Kazimierz Chmurski

Intermolecular Interactions between Doxorubicin and β-Cyclodextrin 4-Methoxyphenol Conjugates

Newly synthesized derivatives of β-cyclodextrin, mono(6-deoxy-6-(1-1,2,3-triazo-4-yl)-1-propane-3-O-(4-methoxyphenyl))β-cyclodextrin (1) and mono(6-deoxy-6thio(1-propane-3-O-(4-methoxyphenyl))) β-cyclodextrin (2) were designed to be receptors of the anticancer drug doxorubicin, which could potentially decrease the adverse effects of the drug during treatment. In both aqueous and aqueous dimethyl sulfoxide (DMSO) solutions, doxorubicin forms an inclusion complex with the new cyclodextrin derivatives with formation constants of K(s) = 2.3 × 10(4) and K(s) = 3.2 × 10(5) M(-1) for cyclodextrins 1 and 2, respectively. The stabilities of the complexes are 2-3 orders of magnitude greater than those with native β-cyclodextrin, and the flexibility of the linker of the side group of the cyclodextrins contributes to this stability. In a hydrogen-bond-accepting solvent, such as pure DMSO, an association that includes hydrogen bonding and chloride ions is favored over the binding of doxorubicin in the cavity of the cyclodextrin derivative. This contrasts with an aqueous medium in which a strong inclusion complex is formed. Cyclic voltammetry, UV-vis, (1)H NMR, and molecular modeling studies of solutions in DMSO and of solutions in water/DMSO demonstrated that the two different modes of intermolecular interaction between doxorubicin and the cyclodextrin derivative depended on the solvent system being utilized.

Cyclodextrin Derivatives Conjugated with Aromatic Moieties as pH-responsive Drug Carriers for Anthracycline

The modification of cyclodextrins (CDs) with side chains containing aromatic groups was found to lead to an increase of the stability of the complex with the anticancer drug doxorubicin (Dox). The formation constants evaluated by voltammetry were several orders of magnitude larger than that of the unmodified β-CD ligand. For the CDs with aromatic moieties connected by linkers containing a triazole group, the formation constants of the complexes at pH 5.5 and 7.4 were very different. At lower pH, binding was much weaker as a result of protonation of the triazole moiety in the linker. The drug was then released from the complex. Molecular modeling of the Dox-β-CD system revealed different possible interactions between Dox and β-CD. The observed pH dependence of the complex formation constant can be exploited for drug delivery to the targeted cells. The toxicities of the synthesized complexes and each of the complex components were tested by the MTT assay on two cell lines, the human lung carcinoma and human cervical cancer cell lines.

A dynamic NMR study of self-inclusion of a pendant group in amphiphilic 6-thiophenyl-6-deoxycyclodextrins

Abstract The dynamic stereochemistry of amphiphilic derivatives of α-, β-, and γ-cyclodextrins ( 1 – 3 ) has been investigated by means of variable temperature 1 H and 13 C NMR spectroscopy in DMF-d 7 solutions. The most significant spectral changes were detected for the smallest hexakis(6-thiophenyl-6-deoxy)-α-cyclodextrin ( 1 ) and they decrease with the increase of the macrocycle size. On the basis of ROESY measurements, these changes reflecting restricted movements of thiophenyl groups upon the temperature decrease were interpreted in terms of self-inclusion of at least one thiophenyl group. Molecular modeling of these compounds is consistent with these findings.

Synthesis and monolayer behavior of amphiphilic per(2,3-di-O-alkyl)-α- and β-cyclodextrins and hexakis(6-deoxy-6-thio-2,3-di-O-pentyl)-α-cyclodextrin at an air–water interface

A synthesis of amphiphilic per(2,3-di-O-alkyl)-α- and β-cyclodextrins and hexakis(6-deoxy-6-thio-2,3-di-O-pentyl)-α-cyclodextrin and their monolayer behavior on a water surface is presented. Long alkyl chains were introduced by a treatment of the per(6-O-tert-butyldimethylsilyl) derivatives with an appropriate alkyl iodide in dimethylformamide in the presence of sodium hydride. A standard desilylation procedure followed by an iodination reaction afforded per(6-deoxy-6-iodo) analogues. In the latter reaction step, sulphur containing groups were introduced by nucleophilic substitution of the iodine with benzothiolate ion in dimethylformamide. The hexakis(6-deoxy-6-S-benzyl-2,3-di-O-pentyl)-α-cyclodextrin was transformed into extremely interesting hexakis(6-deoxy-6-thio-2,3-di-O-pentyl)-α-cyclodextrin. The surface pressure−mean molecular area (π−A) isotherms indicated that the synthesised amphiphilic cyclodextrin derivatives were capable of forming stable monolayers at the air–water interface. The shapes of the isotherms were typical for solid-like monolayers except for hexakis(6-deoxy-6-thio-2,3-di-O-pentyl)cyclomaltohexaoses which formed a more liquid monolayer.

