Metal-binding cyclodextrins: Synthesis and complexation with Zn and Ga cations towards antimicrobial applications.

Highly resistant bacteria producing metallo-β-lactamases (MBLs) to evade β-lactam antibiotics, constitute a major cause of life-threatening infections world-wide. MBLs exert their hydrolytic action via Zn cations in their active center. Presently, there are no approved drugs to target MBLs and combat the associated antimicrobial resistance (AMR).

Continuous flow synthesis of 6-monoamino-6-monodeoxy-β-cyclodextrin.

The first continuous flow method was developed for the synthesis of 6-monoamino-6-monodeoxy-β-cyclodextrin starting from native β-cyclodextrin through three reaction steps, such as monotosylation, azidation and reduction. All reaction steps were studied separately and optimized under continuous flow conditions. After the optimization, the reaction steps were coupled in a semi-continuous flow system, since a solvent exchange had to be performed after the tosylation.

Fully Symmetric Cyclodextrin Polycarboxylates: How to Determine Reliable Protonation Constants from NMR Titration Data.

Acid-base properties of cyclodextrins (CDs), persubstituted at C-6 by 3-mercaptopropionic acid, sualphadex (Suα-CD), subetadex (Suβ-CD) and sugammadex (Suγ-CD, the antidote of neuromuscular blocking steroids) were studied by H NMR-pH titrations. For each CD, the severe overlap in protonation steps prevented the calculation of macroscopic p values using the standard data fitting model. Considering the full symmetry of polycarboxylate structures, we reduced the number of unknown NMR parameters in the "Q-fitting" or the novel "equidistant macroscopic" evaluation approaches.

Sugammadex analogue cyclodextrins as chiral selectors for enantioseparation of cathinone derivatives by capillary electrophoresis.

The present contribution describes the application of three single-isomeric cyclodextrin derivatives for the first time - Sugammadex, Subetadex and Sualphadex as chiral selectors. Their recognition ability was investigated by means of chiral capillary electrophoresis, on a pool of cathinone and amphetamine derivatives. The selectors differ in cavity sizes and in the number of ionizable groups which evidently influenced their enantioselectivity performance.

Testing the Protective Effects of Sulfobutylether-Βeta-Cyclodextrin (SBECD) and Sugammadex against Chlorpromazine-Induced Acute Toxicity in SH-SY5Y Cell Line and in NMRI Mice.

Chlorpromazine (CPZ) is an antipsychotic drug which can cause several adverse effects and drug poisoning. Recent studies demonstrated that CPZ forms highly stable complexes with certain cyclodextrins (CDs) such as sulfobutylether-β-CD (SBECD) and sugammadex (SGD). Since there is no available antidote in CPZ intoxication, and considering the good tolerability of these CDs even if when administered parenterally, we aimed to investigate the protective effects of SBECD and SGD against CPZ-induced acute toxicity employing in vitro (SH-SY5Y neuroblastoma cells) and in vivo (zebrafish embryo) models.

Structural characterization of methyl-β-cyclodextrins by high-performance liquid chromatography and nuclear magnetic resonance spectroscopy and effect of their isomeric composition on the capillary electrophoresis enantioseparation of daclatasvir.

The separation of daclatasvir and its R,R,R,R-enantiomer was studied by capillary electrophoresis using various randomly methylated β-CDs and the single isomer heptakis(2,6-di-O-methyl)-β-CD (2,6-DM-β-CD) as chiral selectors in an acidic background electrolyte. Opposite enantiomer migration order was observed for randomly substituted CDs compared to 2,6-DM-β-CD as well as methylated β-CDs with different composition according to the specifications of the manufacturers. HPLC and NMR analyses confirmed that the presence of a high 2,6-DM-β-CD content in the CDs enables to achieve the migration order R,R,R,R-enantiomer > daclatasvir.

Complexation of daclatasvir by single isomer methylated β-cyclodextrins studied by capillary electrophoresis, NMR spectroscopy and mass spectrometry.

In capillary electrophoresis an enantioseparation of daclatasvir (DCV) was observed in case of heptakis(2,6-di-O-methyl)-β-CD, heptakis(2-O-methyl)-β-CD and β-CD, while two peaks with a plateau were noted for heptakis(2,3,6-tri-O-methyl)-β-CD and heptakis(2,3-di-O-methyl)-β-CD indicating a slow equilibrium. Heptakis(6-O-methyl)-β-CD and heptakis(3-O-methyl)-β-CD yielded broad peaks. Nuclear magnetic resonance experiments including nuclear Overhauser effect-based techniques revealed inclusion complex formation for all CDs with the biphenyl ring of DCV within the cavity and the valine-pyrrolidine moieties protruding from the torus.

Facile synthesis of per(6-O-tert-butyldimethylsilyl)-α-, β-, and γ-cyclodextrin as protected intermediates for the functionalization of the secondary face of the macrocycles.

Per(6-O-tert-butyldimethylsilyl)-α-, β- and γ-cyclodextrin derivatives are well-known as synthetic intermediates that enable the selective mono-, partial, or perfunctionalization of the secondary face of the macrocycles. Although silylation of the primary rim is readily achieved by treatment with tert-butyldimethylsilyl chloride in the presence of pyridine (either alone or mixed with a co-solvent), the reaction typically results in a mixture containing both under- and oversilylated byproducts that are difficult to remove. To address this challenge in preparing a pure product in high yield, we describe an approach that centers on the addition of a controlled excess of silylating agent to avoid the presence of undersilylated species, followed by the removal of oversilylated species by column chromatography elution with carefully designed solvent mixtures.

Single isomer cyclodextrins as chiral selectors in capillary electrophoresis.

