Homo and hetero-difunctionalized β-cyclodextrins: Short direct synthesis in gram scale and analysis of regiochemistry

The regioselective difunctionalization of cyclodextrins (CDs) leading to derivatives amenable to further transformations is a daunting task due to challenging purification and unambiguous characterization of the obtained regioisomers with similar physicochemical properties. The primary-side homo-difunctionalization of β-CD can lead to three regioisomers, while the hetero-difunctionalization can generate three pairs of pseudoenantiomers. Previously, approaches with several synthetic steps, expensive reagents, high purification demands and low yields of the products have been employed. Herein we present direct, short and efficient primary-side difunctionalization strategies featuring reproducibility, ease of product purification, scalability of the reactions and versatility of the substituents introduced. Specifically, the prepared ditosylated β-CDs were separated using preparative reversed-phase column chromatography and their structures were elucidated by NMR experiments. Azidation led to the corresponding pure diazido regioisomers. Direct monotosylation of 6-monoazido-β-CD or monoazidation of the single regioisomers 6A,6X-ditosyl-β-CDs afforded hetero-difunctionalized 6A-monoazido-6X-tosyl-β-CDs in significant yields. Overall, the single regioisomers, 6A,6X-ditosyl-, 6A,6X-diazido- and 6A-monoazido-6X-monotosyl-β-CD were prepared in one or two steps and purified in multigram scale thus opening the way towards further selective and orthogonal functionalizations of β-CD hosts

Novel β-cyclodextrin–eosin conjugates

Eosin B (EoB) and eosin Y (EoY), two xanthene dye derivatives with photosensitizing ability were prepared in high purity through an improved synthetic route. The dyes were grafted to a 6-monoamino-β-cyclodextrin scaffold under mild reaction conditions through a stable amide linkage using the coupling agent 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride. The molecular conjugates, well soluble in aqueous medium, were extensively characterized by 1D and 2D NMR spectroscopy and mass spectrometry. Preliminary spectroscopic investigations showed that the β-cyclodextrin–EoY conjugate retains both the fluorescence properties and the capability to photogenerate singlet oxygen of the unbound chromophore. In contrast, the corresponding β-cyclodextrin–EoB conjugate did not show either relevant emission or photosensitizing activity probably due to aggregation in aqueous medium, which precludes any response to light excitation

Comparative analysis of the full set of methylated β-cyclodextrins as chiral selectors in capillary electrophoresis

The chiral separation ability of the full library of methylated-β-cyclodextrins towards pharmacologically significant racemic drugs including basic compounds was studied by chiral capillary electrophoresis. The syntheses of all the methylated, single isomer β-cyclodextrins were revised and optimized and the aqueous solubility of the derivatives was unambiguously established. The three most relevant commercially available methylated isomeric mixtures were also included in the screening, so a total of ten various methylated CDs were investigated. The effects of the selector concentration on the enantiorecognition properties at acidic pH was investigated. Among the dimethylated β-cyclodextrins, the heptakis (2,6-di-O-methyl)-β-cyclodextrin isomer (2,6-DIMEB) resulted the most versatile chiral selector. Terbutaline was selected as a model compound for the in-depth investigation of host-guest enantiodiscrimination ability. The association constants between the two terbutaline enantiomers and 2,6-DIMEB were determined in order to support that the enantioseparation is driven by differences is host-guest-binding. The migration order of the enantiomers was confirmed by performing spiking experiments with the pure enantiomers. 1D and 2D NMR spectroscopy was applied to the 2,3-, and 2,6-DIMEB/terbutaline systems to rationalize at molecular level the different enantioseparation ability of the dimethylated β-cyclodextrin selectors. This article is protected by copyright. All rights reserved

Az új algoritmusok és kódolási eljárások alkalmazása a mobil hírközlésben és informatikában = Application of new algorithms and coding procedures in mobile communications and computing

