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Benkovics G.,Cyclodextrin R and D Ltd. | Benkovics G.,Charles University | Afonso D.,University of Catania | Darcsi A.,Semmelweis University | And 6 more authors.
Beilstein Journal of Organic Chemistry | Year: 2017

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. © 2017 Benkovics et al.; licensee Beilstein-Institut.


Aykac A.,University of Almeria | Aykac A.,Izmir Kâtip Celebi University | Noiray M.,University Paris - Sud | Malanga M.,Cyclodextrin R and D Ltd. | And 6 more authors.
Biochimica et Biophysica Acta - General Subjects | Year: 2017

Background: Metal-organic framework nanoparticles (nanoMOFs) are biodegradable highly porous materials with a remarkable ability to load therapeutic agents with a wide range of physico-chemical properties. Engineering the nanoMOFs surface may provide nanoparticles with higher stability, controlled release, and targeting abilities. Designing postsynthetic, non-covalent self-assembling shells for nanoMOFs is especially appealing due to their simplicity, versatility, absence of toxic byproducts and minimum impact on the original host-guest ability. Methods: In this study, several β-cyclodextrin-based monomers and polymers appended with mannose or rhodamine were randomly phosphorylated, and tested as self-assembling coating building blocks for iron trimesate MIL-100(Fe) nanoMOFs. The shell formation and stability were studied by isothermal titration calorimetry (ITC), spectrofluorometry and confocal imaging. The effect of the coating on tritium-labeled AZT-PT drug release was estimated by scintillation counting. Results: Shell formation was conveniently achieved by soaking the nanoparticles in self-assembling agent aqueous solutions. The grafted phosphate moieties enabled a firm anchorage of the coating to the nanoMOFs. Coating stability was directly related to the density of grafted phosphate groups, and did not alter nanoMOFs morphology or drug release kinetics. Conclusion: An easy, fast and reproducible non-covalent functionalization of MIL-100(Fe) nanoMOFs surface based on the interaction between phosphate groups appended to β-cyclodextrin derivatives and iron(III) atoms is presented. General significance: This study proved that discrete and polymeric phosphate β-cyclodextrin derivatives can conform non-covalent shells on iron(III)-based nanoMOFs. The flexibility of the β-cyclodextrin to be decorated with different motifs open the way towards nanoMOFs modifications for drug delivery, catalysis, separation, imaging and sensing. This article is part of a Special Issue entitled "Recent Advances in Bionanomaterials" Guest Editors: Dr. Marie-Louise Saboungi and Dr. Samuel D. Bader. © 2017 Elsevier B.V.


Anand R.,CNR Institute of Neuroscience | Malanga M.,Cyclodextrin RandD Ltd. | Manet I.,CNR Institute of Neuroscience | Manoli F.,CNR Institute of Neuroscience | And 7 more authors.
Photochemical and Photobiological Sciences | Year: 2013

Two citric acid crosslinked γ-cyclodextrin oligomers (pγ-CyD) with a MW of 21-33 kDa and 10-15 γ-CyD units per molecule were prepared by following green chemistry methods and were fully characterized. The non-covalent association of doxorubicin (DOX) with these macromolecules was investigated in neutral aqueous medium by means of circular dichroism (CD), UV-vis absorption and fluorescence. Global analysis of multiwavelength spectroscopic CD and fluorescence titration data, taking into account the DOX monomer-dimer equilibrium, evidenced the formation of 1:1 and 1:2 pγ-CyD unit-DOX complexes. The binding constants are 1-2 orders of magnitude higher than those obtained for γ-CyD and depend on the characteristics of the oligomer batch used. The concentration profiles of the species in solution evidence the progressive monomerization of DOX with increasing oligomer concentration. Confocal fluorescence imaging and spectral imaging showed a similar drug distribution within the MCF-7 cell line incubated with either DOX complexed to pγ-CyD or free DOX. In both cases DOX is taken up into the cell nucleus without any degradation. © 2013 The Royal Society of Chemistry and Owner Societies.


Benkovics G.,Charles University | Benkovics G.,Cyclodextrin R and D Ltd. | Hodek O.,Charles University | Havlikova M.,Charles University | And 7 more authors.
Beilstein Journal of Organic Chemistry | Year: 2016

This work focuses on the preparation and application of supramolecular structures based on mono-cinnamyl-α-cyclodextrins (Cin-α-CD). Pure regioisomers of Cin-α-CD having the cinnamyl moiety at the 2-O-or at the 3-O-position, respectively, were prepared, characterized and applied in capillary electrophoresis as additives to the background electrolyte. These new monomer units with a potential to self-organize into supramolecular structures were synthesized via a straightforward one-step synthetic procedure and purified using preparative reversed-phase chromatography allowing a large scale separation of the regioisomers. The ability of the monomers to self-assemble was proved by various methods including NMR spectroscopy and dynamic light scattering (DLS). The light scattering experiments showed that the monomer units have distinguishable ability to form supramolecular structures in different solvents and the size distribution of the aggregates in water can be easily modulated using different external stimuli, such as temperature or competitive guest molecules. The obtained results indicated that the two regioisomers of Cin-α-CD formed different supramolecular assemblies highlighting the fact that the position of the cinnamyl group plays an important role in the intermolecular complex formation. © 2016 Benkovics et al; licensee Beilstein-Institut.


