly efficient alkylations of N-alkyl phosphimines or N-aryl phosphimines with reactive alkyl halides.

The second part of the thesis describes the design and synthesis of three classes of protease inhibitors targeting the cysteine proteases cathepsins S and K, and the serine protease hepatitis C virus (HCV) NS3 protease. Chapter 4 covers the design, solid-phase synthesis, and structure-activity relationships of 4-amidofurane-3-one P1-containing inhibitors of cathepsin S and the effects of P3 sulfonamide groups on the potency and selectivity towards related cathepsin proteases. This work resulted in the discovery of highly potent and selective inhibitors of cathepsin S. Two parallel solid-phase approaches to the synthesis of a series of aminoethylamide inhibitors of cathepsin K are presented in Chapter 5. Finally, Chapter 6 reports peptide-based HCV NS3 protease inhibitors containing a non-electrophilic allylic alcohol moiety as P1 group and also outlines efforts to incorporate this new template into low-molecular-weight drug-like molecules.

Place, publisher, year, edition, pages
Stockholm: Institutionen för organisk kemi , 2008. , 77 p.
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-8038ISBN: 978-91-7155-690-5 (print)OAI: oai:DiVA.org:su-8038DiVA: diva2:199466
Public defence
2008-10-03, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 10:00 (English)
Opponent
Supervisors
Available from: 2008-09-11 Created: 2008-08-25 Last updated: 2010-01-15Bibliographically approved
List of papers
1. An Expeditious Library Synthesis of N-Monoalkylated Aminopiperidines and –pyrrolidines
Open this publication in new window or tab >>An Expeditious Library Synthesis of N-Monoalkylated Aminopiperidines and –pyrrolidines
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2004 In: European Journal of Organic Chemistry, ISSN 1434-193x, no 12, 2723-2737 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-25315 (URN)
Note
Part of urn:nbn:se:su:diva-8038Available from: 2008-09-11 Created: 2008-08-25Bibliographically approved
2. A One-Pot, Solid-Phase Synthesis of Secondary Amines from Reactive Alkyl Halides and an Alkyl Azide
Open this publication in new window or tab >>A One-Pot, Solid-Phase Synthesis of Secondary Amines from Reactive Alkyl Halides and an Alkyl Azide
2008 (English)In: Synlett: Accounts and Rapid Communications in Synthetic Organic Chemistry, ISSN 0936-5214, E-ISSN 1437-2096, no 1, 77-79 p.Article in journal (Refereed) Published
National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-25316 (URN)10.1055/s-2007-990927 (DOI)000252773000019 ()
Note

Part of urn:nbn:se:su:diva-8038

Available from: 2008-09-11 Created: 2008-08-25 Last updated: 2017-12-13Bibliographically approved
3. Solid-phase parallel synthesis and SAR of 4-amidofuran-3-one inhibitors of cathepsin S: Effect of sulfonamides P3 substituents on potency and selectivity.
Open this publication in new window or tab >>Solid-phase parallel synthesis and SAR of 4-amidofuran-3-one inhibitors of cathepsin S: Effect of sulfonamides P3 substituents on potency and selectivity.
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2009 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 17, no 3, 1307-1324 p.Article in journal (Refereed) Published
Abstract [en]

Highly potent and selective 4-amidofuran-3-one inhibitors of cathepsin S are described. The synthesis and structure–activity relationship of a series of inhibitors with a sulfonamide moiety in the P3 position is presented. Several members of the series show sub-nanomolar inhibition of the target enzyme as well as an excellent selectivity profile and good cellular potency. Molecular modeling of the most interesting inhibitors describes interactions in the extended S3 pocket and explains the observed selectivity towards cathepsin K.

Place, publisher, year, edition, pages
Elsevier, 2009
Keyword
Cysteine protease, cathepsin S, cathepsin K, reversible covalent inhibition
National Category
Medicinal Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-35087 (URN)10.1016/j.bmc.2008.12.020 (DOI)
Available from: 2010-01-15 Created: 2010-01-14 Last updated: 2017-12-12Bibliographically approved
4. Preparation and Characterization of Aminoethylamide Inhibitors of the Cysteine Proteinase Cathepsin K
Open this publication in new window or tab >>Preparation and Characterization of Aminoethylamide Inhibitors of the Cysteine Proteinase Cathepsin K
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In: European Journal of Medicinal Chemistry, ISSN 0223-5234Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:su:diva-25318 (URN)
Note
Part of urn:nbn:se:su:diva-8038Available from: 2008-09-11 Created: 2008-08-25Bibliographically approved
5. Investigation of Allylic Alcohols in the P1 Position of Inhibitors of Hepatitis C Virus NS3 Protease
Open this publication in new window or tab >>Investigation of Allylic Alcohols in the P1 Position of Inhibitors of Hepatitis C Virus NS3 Protease
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Manuscript (Other academic)
Identifiers
urn:nbn:se:su:diva-25319 (URN)
Note
Part of urn:nbn:se:su:diva-8038Available from: 2008-09-11 Created: 2008-08-25 Last updated: 2010-01-13Bibliographically approved

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