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Selectively substituted cyclodextrins for analytical and pharmaceutical applications
Benkovics, Gábor ; Jindřich, Jindřich (advisor) ; Lhoták, Pavel (referee) ; Šindelář, Vladimír (referee)
3 Selectively substituted cyclodextrins for analytical and pharmaceutical applications Abstract This thesis is focused on the selective modification of cyclodextrins, and its primary aim is the preparation and characterization of mono- and persubstituted derivatives of cyclodextrins in a regioselective and straightforward manner. The work is divided into two main parts describing synthetic strategies and applications of modified cyclodextrins with one or several substituents, respectively. The first section deals with the introduction of a single chromophoric moiety on the cyclodextrin scaffold such as cinnamyl, rhodaminyl, fluoresceinyl and eosinyl groups. The complete set of monocinnamyl-α-cyclodextrin regioisomers has been prepared by direct alkylation, and the self-assembling properties of the corresponding regioisomers were thoroughly investigated by dynamic light scattering and NMR experiments. These investigations revealed that the different isomers (mono-6-O-, mono-2-O- and mono-3-O- cinnamyl-α-cyclodextrin) form distinct supramolecular species through intermolecular association. A fast method for the unambiguous identification of the pure regioisomers has also been developed based on a series of 2D NMR measurements. Xanthene-modified β-cyclodextrins, other representatives of monosubstituted...
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Synthesis of beta-cyclodextrin derivatives for medicinal applications
Popr, Martin ; Jindřich, Jindřich (advisor) ; Veselý, Jan (referee)
Synthesis of monosubstituted β-cyclodextrin derivatives for medicinal applications Abstract This thesis is focused on preparation of a set of β-cyclodextrin derivatives with potential use as scaffolds for a construction of novel MRI contrast agents. Firstly, the skeleton of native β-CD was selectively persubstituted at possitions 6 and equipped with azide functions. Per-6-azido-β-CD was then monosubstituted on secondary face of the macrocycle. (E)-cinnamylbromide and propargylbromide were chosen as suitable reagents. The monosubstitution reaction afforded two types of regioisomers, substituted at position 2I -O- or 3I -O-. These regioisomers were sucessfully separated via preparative column chromatography after peracetylation of all free hydroxyl groups. 2I -O-, 3I -O-formylmethyl- and 3I -O- karboxymethyl- analogues were prepared by oxidative transformation of cinnamyl group. Finally the usability of the formylmethyl- derivative for covalent binding with suitable substrate via reductive amination was confirmed. Keywords: cyclodextrins, monosubstitution, cinnamyl, propargyl, formylmethyl, carboxymethyl, reductive amination, MRI, contrast agents
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Synthesis of cyclodextrin derivatives for practical applications
Popr, Martin
Synthesis of cyclodextrin derivatives for practical applications Abstract The first part of this PhD thesis is focused on the synthesis of a series of monosubstituted tetraalkylammonium cyclodextrin (CD) derivatives. The emphasis was placed on the possible applicability of the synthetic process to multigram or even industrial scale. Monotosylation of the native cyclodextrins (-, -, -) on the primary side of the macrocycle afforded the starting materials. Derivatives with one cationic group were prepared by the reaction with aqueous trimethylamine. The reaction of the mono-Ts-CD with neat N,N,N'-trimethylethane-1,2-diamine or N,N,N'-trimethylpropane-1,3-diamine and subsequent methylation led to derivatives with the substituent bearing two cationic groups (PEMEDA- and PEMPDA-β-CD). Analogs bearing a moiety with three tetraalkylammonium sites were synthesized by reaction of mono-Ts-CD with bis(3-aminopropyl)amine with subsequent methylation. 1,3-Dipolar cycloaddition of mono-6- azido--CD with diaminoacetylenes followed by methylation led to analogs with a avariable distance of the charged substituent from the CD core. Majority of the presented reactions are straightforward, relatively high-yielding and the workup does not require chromatographic steps. The second part of the work is dealing with the...
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Selectively substituted cyclodextrins for analytical and pharmaceutical applications
Benkovics, Gábor ; Jindřich, Jindřich (advisor) ; Lhoták, Pavel (referee) ; Šindelář, Vladimír (referee)
3 Selectively substituted cyclodextrins for analytical and pharmaceutical applications Abstract This thesis is focused on the selective modification of cyclodextrins, and its primary aim is the preparation and characterization of mono- and persubstituted derivatives of cyclodextrins in a regioselective and straightforward manner. The work is divided into two main parts describing synthetic strategies and applications of modified cyclodextrins with one or several substituents, respectively. The first section deals with the introduction of a single chromophoric moiety on the cyclodextrin scaffold such as cinnamyl, rhodaminyl, fluoresceinyl and eosinyl groups. The complete set of monocinnamyl-α-cyclodextrin regioisomers has been prepared by direct alkylation, and the self-assembling properties of the corresponding regioisomers were thoroughly investigated by dynamic light scattering and NMR experiments. These investigations revealed that the different isomers (mono-6-O-, mono-2-O- and mono-3-O- cinnamyl-α-cyclodextrin) form distinct supramolecular species through intermolecular association. A fast method for the unambiguous identification of the pure regioisomers has also been developed based on a series of 2D NMR measurements. Xanthene-modified β-cyclodextrins, other representatives of monosubstituted...