Malanga M.,Cyclodextrin RandD Ltd | Darcsi A.,Semmelweis University | Balint M.,Cyclodextrin RandD Ltd | Benkovics G.,Cyclodextrin RandD Ltd | And 3 more authors.
Beilstein Journal of Organic Chemistry | Year: 2016

Xanthene dyes can be appended to cyclodextrins via an ester or amide bridge in order to switch the fluorescence on or off. This is made possible through the formation of nonfluorescent lactones or lactams as the fluorophore can reversibly cyclize. In this context we report a green approach for the synthesis of switchable xanthene-dye-appended cyclodextrins based on the coupling agent 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM). By using 6-monoamino-β-cyclodextrin and commercially available inexpensive dyes, we prepared rhodamine- and fluorescein-appended cyclodextrins. The compounds were characterized by NMR and IR spectroscopy and MS spectrometry, their UV-vis spectra were recorded at various pH, and their purity was determined by capillary electrophoresis. Two potential models for the supramolecular assembly of the xanthene-dyeappended cyclodextrins were developed based on the set of data collected by the extensive NMR characterization. © 2016 Malanga et al; licensee Beilstein-Institut.


Fejos I.,Semmelweis University | Varga E.,Cyclodextrin RandD Ltd | Benkovics G.,Cyclodextrin RandD Ltd | Benkovics G.,Charles University | And 6 more authors.
Journal of Chromatography A | Year: 2016

The enantioselectivity of neutral single-isomer synthetic precursors of sulfated-β-cyclodextrins was studied. Four neutral single-isomer cyclodextrins substituted on the secondary side with acetyl and/or methyl functional groups, heptakis(2-O-methyl-3,6-dihydroxy)-β-cyclodextrin (HM-β-CD), heptakis(2,3-di-O-acetyl-6-hydroxy)-β-cyclodextrin (HDA-β-CD), heptakis(2,3-di-O-methyl-6-hydroxy)-β-cyclodextrin (HDM-β-CD), heptakis(2-O-methyl-3-O-acetyl-6-hydroxy)-β-cyclodextrin (HMA-β-CD), and their sulfated analogs the negatively charged heptakis(2,3-di-O-methyl-6-sulfato)-β-cyclodextrin (HDMS-β-CD) and heptakis(2,3-di-O-acetyl-6-sulfato)-β-cyclodextrin (HDAS-β-CD) were investigated by non-aqueous capillary electrophoresis in the view of enantiodiscrimination for various drugs and related pharmaceutical compounds. The focus of the present work was on the chiral selectivity studies of the neutral derivatives, which are the synthesis intermediates of the sulfated products. The chiral recognition experiments proved that among the neutral compounds the HMA-β-CD shows remarkable enantioselectivity towards chiral guests in non-aqueous capillary electrophoresis, while HM-β-CD, HDA-β-CD and HDM-β-CD failed to resolve any of the 25 studied racemates under the applied experimental conditions. In order to get deeper insight into the molecular interactions between the studied single-isomer cyclodextrin and chiral fluoroquinolones (ofloxacin, gatifloxacin and lomefloxacin) and β-blockers (propranolol), 1H and ROESY NMR experiments were performed. The 2-O-methylation in combination with the 3-O-acetylation of the host was evidenced to exclusively carry the essential spatial arrangement for chiral recognition. © 2016 Elsevier B.V.


Anand R.,CNR Institute for Organic Syntheses and Photoreactivity | Manoli F.,CNR Institute for Organic Syntheses and Photoreactivity | Manet I.,CNR Institute for Organic Syntheses and Photoreactivity | Donzello M.P.,University of Rome La Sapienza | And 5 more authors.
RSC Advances | Year: 2014

A nitro-benzofurazan-triazolyl carboxymethylated β-cyclodextrin (NBFT-CMβCyD) and an oligomer of carboxymethyl β-cyclodextrin (sodium salt), crosslinked with epichlorohydrin and labeled with rhodaminyl groups (pβCyD-Rh), exhibit very high affinity in aqueous solution for octacationic photosensitizer [(CH3)8LZn]8+ neutralized by I- ions (L = tetrakis-2,3-[5,6-di(2-(pyridiniumyl)pyrazino] porphyrazinato dianion). The photosensitizer (PS) forms complexes with 1 : 2 and 2 : 2 CyD:PS stoichiometry, which were characterized as binding constants and UV-Vis absorption and fluorescence properties. The self-association tendency of [(CH3)8LZn]8+, leading to a monomer-dimer equilibrium shift towards the dimer even at very low concentrations (≈10 -6 M), is not contrasted by either NBFT-CMβCyD or the pβCyD-Rh oligomer, both of which completely convert the [(CH 3)8LZn]8+ monomer fraction to the dimer form in the bound state. Quenching of fluorescence observed in [(CH3) 8LZn]8+ upon binding with either hosts is consistent with the conversion of the monomer to the negligibly fluorescent dimer. The complexes formed with the CMβCyD units of the pβCyD-Rh oligomer have average association constants, which are larger by 6-7 orders of magnitude than those with the CMβCyD monomer in the NBFT-labeled derivative. © 2014 the Partner Organisations.

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