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Reversible Sulfur Reactions in Pre-Equilibrated and Catalytic Self-Screening Dynamic Combinatorial Chemistry Protocols
KTH, School of Chemical Science and Engineering (CHE), Chemistry.
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 [en]
Dynamic Combinatorial Chemistry, Reversible sulfur reactions, Catalytic self-screening, Carbohydrates, Lectins, Quartz Crystal Microbalance
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-3917ISBN: 91-7178-323-7 (print)OAI: oai:DiVA.org:kth-3917DiVA: diva2:10008
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
List of papers
1. Catalytic Self-Screening of Cholinesterase Substrates from a Dynamic Combinatorial Thioester Library
Open this publication in new window or tab >>Catalytic Self-Screening of Cholinesterase Substrates from a Dynamic Combinatorial Thioester Library
2004 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 43, no 28, 3716-3718 p.Article in journal (Refereed) Published
Abstract [en]

Simply the best: Dynamic combinatorial chemistry coupled to enzyme catalysis was used to identify enzyme substrates in a library constructed from a series of thioesters and thiols by transesterification. The library was directly coupled to the catalytic action of acetylcholinesterase, which selectively hydrolyzed the best substrate candidates (see schematic representation). The process allowed rapid identification of discrete substrates.

Keyword
combinatorial chemistry; enzyme catalysis hydrolysis; proteomics; transesterification
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-8265 (URN)10.1002/anie.200454165 (DOI)000222793600019 ()2-s2.0-4544244707 (Scopus ID)
Note
QC 20100818Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2017-12-14Bibliographically approved
2. Dynamic Combinatorial Thiolester Libraries for Efficient Catalytic Self-Screening of Hydrolase Substrates
Open this publication in new window or tab >>Dynamic Combinatorial Thiolester Libraries for Efficient Catalytic Self-Screening of Hydrolase Substrates
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.

Keyword
combinatorial chemistry; enzyrne catalysis; hydrolysis; transesterification
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-8266 (URN)10.1002/ejoc.200500699 (DOI)000234237500028 ()2-s2.0-33745819380 (Scopus ID)
Note
QC 20100818Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2017-12-14Bibliographically approved
3. Quartz crystal microbalance bioaffinity sensor for rapid identification of glycosyldisulfide lectin inhibitors from a dynamic combinatorial library
Open this publication in new window or tab >>Quartz crystal microbalance bioaffinity sensor for rapid identification of glycosyldisulfide lectin inhibitors from a dynamic combinatorial library
Show others...
2006 (English)In: Biosensors & bioelectronics, ISSN 0956-5663, E-ISSN 1873-4235, Vol. 22, no 1, 42-48 p.Article in journal (Refereed) Published
Abstract [en]

Carbohydrate-lectin,interactions were probed with dynamic combinatorial libraries, using the plant lectin Concanavalin A as target species. The dynamic combinatorial libraries were generated from a pool of thiol components through reversible thiol-disulfide interchange, and screened using a simple and efficient method based on a quartz crystal microbalance setup. It was found that dimers based on 1-thio- and 6-thin-mannose analogues were the most active inhibitors. Furthermore, the results clearly show that the 6-thio-mannose possess unique characteristics compared to its oxygen-containing counterpart.

Keyword
quartz crystal microbalance; dynamic combinatorial chemistry; glycochemistry; carbohydrates; lectins; molecular recognition
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-8269 (URN)10.1016/j.bios.2005.11.024 (DOI)000241040600006 ()2-s2.0-33746607715 (Scopus ID)
Note
QC 20100818Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2017-12-14Bibliographically approved

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