Structure-Based Design and Synthesis of Protease Inhibitors Using Cycloalkenes as Proline Bioisosteres and Combinatorial Syntheses of a Targeted Library
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
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.
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 990
organic chemistry, organic synthesis, combinatorial synthesis, metathesis, olefin metathesis, thrombin, HCV, NS3, protease, proline isosteres, inhibitor
National CategoryOrganic Chemistry
IdentifiersURN: urn:nbn:se:liu:diva-4938ISBN: 91-85457-78-7OAI: oai:DiVA.org:liu-4938DiVA: diva2:20824
2005-12-09, Sal Planck, Fysikhuset, Campus Vall, Linköpings universitet, Linköping, 13:00 (English)
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