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Design and Synthesis of Serine and Aspartic Protease Inhibitors
Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
2006 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes the design and synthesis of compounds that are

intended to inhibit serine and aspartic proteases. The first part of the text deals with preparation of inhibitors of the hepatitis C virus (HCV) NS3 serine protease. Hepatitis C is predominantly a chronic disease that afflicts about 170 million people worldwide. The NS3 protease, encoded by HCV, is essential for replication of the virus and has become one of the main targets when developing drugs to fight HCV. The inhibitors discussed here constitute surrogates for the widely used N-acyl-hydroxyproline isostere designated 4-hydroxy-cyclopentene. The stereochemistry of the 4-hydroxy-cyclopentene scaffold was determined by nuclear overhauser effect spectroscopy (NOESY) and the regiochemistry by heteronuclear multiple bond correlation (HMBC). The scaffold was decorated with different substituents to obtain both linear and macrocyclic HCV NS3 protease inhibitors that display low nanomolar activity. The second part of the thesis describes the design and synthesis of potential aspartic protease inhibitors. The hydroxyethylene motif was used as a noncleavable transition state isostere. The synthetic route yielded a pivotal intermediate with excellent stereochemical control, which was corroborated by NOESY experiments. This intermediate can be diversified with different substituents to furnish novel aspartic protease inhibitors.

Place, publisher, year, edition, pages
Institutionen för fysik, kemi och biologi , 2006. , 51 p.
Series
Linköping Studies in Science and Technology. Thesis, ISSN 0280-7971 ; 1264
Keyword [en]
organic chemistry, organic synthesis, metathesis, HCV, NS3, protease, proline isosteres, inhibitor, aspartic protease inhibitors, hydroxyethylene
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:liu:diva-7372ISBN: 9185523216 (print)OAI: oai:DiVA.org:liu-7372DiVA: diva2:22385
Presentation
2006-09-29, Schrödinger (E324), Hus E, Campus Valla, Linköpings universitet, Linköping, 14:00 (English)
Opponent
Supervisors
Note

Report code: LIU-TEK-LIC-2006:45

Available from: 2006-09-14 Created: 2006-09-14 Last updated: 2017-12-14
List of papers
1. Synthesis of Novel Potent Hepatitis C Virus NS3 Protease Inhibitors: Discovery of 4-Hydroxy-cyclopent-2-ene-1,2-dicarboxylic Acid as a N-Acyl-L-Hydroxyproline Bioisostere
Open this publication in new window or tab >>Synthesis of Novel Potent Hepatitis C Virus NS3 Protease Inhibitors: Discovery of 4-Hydroxy-cyclopent-2-ene-1,2-dicarboxylic Acid as a N-Acyl-L-Hydroxyproline Bioisostere
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2007 (English)In: Bioorganic & medicinal chemistry, ISSN 0968-0896, Vol. 15, no 2, 827-838 p.Article in journal (Refereed) Published
Abstract [en]

Potent tetrapeptidic inhibitors of the HCV NS3 protease have been developed incorporating 4-hydroxy-cyclopent-2-ene-1,2-dicarboxylic acid as a new N-acyl-l-hydroxyproline mimic. The hydroxycyclopentene template was synthesized in eight steps from commercially available (syn)-tetrahydrophthalic anhydride. Three different amino acids were explored in the P1-position and in the P2-position the hydroxyl group of the cyclopentene template was substituted with 7-methoxy-2-phenyl-quinolin-4-ol. The P3/P4-positions were then optimized from a set of six amino acid derivatives. All inhibitors were evaluated in an in vitro assay using the full-length NS3 protease. Several potent inhibitors were identified, the most promising exhibiting a Ki value of 1.1 nM.

Keyword
HCV; NS3; Protease inhibitor; N-Acyl-l-hydroxyproline mimic; 4-Hydroxy-cyclopent-2-ene-1, 2-dicarboxylic acid; Cyclopentene
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-13983 (URN)10.1016/j.bmc.2006.10.044 (DOI)
Available from: 2006-09-14 Created: 2006-09-14 Last updated: 2009-05-15
2. Potent Macrocyclic Inhibitors of the Hepatitis C Virus NS3 Protease Incorporating Cyclopentane and Cyclopentene Derived Scaffolds
Open this publication in new window or tab >>Potent Macrocyclic Inhibitors of the Hepatitis C Virus NS3 Protease Incorporating Cyclopentane and Cyclopentene Derived Scaffolds
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Manuscript (Other academic)
Identifiers
urn:nbn:se:liu:diva-13984 (URN)
Available from: 2006-09-14 Created: 2006-09-14 Last updated: 2010-01-13

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