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Solid-phase synthesis of libraries generated from a 4-phenyl-2-carboxy-piperazine Scaffold
Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, Stockholm, Sweden.
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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%.

Place, publisher, year, edition, pages
2001. Vol. 3, no 6, 546-553 p.
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:liu:diva-13467DOI: 10.1021/cc010013oOAI: oai:DiVA.org:liu-13467DiVA: diva2:20821
Available from: 2005-11-24 Created: 2005-11-24
In thesis
1. Design, Synthesis and Characterization of Small Molecule Inhibitors and Small Molecule: Peptide Conjugates as Protein Actors
Open this publication in new window or tab >>Design, Synthesis and Characterization of Small Molecule Inhibitors and Small Molecule: Peptide Conjugates as Protein Actors
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes different aspects of protein interactions. Initially the function of peptides and their conjugates with small molecule inhibitors on the surface of Human Carbonic Anhydrase isoenzyme II (HCAII) is evaluated.

The affinities for HCAII of the flexible, synthetic helix-loop-helix motif conjugated with a series of spacered inhibitors were measured by fluorescence spectroscopy and found in the best cases to be in the low nM range. Dissociation constants show considerable dependence on linker length and vary from 3000 nM for the shortest spacer to 40 nM for the longest with a minimum of 5 nM for a spacer with an intermediate length. A rationale for binding differences based on cooperativity is presented and supported by affinities as determined by fluorescence spectroscopy. Heteronuclear Single Quantum Correlation Nuclear Magnetic Resonance (HSQC) spectroscopic experiments with 15N-labeled HCAII were used for the determination of the site of interaction.

The influence of peptide charge and hydrophobicity was evaluated by surface plasmon resonance experiments. Hydrophobic sidechain branching and, more pronounced, peptide charge was demonstrated to modulate peptide – HCAII binding interactions in a cooperative manner, with affinities spanning almost two orders of magnitude.

Detailed synthesis of small molecule inhibitors in a general lead discovery library as well as a targeted library for inhibition of α-thrombin is described. For the lead discovery library 160 members emanate from two N4-aryl-piperazine-2-carboxylic acid scaffolds derivatized in two dimensions employing a combinatorial approach on solid support.

The targeted library was based on peptidomimetics of the D-Phe-Pro-Arg showing the scaffolds cyclopropane-1R,2R-dicarboxylic acid and (4-amino-3-oxo-morpholin-2-yl)- acetic acid as proline isosters. Employing 4-aminomethyl-benzamidine as arginine mimic and different hydrophobic amines and electrophiles as D-phenylalanine mimics resulted in 34 compounds showing IC50 values for α-thrombin ranging more than three orders of magnitude with the best inhibitor showing an IC50 of 130 nM. Interestingly, the best inhibitors showed reversed stereochemistry in comparison with a previously reported series employing a 3-oxo-morpholin-2-yl-acetic acid scaffold.

Place, publisher, year, edition, pages
Institutionen för fysik, kemi och biologi, 2005
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 960
Keyword
Synthetic receptor, Peptide inhibitor conjugate, Peptide protein surface interactions, General Lead Discovery Library, Combinatorial Chemistry, Solid Phase Chemistry, Targeted Library, Thrombin inhibitor, Fluorescence, Surface Plasmon Resonance
National Category
Organic Chemistry
Identifiers
urn:nbn:se:liu:diva-3943 (URN)91-85457-00-0 (ISBN)
Public defence
2005-09-16, Planck, Fysikhuset, Campus Valla, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2005-09-21 Created: 2005-09-21 Last updated: 2009-03-06
2. Structure-Based Design and Synthesis of Protease Inhibitors Using Cycloalkenes as Proline Bioisosteres and Combinatorial Syntheses of a Targeted Library
Open this publication in new window or tab >>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)
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
organic chemistry, organic synthesis, combinatorial synthesis, metathesis, olefin metathesis, thrombin, HCV, NS3, protease, proline isosteres, inhibitor
National Category
Organic Chemistry
Identifiers
urn:nbn:se:liu:diva-4938 (URN)91-85457-78-7 (ISBN)
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

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Nilsson, Jonas W.Thorstensson, FredrikKvarnström, Ingemar

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