Dynamic Sulfur Chemistry: Screening, Evaluation and Catalysis
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
This thesis deals with the design, formation and evaluation of dynamic systems constructed by means of sulfur-containing reversible reactions, in organic and aqueous media and under mild conditions.
In a first part, the synthesis of thioglycoside derivatives, constituting the biologically relevant starting components of the dynamic systems, is described. In addition, the pD-profile of the mutarotation process in aqueous media for a series of 1-thioaldoses is reported and revealed an astonishing beta-anomeric preference for all the carbohydrate analogs under acidic or neutral conditions.
In a second part, the phosphine-catalyzed or -mediated disulfide metathesis for dynamic system generation in organic or aqueous media is presented, respectively. The direct in situ 1H STD-NMR resolution of a dynamic carbohydrate system in the presence of a target protein (Concanavalin A) proved the suitability and compatibility of such disulfide metathesis protocols for the discovery of biologically relevant ligands.
In a third part, hemithioacetal formation is demonstrated as a new and efficient reversible reaction for the spontaneous generation of a dynamic system, despite a virtual character of the component associations in basic aqueous media. The direct in situ 1H STD-NMR identification of the best dynamic beta-galactosidase inhibitors from the dynamic HTA system was performed and the results were confirmed by inhibition studies. Thus, the HTA product formed from the reaction between 1-thiogalactopyranose and a pyridine carboxaldehyde derivative provided the best dynamic inhibitor.
In a fourth and final part, a dynamic drug design strategy, where the best inhibitors from the aforementioned dynamic HTA system were used as model for the design of non-dynamic (or “static”) beta-galactosidase inhibitors, is depicted. Inhibition studies disclosed potent leads among the set of ligands.
Place, publisher, year, edition, pages
Stockholm: KTH , 2010. , 84 p.
Trita-CHE-Report, ISSN 1654-1081 ; 2010:14
Dynamic combinatorial chemistry; dynamic sulfur chemistry; thioglycoside; mutarotation; disulfide metathesis; hemithioacetal formation; 1H STD-NMR; inhibition; phosphine; Concanavalin A; beta-galactosidase; dynamic drug discovery.
Chemical Sciences Organic Chemistry Organic Chemistry
IdentifiersURN: urn:nbn:se:kth:diva-12414ISBN: 978-91-7415-618-8OAI: oai:DiVA.org:kth-12414DiVA: diva2:311101
2010-05-12, F3, Lindstedtsvägen 26, KTH, Stockholm, 10:00 (English)
Giuseppone, Nicolas, Professor
Ramström, Olof, Professor
QC 201006212010-04-222010-04-202010-11-29Bibliographically approved
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