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Cyclodextrin derivatives for construction of supramolecular dendrimers
Kouřilová, Ema ; Jindřich, Jindřich (advisor) ; Veselý, Jan (referee)
This bachelor thesis deals with the synthesis of derivatives of α-, β- and γ-cyclodextrins which are potentially usable for the supramolecular dendrimers construction. These dendrimers could be used in medicinal chemistry as carriers of drugs or in other areas of chemistry as well. Firstly, the tosyloxy group of mono-6-O-tosylates of cyclodextrins was substituted with cyanoarylphenolates and then the intermediate permethylated at the remaining hydroxy groups. As reactants for monosubstitutions, 4-hydroxybenzonitrile and 4'-hydroxy-[1,1'-biphenyl]-4-carbonitrile were chosen. The reagent used for permethylations was iodomethane. In the last phase, attempts to trimerize the cyano groups of the permethylated derivatives under basic and acidic conditions were made, but the wanted product was not obtained. Key words: cyclodextrin, monosubstitution, dendrimer, nitrile trimerization, supramolecular polymers
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Synthesis of cyclodextrin derivatives for practical applications
Popr, Martin
Synthesis of cyclodextrin derivatives for practical applications Abstract The first part of this PhD thesis is focused on the synthesis of a series of monosubstituted tetraalkylammonium cyclodextrin (CD) derivatives. The emphasis was placed on the possible applicability of the synthetic process to multigram or even industrial scale. Monotosylation of the native cyclodextrins (-, -, -) on the primary side of the macrocycle afforded the starting materials. Derivatives with one cationic group were prepared by the reaction with aqueous trimethylamine. The reaction of the mono-Ts-CD with neat N,N,N'-trimethylethane-1,2-diamine or N,N,N'-trimethylpropane-1,3-diamine and subsequent methylation led to derivatives with the substituent bearing two cationic groups (PEMEDA- and PEMPDA-β-CD). Analogs bearing a moiety with three tetraalkylammonium sites were synthesized by reaction of mono-Ts-CD with bis(3-aminopropyl)amine with subsequent methylation. 1,3-Dipolar cycloaddition of mono-6- azido--CD with diaminoacetylenes followed by methylation led to analogs with a avariable distance of the charged substituent from the CD core. Majority of the presented reactions are straightforward, relatively high-yielding and the workup does not require chromatographic steps. The second part of the work is dealing with the...
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Synthesis of beta-cyclodextrin derivatives for medicinal applications
Popr, Martin ; Jindřich, Jindřich (advisor) ; Veselý, Jan (referee)
Synthesis of monosubstituted β-cyclodextrin derivatives for medicinal applications Abstract This thesis is focused on preparation of a set of β-cyclodextrin derivatives with potential use as scaffolds for a construction of novel MRI contrast agents. Firstly, the skeleton of native β-CD was selectively persubstituted at possitions 6 and equipped with azide functions. Per-6-azido-β-CD was then monosubstituted on secondary face of the macrocycle. (E)-cinnamylbromide and propargylbromide were chosen as suitable reagents. The monosubstitution reaction afforded two types of regioisomers, substituted at position 2I -O- or 3I -O-. These regioisomers were sucessfully separated via preparative column chromatography after peracetylation of all free hydroxyl groups. 2I -O-, 3I -O-formylmethyl- and 3I -O- karboxymethyl- analogues were prepared by oxidative transformation of cinnamyl group. Finally the usability of the formylmethyl- derivative for covalent binding with suitable substrate via reductive amination was confirmed. Keywords: cyclodextrins, monosubstitution, cinnamyl, propargyl, formylmethyl, carboxymethyl, reductive amination, MRI, contrast agents
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Synthesis of cyclodextrin derivatives for practical applications
Popr, Martin ; Jindřich, Jindřich (advisor) ; Kraus, Tomáš (referee) ; Šindelář, Vladimír (referee)
Synthesis of cyclodextrin derivatives for practical applications Abstract The first part of this PhD thesis is focused on the synthesis of a series of monosubstituted tetraalkylammonium cyclodextrin (CD) derivatives. The emphasis was placed on the possible applicability of the synthetic process to multigram or even industrial scale. Monotosylation of the native cyclodextrins (-, -, -) on the primary side of the macrocycle afforded the starting materials. Derivatives with one cationic group were prepared by the reaction with aqueous trimethylamine. The reaction of the mono-Ts-CD with neat N,N,N'-trimethylethane-1,2-diamine or N,N,N'-trimethylpropane-1,3-diamine and subsequent methylation led to derivatives with the substituent bearing two cationic groups (PEMEDA- and PEMPDA-β-CD). Analogs bearing a moiety with three tetraalkylammonium sites were synthesized by reaction of mono-Ts-CD with bis(3-aminopropyl)amine with subsequent methylation. 1,3-Dipolar cycloaddition of mono-6- azido--CD with diaminoacetylenes followed by methylation led to analogs with a avariable distance of the charged substituent from the CD core. Majority of the presented reactions are straightforward, relatively high-yielding and the workup does not require chromatographic steps. The second part of the work is dealing with the...
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