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Dynamic Sulfur Chemistry: Screening, Evaluation and Catalysis
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry. (Ramström Research Group)
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Stockholm: KTH , 2010. , 84 p.
Series
Trita-CHE-Report, ISSN 1654-1081 ; 2010:14
Keyword [en]
Dynamic combinatorial chemistry; dynamic sulfur chemistry; thioglycoside; mutarotation; disulfide metathesis; hemithioacetal formation; 1H STD-NMR; inhibition; phosphine; Concanavalin A; beta-galactosidase; dynamic drug discovery.
National Category
Chemical Sciences Organic Chemistry Organic Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-12414ISBN: 978-91-7415-618-8 (print)OAI: oai:DiVA.org:kth-12414DiVA: diva2:311101
Public defence
2010-05-12, F3, Lindstedtsvägen 26, KTH, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
QC 20100621Available from: 2010-04-22 Created: 2010-04-20 Last updated: 2010-11-29Bibliographically approved
List of papers
1. Synthesis of Positional Thiol Analogs of β-D-Galactopyranose
Open this publication in new window or tab >>Synthesis of Positional Thiol Analogs of β-D-Galactopyranose
2007 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, Vol. 29, 4927-4934 p.Article in journal (Refereed) Published
Abstract [en]

Approaches toward the synthesis of thio- beta -D -galactose derivatives are described. These compounds were prepared from the parent carbohydrates: D-galactose, methyl P-D-galactoside and methyl P-D-glucoside, respectively. It was found that not only the strategies of protecting group introduction and selective deprotection, but also the choices of solvent and nucleophilic reagent concentration were crucial to allow the efficient introduction of sulfur at different positions of the galactose ring. The effects from the solvent, the nucleophilic reagent concentration, and the protecting group patterns have been investigated. The results clearly show that ester protecting groups play highly important roles for the synthesis of thio-containing carbohydrates, requiring nonpolar solvents to suppress the neighboring group participation. For the Lattrell-Dax (nitrite -mediated) inversion reaction, employed in the synthetic route to the 2-thio-beta-D-galactoside, intramolecular nucleophilic attack, as well as stronger stereospecific ester activation, are necessary to overcome hindrance from 4,6-O-benzylidene protection.

Keyword
thiosaccharides, galactose, lattrell-dax, inversion
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-9887 (URN)10.1002/ejoc.200700364 (DOI)000250367600015 ()2-s2.0-35349025393 (Scopus ID)
Note
QC 20100709. Tidigare titel: Synthesis of Thiogalactose derivatives for S-linked OligosaccharidesAvailable from: 2009-01-27 Created: 2009-01-27 Last updated: 2017-12-14Bibliographically approved
2. pH-Dependent Mutarotation of 1-Thioaldoses in Water. Unexpected Behavior of (2S)-D-Aldopyranoses
Open this publication in new window or tab >>pH-Dependent Mutarotation of 1-Thioaldoses in Water. Unexpected Behavior of (2S)-D-Aldopyranoses
Show others...
2010 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 75, no 18, 6115-6121 p.Article in journal (Refereed) Published
Abstract [en]

The pH-dependent mutarotation of 1-thioaldopyranoses in aqueous media has been investigated. Anomerization readily occurred at lower and neutral pH for all aldopyranoses studied, whereas mainly for (2S)-D-aldopyranoses at higher pH. 1-Thio-D-mannopyranose and 1-thio-D-altropyranose showed very strong pH dependence where the anomeric equilibrium ratios changed dramatically from a preference for the beta-anomer at lower pH to the alpha-anomer at higher pH.

Keyword
Anomeric equilibrium, Anomerization, Aqueous media, Mannopyranose, Mutarotation, Neutral pH, PH dependence, PH-dependent
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-26704 (URN)10.1021/jo100826e (DOI)000281585600007 ()2-s2.0-77956498793 (Scopus ID)
Note
QC 20101129 Uppdaterad från manuskript till artikel (20101129).Available from: 2010-11-29 Created: 2010-11-26 Last updated: 2017-12-12Bibliographically approved
3. Phosphine-catalyzed disulfide metathesis
Open this publication in new window or tab >>Phosphine-catalyzed disulfide metathesis
Show others...
2008 (English)In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, no 48, 6603-6605 p.Article in journal (Refereed) Published
Abstract [en]

The reaction between disulfides and phosphines generates a reversible disulfide metathesis process.

