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Design and Synthesis of Amine Building Blocks and Protease Inhibitors
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
Ansvarlig organisasjon
2008 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Stockholm: Institutionen för organisk kemi , 2008. , s. 77
HSV kategori
Forskningsprogram
organisk kemi
Identifikatorer
URN: urn:nbn:se:su:diva-8038ISBN: 978-91-7155-690-5 (tryckt)OAI: oai:DiVA.org:su-8038DiVA, id: diva2:199466
Disputas
2008-10-03, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 10:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2008-09-11 Laget: 2008-08-25 Sist oppdatert: 2010-01-15bibliografisk kontrollert
Delarbeid
1. An Expeditious Library Synthesis of N-Monoalkylated Aminopiperidines and –pyrrolidines
Åpne denne publikasjonen i ny fane eller vindu >>An Expeditious Library Synthesis of N-Monoalkylated Aminopiperidines and –pyrrolidines
Vise andre…
2004 Inngår i: European Journal of Organic Chemistry, ISSN 1434-193x, nr 12, s. 2723-2737Artikkel i tidsskrift (Fagfellevurdert) Published
Identifikatorer
urn:nbn:se:su:diva-25315 (URN)
Merknad
Part of urn:nbn:se:su:diva-8038Tilgjengelig fra: 2008-09-11 Laget: 2008-08-25bibliografisk kontrollert
2. A One-Pot, Solid-Phase Synthesis of Secondary Amines from Reactive Alkyl Halides and an Alkyl Azide
Åpne denne publikasjonen i ny fane eller vindu >>A One-Pot, Solid-Phase Synthesis of Secondary Amines from Reactive Alkyl Halides and an Alkyl Azide
2008 (engelsk)Inngår i: Synlett: Accounts and Rapid Communications in Synthetic Organic Chemistry, ISSN 0936-5214, E-ISSN 1437-2096, nr 1, s. 77-79Artikkel i tidsskrift (Fagfellevurdert) Published
HSV kategori
Identifikatorer
urn:nbn:se:su:diva-25316 (URN)10.1055/s-2007-990927 (DOI)000252773000019 ()
Merknad

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

Tilgjengelig fra: 2008-09-11 Laget: 2008-08-25 Sist oppdatert: 2017-12-13bibliografisk kontrollert
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.
Åpne denne publikasjonen i ny fane eller vindu >>Solid-phase parallel synthesis and SAR of 4-amidofuran-3-one inhibitors of cathepsin S: Effect of sulfonamides P3 substituents on potency and selectivity.
Vise andre…
2009 (engelsk)Inngår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 17, nr 3, s. 1307-1324Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
Elsevier, 2009
Emneord
Cysteine protease, cathepsin S, cathepsin K, reversible covalent inhibition
HSV kategori
Forskningsprogram
organisk kemi
Identifikatorer
urn:nbn:se:su:diva-35087 (URN)10.1016/j.bmc.2008.12.020 (DOI)
Tilgjengelig fra: 2010-01-15 Laget: 2010-01-14 Sist oppdatert: 2018-01-12bibliografisk kontrollert
4. Preparation and Characterization of Aminoethylamide Inhibitors of the Cysteine Proteinase Cathepsin K
Åpne denne publikasjonen i ny fane eller vindu >>Preparation and Characterization of Aminoethylamide Inhibitors of the Cysteine Proteinase Cathepsin K
Vise andre…
Inngår i: European Journal of Medicinal Chemistry, ISSN 0223-5234Artikkel i tidsskrift (Fagfellevurdert) Submitted
Identifikatorer
urn:nbn:se:su:diva-25318 (URN)
Merknad
Part of urn:nbn:se:su:diva-8038Tilgjengelig fra: 2008-09-11 Laget: 2008-08-25bibliografisk kontrollert
5. Investigation of Allylic Alcohols in the P1 Position of Inhibitors of Hepatitis C Virus NS3 Protease
Åpne denne publikasjonen i ny fane eller vindu >>Investigation of Allylic Alcohols in the P1 Position of Inhibitors of Hepatitis C Virus NS3 Protease
Vise andre…
Manuskript (Annet vitenskapelig)
Identifikatorer
urn:nbn:se:su:diva-25319 (URN)
Merknad
Part of urn:nbn:se:su:diva-8038Tilgjengelig fra: 2008-09-11 Laget: 2008-08-25 Sist oppdatert: 2010-01-13bibliografisk kontrollert

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