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Towards Dynamic Drug Design: Identification and Optimization of β-Galactosidase Inhibitors from a Dynamic Hemithioacetal System
KTH, Skolan för kemivetenskap (CHE), Kemi, Organisk kemi.
KTH, Skolan för kemivetenskap (CHE), Kemi, Organisk kemi.
KTH, Skolan för kemivetenskap (CHE), Kemi, Organisk kemi.
2010 (engelsk)Inngår i: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 11, nr 11, s. 1600-1606Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

A discovery strategy relying on the identification of fragments through resolution of a constitutional dynamic system, coupled to subsequent static ligand design and optimization, is demonstrated. The strategic design and synthesis of the best molecular fragments identified from a dynamic hemithioacetal system into static ligand structures yielded a range of -galactosidase inhibitors. Two series of structures mimicking the hemithioacetal motif were envisaged: thioglycosides and C-glycosides. Inhibition studies provided important structural information for the two groups, and 1-thiobenzyl--D-galactopyranoside demonstrated the best inhibitory effects.

sted, utgiver, år, opplag, sider
2010. Vol. 11, nr 11, s. 1600-1606
Emneord [en]
beta-galactosidase • dynamic chemistry • fragment-based drug discovery • inhibitors • ligand design
HSV kategori
Identifikatorer
URN: urn:nbn:se:kth:diva-13510DOI: 10.1002/cbic.201000158ISI: 000281383200019Scopus ID: 2-s2.0-77955157787OAI: oai:DiVA.org:kth-13510DiVA, id: diva2:325952
Forskningsfinansiär
Swedish Research Council
Merknad
QC 20100621Tilgjengelig fra: 2010-06-21 Laget: 2010-06-21 Sist oppdatert: 2017-12-12bibliografisk kontrollert
Inngår i avhandling
1. Dynamic Sulfur Chemistry: Screening, Evaluation and Catalysis
Åpne denne publikasjonen i ny fane eller vindu >>Dynamic Sulfur Chemistry: Screening, Evaluation and Catalysis
2010 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

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.

sted, utgiver, år, opplag, sider
Stockholm: KTH, 2010. s. 84
Serie
Trita-CHE-Report, ISSN 1654-1081 ; 2010:14
Emneord
Dynamic combinatorial chemistry; dynamic sulfur chemistry; thioglycoside; mutarotation; disulfide metathesis; hemithioacetal formation; 1H STD-NMR; inhibition; phosphine; Concanavalin A; beta-galactosidase; dynamic drug discovery.
HSV kategori
Identifikatorer
urn:nbn:se:kth:diva-12414 (URN)978-91-7415-618-8 (ISBN)
Disputas
2010-05-12, F3, Lindstedtsvägen 26, KTH, Stockholm, 10:00 (engelsk)
Opponent
Veileder
Merknad
QC 20100621Tilgjengelig fra: 2010-04-22 Laget: 2010-04-20 Sist oppdatert: 2010-11-29bibliografisk kontrollert
2. Dynamic Systems: Evaluation, Screening and Synthetic Application
Åpne denne publikasjonen i ny fane eller vindu >>Dynamic Systems: Evaluation, Screening and Synthetic Application
2011 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

The research work reported in the thesis deals with the development of dynamic covalent systems and their applications in evaluation and screening of protein-ligands and enzyme inhibitors, as well as in synthetic methodologies. The thesis is divided into four parts as described below.

In part one, synthetic methodologies to access 3-functionalized phthalides and 3-thioisoindolinones using the concept of cascade reactions are demonstrated. Efficient syntheses of the target products are designed and performed in one-pot process under mild reaction conditions.

 In part two, phosphine-catalyzed disulfide metathesis for the generation of dynamic carbohydrate system in aqueous solution is demonstrated. In the presence of biological target (Concanavalin A), the optimal dynamic ligand is successfully identified in situ by the 1H STD-NMR spectroscopy.

In part three, lipase-catalyzed resolutions of dynamic reversible systems using reversible cyanohydrin and hemithioacetal reactions in one-pot processes are demonstrated. The dynamic systems are generated under thermodynamic control in organic solution and subsequently resolved by lipase-mediated resolution under kinetic control. The resolution processes resulted in the lipase-selected substrates with high structural and stereochemical specificities.

In the last part, dynamic fragment-based strategy is presented using β-galactosidase as a model target enzyme. Based on our previous study, the best dynamic inhibitor of β-galactosidase was identified using 1H STD-NMR technique from dynamic hemithioacetal systems. The structure of the dynamic inhibitor is tailored by fragment linking and optimization processes. The designed inhibitor structures are then synthesized and tested for inhibition activities against β-galactosidase. 

 

sted, utgiver, år, opplag, sider
Stockholm: KTH Royal Institute of Technology, 2011. s. 69
Serie
Trita-CHE-Report, ISSN 1654-1081 ; 2011:33
Emneord
constitutional dynamic chemistry; dynamic combinatorial chemistry/ resolution; dynamic fragment-based approach; dynamic kinetic resolution; dynamic reversible systems; 1H STD-NMR; multicomponent reaction; tandem reaction
HSV kategori
Identifikatorer
urn:nbn:se:kth:diva-34100 (URN)978-91-7415-986-8 (ISBN)
Disputas
2011-06-07, F3, KTH, Lindstedtsvägen 26, KTH, Stockholm, 10:00 (engelsk)
Opponent
Veileder
Forskningsfinansiär
EU, European Research Council, MRTN-CT-2006-035614
Merknad
QC 20110526Tilgjengelig fra: 2011-05-26 Laget: 2011-05-25 Sist oppdatert: 2011-05-26bibliografisk kontrollert

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