A kutatási munka során az alábbi résztémákban értünk el eredményeket: - mobil IP, - all IP hálózatok, - útkeresési algoritmusok, - hívásátadási algoritmusok, - mobil technológiák együttműködése, - a szolgáltatás minősége (QoS), - a mobil és informatikai hálózatok és rendszerek biztonsági kérdései, - több-felhasználós vétel, - kódosztásos többszörös hozzáférés, - forgalmi modellezés, - kódkonstrukció kódosztásos technológiákhoz, - kvantum számítástechnikai eljárások, - gráfelmélet, - kombinatorikus optimalizálás. A fenti szakterületeken végzett kutatásaink eredményei közül azokat emeljük ki, amelyeket az alábbi témákban értünk el: - A heterogén mobil hálózatok együttműködési problémái, - A mobil Internet Protokoll alkalmazásával kapcsolatos vizsgálatok, - Többfelhasználós detekciós módszerek a kódosztásos többszörös hozzáféréses mobil rendszerekben, - A heterogén mobil hálózatok forgalmi modellezése, - A mobil informatikai és távközlési hálózatok, rendszerek és szolgáltatások - biztonsági kérdései, - Kvantum számítástechnika és mérnöki alkalmazásai, - Útkeresési és csatornakijelölési algoritmusok fejlesztése és vizsgálata mobil hálózatok számára, alkalmazott gráfelmélet. A kutatásban résztvevők az eredményeket három megvédett PhD disszertációban, egy benyújtás előtt álló akadémiai doktori értekezésben és több beadás előtt álló PhD értekezésben használták fel. A tudományos iskola publikációs listája 135 elemből áll. | The members of the Scientific School have got new results in the following scientific fields: - Mobile IP, all IP networks, - Routing algorithms, - Hand-over algorithms, - Interworking of heterogeneous mobile technologies, - Quality of services (QoS), - Security problems of mobile and information networks and systems, - Multi-user detection, - Code division multiple access, - Traffic modeling, - Code construction for code division technologies, - Quantum computing, - Graph theory, - Combinatorial optimization. On the above mentioned scientific field we have the most important results in the following areas: - Interoperability issues of heterogeneous mobile networks, - Investigations on the applicability of mobile Internet Protocol, - Multi-user detection methods in code division multiple access systems, - Traffic models of heterogeneous mobile networks, - Security issues of mobile information and telecommunication networks, systems and services, - Quantum computing and its engineering applications, - Development and research of routing and channel assigning algorithms for mobile networks, application of the graph theory. The participants of the research used their results in three defended PhD theses, in a dissertation for DSc title, and in some other PhD theses before the final process. The number of the publications of the Scientific School is 135

Design of engineered cyclodextrin derivatives for spontaneous coating of highly porous metal-organic framework nanoparticles in aqueous media

Nanosized metal-organic frameworks (nanoMOFs) MIL-100(Fe) are highly porous and biodegradable materials that have emerged as promising drug nanocarriers. A challenging issue concerns their surface functionalization in order to evade the immune system and to provide molecular recognition ability, so that they can be used for specific targeting. A convenient method for their coating with tetraethylene glycol, polyethylene glycol, and mannose residues is reported herein. The method consists of the organic solvent-free self-assembly on the nanoMOFs of building blocks based on beta-cyclodextrin facially derivatized with the referred functional moieties, and multiple phosphate groups to anchor to the nanoparticles’ surface. The coating of nanoMOFs with cyclodextrin phosphate without further functional groups led to a significant decrease of macrophage uptake, slightly improved by polyethylene glycol or mannose-containing cyclodextrin phosphate coating. More notably, nanoMOFs modified with tetraethylene glycol-containing cyclodextrin phosphate displayed the most effcient “stealth” effect. Mannose-coated nanoMOFs displayed a remarkably enhanced binding affnity towards a specific mannose receptor, such as Concanavalin A, due to the multivalent display of the monosaccharide, as well as reduced macrophage internalization. Coating with tetraethylente glycol of nanoMOFs after loading with doxorubicin is also described. Therefore, phosphorylated cyclodextrins o er a versatile platform to coat nanoMOFs in an organic solvent-free, one step manner, providing them with new biorecognition and/or “stealth” properties

Selectively substituted cyclodextrins for analytical and pharmaceutical applications

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..

Selectively substituted cyclodextrins for analytical and pharmaceutical applications

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..

Selektivně susbstituované cyklodextriny pro analytické a farmaceutické aplikace

5 Selektivně susbstituované cyklodextriny pro analytické a farmaceutické aplikace Abstrakt Tato práce se zabývá selektivní modifikací cyklodextrinů. Jejím hlavním cílem je příprava a charakterizace mono- a persubstituovaných derivátů cyklodextrinu syntetizovaných regioselektivně a přímočaře. Práce je tedy rozdělena na dvě hlavní části popisující syntetické přístupy a aplikace modifikovaných cyklodextrinů jednak s jedním substituentem, jednak s více substituenty. První část představuje cyklodextrinové skelety s jednou chromoforní skupinou, jako je cinammylová, rhodaminylová, fluoresceinylová a eosinylová funkční skupina. Kompletní série regioisomerů monocinammylových derivátů α-CD byla připravena pomocí přímé alkylace a jejich samoskladné vlastnosti byly následně podrobně zkoumány pomocí metod dynamického rozptylu světla a NMR. Tento výzkum odhalil, že jednotlivé regioisomery (mono-6-O-, mono-2-O- a mono-3-O-cinnamyl-α-cyklodextriny) jsou schopny tvořit rozdílná supramolekulární uskupení pomocí intermolekulárních asociací. Byla vyvinuta rychlá metoda pro jednoznačnou identifikaci čistých regioisomerů na základě série změřených 2D spekter. Byly syntetizovány deriváty β-cyklodextrinu s xantinovým skeletem, představující další zástupce monosubstituovaných cyklodextrinů. Byly vyvinuty nové syntetické strategie...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...Katedra organické chemieDepartment of Organic ChemistryPřírodovědecká fakultaFaculty of Scienc