Keyword
DYNAMIC COMBINATORIAL CHEMISTRY, ORGANIC SULFUR CHEMISTRY, EXCHANGE-REACTION, PHOSPHORUS NUCLEOPHILES, EQUILIBRIUM-CONSTANTS, INTERCHANGE REACTIONS, DRUG DISCOVERY, BOND FORMATION, LIBRARIES, WATER
Identifiers
urn:nbn:se:kth:diva-12443 (URN)10.1039/b815710c (DOI)000261742500041 ()2-s2.0-57249086290 (Scopus ID)
Note

QC20100621

Available from: 2010-04-22 Created: 2010-04-22 Last updated: 2017-12-12Bibliographically approved
4. Phosphine-Mediated Disulfide Metathesis in Aqueous Media
Open this publication in new window or tab >>Phosphine-Mediated Disulfide Metathesis in Aqueous Media
2010 (English)In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 46, no 44, 8469-8471 p.Article in journal (Refereed) Published
Abstract [en]

Dynamic carbohydrate systems have been efficiently generated through phosphine-mediated disulfide metathesis in aqueous media. The protein compatibility and binding features of the dynamic systems were demonstrated in situ using H-1 STD NMR.

Keyword
ORGANIC SULFUR CHEMISTRY, DYNAMIC COMBINATORIAL CHEMISTRY, EXCHANGE-REACTION, PHOSPHORUS NUCLEOPHILES, EQUILIBRIUM-CONSTANTS, INTERCHANGE REACTIONS, LIBRARIES, WATER, DESULFURIZATION, TRIPHENYLPHOSPHINE
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-13508 (URN)10.1039/c0cc03622f (DOI)000283690400048 ()2-s2.0-78049406031 (Scopus ID)
Note
QC 20100621. Uppdaterad från manuskript till artikel (20101209).Available from: 2010-06-21 Created: 2010-06-21 Last updated: 2017-12-12Bibliographically approved
5. Direct STD NMR Identification of beta-Galactosidase Inhibitors from a Virtual Dynamic Hemithioacetal System
Open this publication in new window or tab >>Direct STD NMR Identification of beta-Galactosidase Inhibitors from a Virtual Dynamic Hemithioacetal System
Show others...
2010 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 49, no 3, 589-593 p.Article in journal (Refereed) Published
Abstract [en]

 The formation of a dynamic hemithioacetal system and its application toward the discovery of ß-galactosidase inhibitors were successfully investigated. The designed dynamic system, which has a virtual character in neutral aqueous media, was subjected to a direct in situ identification of the best inhibitors by 1H STD NMR spectroscopy (ONPC : o-nitrophenyl-β-galactopyranoside).

Keyword
beta-galactosidase, dynamic chemistry, hemithioacetals, inhibition, NMR spectroscopy, NUCLEAR-MAGNETIC-RESONANCE, COMBINATORIAL LIBRARIES, ESCHERICHIA-COLI, LIGAND-BINDING, LIVING CELLS, ACTIVE-SITE, CHEMISTRY, SPECTROSCOPY, RECEPTORS, PROTEIN
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-12442 (URN)10.1002/anie.200903920 (DOI)000274262800023 ()2-s2.0-74549200492 (Scopus ID)
Funder
Swedish Research Council
Note
QC 20100908Available from: 2010-04-22 Created: 2010-04-22 Last updated: 2017-12-12Bibliographically approved
6. Towards Dynamic Drug Design: Identification and Optimization of β-Galactosidase Inhibitors from a Dynamic Hemithioacetal System
Open this publication in new window or tab >>Towards Dynamic Drug Design: Identification and Optimization of β-Galactosidase Inhibitors from a Dynamic Hemithioacetal System
2010 (English)In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 11, no 11, 1600-1606 p.Article in journal (Refereed) 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.

Keyword
beta-galactosidase • dynamic chemistry • fragment-based drug discovery • inhibitors • ligand design
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:kth:diva-13510 (URN)10.1002/cbic.201000158 (DOI)000281383200019 ()2-s2.0-77955157787 (Scopus ID)
Funder
Swedish Research Council
Note
QC 20100621Available from: 2010-06-21 Created: 2010-06-21 Last updated: 2017-12-12Bibliographically approved

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