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Dynamic Combinatorial Thiolester Libraries for Efficient Catalytic Self-Screening of Hydrolase Substrates
KTH, School of Chemical Science and Engineering (CHE), Chemistry.
KTH, School of Chemical Science and Engineering (CHE), Chemistry.
2006 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 1, 285-291 p.Article in journal (Refereed) Published
Abstract [en]

Dynamic combinatorial thiolester libraries were efficiently generated from pools of thiols and acyl functionalities through reversible transthiolesterification in aqueous media at neutral pH. The dynamic features of the library generation were investigated, and the libraries were screened against acetylcholinesterase, clearly demonstrating the catalytic self-screening of its substrates from the constituents. Acetyl- and propionylthiocholine were easily identified as the best substrates for the enzyme, whereas other constituents showed lower efficiency or were inactive. A range of hydrolases was furthermore screened for rapid substrate identification, clearly demonstrating the differences in selectivity. The results show that transthiolesterification is a useful method to generate dynamic libraries, and that the catalytic self -screening concept is highly valuable for substrate identification.

Place, publisher, year, edition, pages
2006. no 1, 285-291 p.
Keyword [en]
combinatorial chemistry; enzyrne catalysis; hydrolysis; transesterification
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-8266DOI: 10.1002/ejoc.200500699ISI: 000234237500028Scopus ID: 2-s2.0-33745819380OAI: oai:DiVA.org:kth-8266DiVA: diva2:13543
Note
QC 20100818Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Dynamic Systems for Screening, Control and Identification of Protein-Ligand Interactions
Open this publication in new window or tab >>Dynamic Systems for Screening, Control and Identification of Protein-Ligand Interactions
2008 (English)Doctoral thesis, comprehensive summary (Other scientific)
Abstract [en]

Dynamic systems for screening, control and identification of different protein-ligand interactions are presented. Dynamic chemistry is used to produce new compounds/constituents in situ that can interact with a target molecule. Several entities can be introduced at the same time and interact with one another. These molecules make a dynamic combinatorial library (DCL) which is used in dynamic combinatorial chemistry (DCC). DCC is a recently introduced approach to generate dynamically interchanging libraries of compounds. These libraries are made of different building blocks that reversibly interact with one another and spontaneously assemble to encompass all possible combinations. If a target molecule, for instance a receptor is added to the system and one or more molecules show affinity to the target species, these compounds will, according to Le Châtelier´s principle, be amplified on the expense of the other non-bonding constituents. To further advance the technique, especially when biological systems are targeted, new reaction types and new screening methods are necessary. This thesis describes the development of different reversible reactions, thiol/disulfide interchange, transthiolesterification and the nitroaldol (Henry) reaction as means of generating reversible covalent bond reactions. Two different types of target proteins are used, enzymes belonging to the hydrolase family and the plant lectin Concanavalin A.

Dynamic combinatorial resolution (DCR) is presented. This new concept relies on the consecutive kinetic resolution of dynamic combinatorial libraries, leading to complete amplification and control of dynamically interchangeable processes. By applying a kinetically controlled step to a thermodynamically controlled system, complete transformation and amplification can be obtained. The concept has been demonstrated by developing transthiolesterification and nitroaldol exchange reactions to generate diversity, forming libraries under thermodynamic control, and used in one-pot processes with kinetically controlled enzyme-mediated resolution. The results demonstrate that the reaction types are useful for the generation of dynamic libraries, and that the dynamic combinatorial resolution concept is highly valuable for efficient substrate identification, asymmetric synthesis, and library screening.

The thesis also describes three other dynamic chemistry protocols. The first one describes dynamic kinetic resolution (DKR) of nitroaldol adducts by combined lipase catalysis. The second one describes finding lectin inhibitors from a glycodisulfide library and the third one describes finding an inhibitor of acetylcholinesterase using a tandem driven dynamic self-inhibition approach.

Place, publisher, year, edition, pages
Stockholm: KTH, 2008. 64 p.
Series
TRITA-CHE-Report, ISSN 1654-1081 ; 2008:31
Keyword
Dynamic combinatorial chemistry, Dynamic kinetic/combinatorial resolution, Catalytic screening, Transthiolesterification, Thiol/disulfide interchange, Nitroaldol reaction, Lectins, Hydrolases, Dynamic self-inhibition
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-4709 (URN)978-91-7178-944-0 (ISBN)
Public defence
2008-05-09, F3, Lindstedtsvägen 26, Stockholm, 13:00
Opponent
Supervisors
Note

QC 20100818

Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2017-02-23Bibliographically approved
2. Reversible Sulfur Reactions in Pre-Equilibrated and Catalytic Self-Screening Dynamic Combinatorial Chemistry Protocols
Open this publication in new window or tab >>Reversible Sulfur Reactions in Pre-Equilibrated and Catalytic Self-Screening Dynamic Combinatorial Chemistry Protocols
2006 (English)Licentiate thesis, comprehensive summary (Other scientific)
Abstract [en]

Dynamic Combinatorial Chemistry (DCC) is a recently introduced supramolecular approach to generate dynamically interchanging libraries of compounds. These libraries are made of different building blocks that reversibly interact with one another and spontaneously assemble to encompass all possible combinations. If a target molecule, for instance a receptor is added to the system and one or more molecules show affinity to the target species, these compounds will, according to Le Châtelier´s principle, be amplified on the expense of the other non-bonding constituents. To date, only a handful of different systems and formats have been used. Hence, to further advance the technique, especially when biological systems are targeted, new reaction types and new screening methods are necessary. This thesis describes the development of reversible sulfur reactions, thiol/disulfide interchange and transthiolesterification (the latter being a new reaction type for DCC), as means of generating reversible covalent bond reactions. Two different types of target proteins are used, enzymes belonging to the hydrolase family and the plant lectin Concanavalin A. Furthermore, two new screening/analysis methods not previously used in DCC are also presented; the quartz crystal microbalance (QCM)-technique and catalytic self-screening.

Place, publisher, year, edition, pages
Stockholm: KTH, 2006. 44 p.
Series
Trita-IOK, ISSN 1100-7974 ; 2006:102
Keyword
Dynamic Combinatorial Chemistry, Reversible sulfur reactions, Catalytic self-screening, Carbohydrates, Lectins, Quartz Crystal Microbalance
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-3917 (URN)91-7178-323-7 (ISBN)
Presentation
2006-05-02, F3, Lindstedtsvägen 26, KTH, Stockholm, 10:00
Note
QC 20101118Available from: 2006-04-10 Created: 2006-04-10 Last updated: 2010-11-18Bibliographically approved

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