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Dynamic Systems: Evaluation, Screening and Synthetic Application
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
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. 

 

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology , 2011. , 69 p.
Series
Trita-CHE-Report, ISSN 1654-1081 ; 2011:33
Keyword [en]
constitutional dynamic chemistry; dynamic combinatorial chemistry/ resolution; dynamic fragment-based approach; dynamic kinetic resolution; dynamic reversible systems; 1H STD-NMR; multicomponent reaction; tandem reaction
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-34100ISBN: 978-91-7415-986-8OAI: oai:DiVA.org:kth-34100DiVA: diva2:419103
Public defence
2011-06-07, F3, KTH, Lindstedtsvägen 26, KTH, Stockholm, 10:00 (English)
Opponent
Supervisors
Funder
EU, European Research Council, MRTN-CT-2006-035614
Note
QC 20110526Available from: 2011-05-26 Created: 2011-05-25 Last updated: 2011-05-26Bibliographically approved
List of papers
1. Tandem reversible addition-intramolecular lactonization for the synthesis of 3-functionalized phthalides
Open this publication in new window or tab >>Tandem reversible addition-intramolecular lactonization for the synthesis of 3-functionalized phthalides
2010 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1873-3581, Vol. 51, no 1, 75-78 p.Article in journal (Refereed) Published
Abstract [en]

A new tandem process based on reversible nucleophilic addition and intramolecular lactonization of methyl 2-formylbenzoate leads to the efficient synthesis of 3-functionalized phthalides, which are important precursors for the synthesis of quinone skeletons via Hauser–Kraus annulation. The reactions are successfully carried out under mild conditions in single operations.

Keyword
DYNAMIC COMBINATORIAL RESOLUTION, ANNULATION REACTIONS, CHEMISTRY, ANNELATION
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-12736 (URN)10.1016/j.tetlet.2009.10.079 (DOI)000274232200018 ()2-s2.0-70649083235 (ScopusID)
Funder
Swedish Research Council
Note
QC 20110126Available from: 2010-05-07 Created: 2010-05-07 Last updated: 2011-05-26Bibliographically approved
2. A Dynamic Multicomponent Approach for One-Pot Synthesis of 3-Thioisoindolinones
Open this publication in new window or tab >>A Dynamic Multicomponent Approach for One-Pot Synthesis of 3-Thioisoindolinones
2013 (English)In: Israel Journal of Chemistry, ISSN 0021-2148, Vol. 53, no 1-2, 127-132 p.Article in journal (Refereed) Published
Abstract [en]

A dynamic multicomponent reaction concept has been successfully applied to the syntheses of 3-thioisoindolinones and tricyclic gamma-lactams. The reactions were efficiently designed and operated in the absence of any catalyst under mild reaction conditions, resulting in the convenient variation of substituents on the N- and S-positions of the target products.

Keyword
cyclization, dynamic chemistry, heterocycles, isoindolinone, multicomponent reactions
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-34126 (URN)10.1002/ijch.201200101 (DOI)000316506000017 ()2-s2.0-84876252158 (ScopusID)
Funder
Swedish Research CouncilEU, European Research Council, MRTN-CT-2006-035614
Note

QC 20130419. Updated from submitted to published.

Available from: 2011-05-26 Created: 2011-05-26 Last updated: 2013-04-19Bibliographically approved
3. 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 (ScopusID)
Note
QC 20100621. Uppdaterad från manuskript till artikel (20101209).Available from: 2010-06-21 Created: 2010-06-21 Last updated: 2011-05-26Bibliographically approved
4. In Situ Evaluation of Lipase Performances Through Dynamic Asymmetric Cyanohydrin Resolution
Open this publication in new window or tab >>In Situ Evaluation of Lipase Performances Through Dynamic Asymmetric Cyanohydrin Resolution
(English)Manuscript (preprint) (Other academic)
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-24147 (URN)
Note
QC 20100818Available from: 2010-08-18 Created: 2010-08-18 Last updated: 2011-05-26Bibliographically approved
5. Dynamic Asymmetric Hemithioacetal Transformation by Lipase-Catalyzed gamma-Lactonization: In Situ Tandem Formation of 1,3-Oxathiolan-5-one Derivatives
Open this publication in new window or tab >>Dynamic Asymmetric Hemithioacetal Transformation by Lipase-Catalyzed gamma-Lactonization: In Situ Tandem Formation of 1,3-Oxathiolan-5-one Derivatives
2012 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 18, no 20, 6129-6132 p.Article in journal (Refereed) Published
Abstract [en]

Dynamic hemithioacetal systems were efficiently generated in organic solvents and subsequently allowed to react with a range of lipases. This resulted in direct, dynamic asymmetric transformation of the systems, leading to optically active 1,3-oxathiolan-5-one products. The tandem process identified lipase-catalyzed lactonization as a useful method for the resolution of optimal constituents with high chemo- and stereoselectivities.

Keyword
asymmetric transformation, dynamic chemistry, enzyme catalysis, hemithioacetal, lactone, lipase
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-34125 (URN)10.1002/chem.201102139 (DOI)000303497600002 ()2-s2.0-84860758898 (ScopusID)
Funder
Swedish Research Council, 621-2010-4866
Note
Updated from in press to published. Previous title: Dynamic Asymmetric Hemithioacetal Resolution by Lipase-Catalyzed γ-Lactonization: In Situ Tandem Formation of 1,3-Oxathiolan-5-one DerivativesAvailable from: 2011-05-26 Created: 2011-05-26 Last updated: 2013-06-14Bibliographically 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 (ScopusID)
Funder
Swedish Research Council
Note
QC 20100621Available from: 2010-06-21 Created: 2010-06-21 Last updated: 2011-11-06Bibliographically approved

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