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Structure-Based Design and Synthesis of Protease Inhibitors Using Cycloalkenes as Proline Bioisosteres and Combinatorial Syntheses of a Targeted Library
Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Structure-based drug design and combinatorial chemistry play important roles in the search for new drugs, and both these elements of medicinal chemistry were included in the present studies. This thesis outlines the synthesis of protease inhibitors against thrombin and the HCV NS3 protease, as well as the synthesis of a combinatorial library using solid phase chemistry.In the current work potent thrombin inhibitors were generated based on the D-Phe-Pro-Arg motif incorporating cyclopentene and cyclohexene scaffolds that were synthesized by ring-closing metathesis chemistry. A structure-activity relationship study was carried out using the crystallographic results for one of the inhibitors co-crystallized with thrombin. HCV NS3 protease inhibitors comprising the proline bioisostere 4-hydroxy-cyclopent-2-ene-1,2-dicarbboxylic acid were synthesized displaying low nanomolar activity. The stereochemistry and regiochemistry of the scaffolds were determined by NOESY and HMBC spectra, respectively. The final diastereomeric target compounds were isolated and annotated by applying TOCSY and ROESY NMR experiments. Furthermore, a 4-phenyl-2-carboxypiperazine targeted combinatorial chemistry library was synthesized to be used early in the lead discovery phase. This was done using a scaffold that was synthesized by palladiumcatalyzed aromatic amination chemistry and subsequently derivatized with eight electrophiles and ten nucleophiles.

Place, publisher, year, edition, pages
Institutionen för fysik, kemi och biologi , 2005.
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 990
Series
Keyword [en]
organic chemistry, organic synthesis, combinatorial synthesis, metathesis, olefin metathesis, thrombin, HCV, NS3, protease, proline isosteres, inhibitor
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:liu:diva-4938ISBN: 91-85457-78-7 (print)OAI: oai:DiVA.org:liu-4938DiVA: diva2:20824
Public defence
2005-12-09, Sal Planck, Fysikhuset, Campus Vall, Linköpings universitet, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2005-11-24 Created: 2005-11-24 Last updated: 2009-06-05
List of papers
1. Solid-phase synthesis of libraries generated from a 4-phenyl-2-carboxy-piperazine Scaffold
Open this publication in new window or tab >>Solid-phase synthesis of libraries generated from a 4-phenyl-2-carboxy-piperazine Scaffold
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2001 (English)In: Journal of Combinatorial Chemistry, Vol. 3, no 6, 546-553 p.Article in journal (Refereed) Published
Abstract [en]

Strategies for finding novel structures of therapeutical interest are discussed. The rationale for the selection of the two scaffolds N4-(m-aminophenyl)-piperazine-2-carboxylic acid E and N4-(o-aminophenyl)-piperazine-2-carboxylic F is described. The synthesis of the appropriate precursors to scaffold E and F and their use in solid-phase chemistry are described. A 160-member library was produced combining these novel piperazine scaffolds with eight sulfonyl chlorides/acid chlorides and 10 amines. The compound library prepared was analyzed using LC-MS, showing the expected base peak in all wells at an average purity of 82%.

National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-13467 (URN)10.1021/cc010013o (DOI)
Available from: 2005-11-24 Created: 2005-11-24
2. Synthesis of Novel Thrombin Inhibitors. Use of Ring-Closing Metathesis Reactions for Synthesis of P2 Cyclopentene and Cyclohexene Dicarboxylic Acid Derivatives
Open this publication in new window or tab >>Synthesis of Novel Thrombin Inhibitors. Use of Ring-Closing Metathesis Reactions for Synthesis of P2 Cyclopentene and Cyclohexene Dicarboxylic Acid Derivatives
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2003 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. 46, no 7, 1165-1179 p.Article in journal (Refereed) Published
Abstract [en]

The thrombin inhibitory tripeptide d-Phe-Pro-Arg has been mimicked using either cyclopentenedicarboxylic derivatives or a cyclohexenedicarboxylic derivative as surrogate for the P2 proline. In the P3 position, tertiary amides were optimized as d-Phe P3 replacements. The P1 arginine was, in all compounds, substituted with the more rigid and biocompatible 4-aminomethylbenzamidine. One of the novel inhibitors was cocrystallized with α-thrombin and subjected to X-ray analysis. From analysis of the X-ray crystal structure, new ligands were designed leading to significantly improved binding affinity, the lead candidate exhibiting an in vitro IC50 of 49 nM.

National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-13468 (URN)10.1021/jm021065a (DOI)
Available from: 2005-11-24 Created: 2005-11-24 Last updated: 2009-06-05
3. 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

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Thorstensson, Fredrik

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