Direct Synthesis of Amphiphilic α-, β-, and γ-Cyclodextrins

ABSTRACT The clean one step synthesis of the amphiphilic α-, β-, and γ-cyclodextrins starting from per-(6-bromo-6-deoxy)-α-, -β-, and -γ-cyclodextrins is described. The role of the lipophilic tail is played by various aryl groups (phenyl, p-bromophenyl, p-O-butoxyphenyl, p-pentylphenyl, and o-, m-, and p-nitrophenyl) linked by a thioether bridge to the position C-6 of each glucopyranose unit. The yields of the S-alkylation reactions were very high (85-95%).

Study of near-symmetric cyclodextrins by compressed sensing 2D NMR

The compressed sensing NMR (CS‐NMR) is an approach to processing of nonuniformly sampled NMR data. Its idea is to introduce minimal lp‐norm (0 < p ≤ 1) constraint to a penalty function used in a reconstruction algorithm. Here, we demonstrate that 2D CS‐NMR spectra allow the full spectral assignment of near‐symmetric β‐cyclodextrin derivatives (mono‐modified at the C6 position). The application of CS‐NMR ensures experimental time saving and the resolution improvement, necessary because of very low chemical shift dispersion. In the overnight experimental time, the set of properly resolved 2D NMR spectra required for the unambiguous assignment of mono(6‐deoxy‐6‐(1‐1,2,3‐triazo‐4‐yl)‐1‐propane‐3‐O‐(phenyl)) β‐cyclodextrin was obtained. The highly resolved HSQC spectrum was reconstructed from 5.12% of the data. Moreover, reconstructed 2D HSQC–TOCSY spectrum yielded information about the correlations within one sugar unit, and 2D HSQC–NOESY technique allowed the sequential assignment of the glucosidic units. Copyright

Long-chain-linked β-cyclodextrin dimers: Synthesis and relationship between reactivity and inclusion complex formation

We synthesized ditopic compounds bearing two β-cyclodextrin moieties linked by long aryl-alkyl linkers. The process of linker inclusion into β-cyclodextrin cavity was observed during Sharpless click-chemistry conjugation. The target cyclodextrin dimers exhibit self-complexation via a glucose unit inversion phenomenon that is significantly weaker as compared with earlier reported analogs. It was confirmed that both cavities of such cyclodextrin dimers are available for interaction with larger guest molecules.

The effect of urea moiety in amino acid binding by β-cyclodextrin derivatives: A 1000-fold increase in efficacy comparing to native β-cyclodextrin

Water soluble amphiphilic anion receptors based on urea-substituted β-cyclodextrin were synthesized via a copper(I) mediated azide-alkyne coupling reaction. The synthetic route was designed to minimize the number of operations of cyclodextrins. Stable products were obtained in 90% yield. They were successfully tested as amino acid receptors, showing excellent affinity constants (103-104M-1) in a highly competitive environment (pH 8 phosphate-buffered water solution). Isothermal titration calorimetry indicated that complex formation strongly depends on the hydrophobic nature of the guest and that the urea moiety of the receptor is necessary to efficiently bind amino acids.

Molecular building blocks: chromophoric amphiphilic cyclodextrin derivatives

Abstract The primary hydroxyl face of β-cyclodextrin can be selectively modified with ortho-, meta-, and para-nitro-thiophenol groups. Rigid alignment of the chromophoric groups has been obtained in the formation of mono-molecular layers at the air-water interface.

pH-Controlled recognition of amino acids by urea derivatives of β-cyclodextrin

Water soluble amphiphilic urea-substituted β-cyclodextrins were synthesized and applied as amino acid receptors. A great affinity towards nonpolar amino acids was observed, ranging from 2300 M−1 for alanine to 54 800 M−1 for tryptophan in a highly competitive environment (pH 8 phosphate-buffered water solution). Significant selectivity was observed, since carboxylates without the amino group (or having hydroxyl instead) remained not bound. Endoenthalpic effects were recorded for amino acids during titrations, pointing to a different mode of complex formation as compared to native β-cyclodextrin. We found a dramatic change in binding strength within the physiological pH range: with pH change from 8 to 6, affinity towards amino acids dropped from 54 000 to 500 M−1, making the receptors potentially appropriate for biotechnological purposes.