Since decades, cyclodextrins are one of the most powerful selectors in chiral capillary electrophoresis for the enantioseparation of diverse organic compounds. This review concerns papers published over the last decade (from 2009 until nowadays), dealing with the capillary electrophoretic application of single isomer cyclodextrin derivatives in chiral separations. Following a brief overview of their synthetic approaches, the inventory of the neutral, negatively and positively charged (including both permanently ionic and pH-tunable ionizable substituents) and zwitterionic CD derivatives is presented, with insights to underlying structural aspects by NMR spectroscopy and molecular modeling.

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.

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 CE. 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.

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.

Synthesis of the chiral selector heptakis(6-O-methyl)-β-cyclodextrin by phase-transfer catalysis and hydrazine-mediated transfer-hydrogenation.

The exhaustive primary-side alkylation of cyclodextrins has never been achieved directly. The undesired and simultaneous derivatization of the secondary hydroxyl moieties generates intricate isomeric mixtures that are challenging to purify, analyse and characterize. The aim of this study was to develop a chromatography-free and up-scalable strategy towards the preparation of per-6-O-methylated cyclodextrin and to test the compound as potential chiral selector.

Enhanced single-isomer separation and pseudoenantiomer resolution of new primary rim heterobifunctionalized α-cyclodextrin derivatives.

The synthesis of batch-to-batch reproducible cyclodextrin (CD) derivatives often requires functionalization at specific positions of the CD skeleton. However, the regioselective preparation of this type of CD derivatives remains a challenge in synthetic chemistry. Thus, the present study aimed to prepare all positional regioisomers on the primary rim of homobifunctionalized diazido-α-CDs by selective substitution on the primary rim.

Mannoside and 1,2-mannobioside β-cyclodextrin-scaffolded NO-photodonors for targeting antibiotic resistant bacteria.

Two β-cyclodextrin derivatives randomly appended on the primary face with both the nitric oxide (NO) photodonor 4-nitro-3-(trifluoromethyl)aniline and a mannose or α(1→2)mannobioside residue are reported to construct targeted NO photoreleasing nanocarriers. 2D ROESY and PGSE NMR suggested supramolecular homodimerization in water by inclusion of the nitroaniline group into the facing macrocycle cavities. Isothermal titration calorimetry on their concanavalin A lectin binding showed an exothermic binding event to the lectin and an endothermic process during the dilution of the conjugates.

Widening the Therapeutic Perspectives of Clofazimine by Its Loading in Sulfobutylether β-Cyclodextrin Nanocarriers: Nanomolar IC Values against MDR S. epidermidis.

Clofazimine (CLZ) is an antibiotic with a promising behavior against Gram-positive bacteria; however, the drug is completely insoluble in water and accumulates in fat tissues. We explored nanocarriers, labeled and not labeled with rhodamine, consisting of negatively charged sulfobutylether-β-cyclodextrins for CLZ loading. A new oligomeric carrier was obtained cross-linking βCyD with epichlorohydrin followed by sulfonation in a strongly alkaline aqueous medium.

Synthesis, analytical characterization and capillary electrophoretic use of the single-isomer heptakis-(6-O-sulfobutyl)-beta-cyclodextrin.

This contribution reports the synthesis, characterization and capillary electrophoretic application of heptakis-(6-O-sulfobutyl-ether)-β-cyclodextrin sodium salt, (6-(SB)-β-CD). The compound was obtained through a five-steps synthesis and it represents the first example of single-isomer sulfobutylated cyclodextrin that carries the negatively charged functions exclusively on its primary side and it is unmodified on the lower rim. The purity of each intermediate was determined by appropriate liquid chromatographic methods, while the isomeric purity of the final product was established by an ad-hoc developed HPLC method based on a CD-Screen-IEC column.

Delivery of cyclodextrin polymers to bacterial biofilms - An exploratory study using rhodamine labelled cyclodextrins and multiphoton microscopy.

Cyclodextrin (CD) polymers are interesting nanoparticulate systems for pharmaceutical delivery; however, knowledge regarding their applications towards delivery into complex microbial biofilm structures is so far limited. The challenge is to demonstrate penetration and transport through the biofilm and its exopolysaccharide matrix. The ideal functionalization for penetration into mature biofilms is unexplored.

Cyclodextrin-mesoporous silica particle composites for controlled antibiotic release. A proof of concept toward colon targeting.

Cyclodextrins (CDs) and mesoporous silica particles (MSPs) have been combined as composite carriers for controlled antibiotic release. CDs were employed as "gatekeeper" agents and grafted onto MSPs to retain drug molecules inside the MSP carrier. A variety of CDs (unfunctionalized, positively charged and carboxymethylated) and three different coupling strategies (covalent binding, electrostatic adsorption and inclusion complexation) were systematically investigated for their ability to control the release of two antibiotic drugs, metronidazole and clofazimine.

Efficient loading of ethionamide in cyclodextrin-based carriers offers enhanced solubility and inhibition of drug crystallization.

Ethionamide (ETH) is a second line antitubercular drug suffering from poor solubility in water and strong tendency to crystallize. These drawbacks were addressed by loading ETH in β-cyclodextrin (βCyD)-based carriers. The drug was incorporated in a molecular state avoiding crystallization even for long-term storage and obtaining a tenfold increased solubility up to 25mM.

Designed positively charged cyclodextrin hosts with enhanced binding of penicillins as carriers for the delivery of antibiotics: The case of oxacillin.

In an effort to identify the optimal cyclodextrin (CD) host for delivery of penicillins to mammalian cells that will also offer protection against β-lactamase-induced hydrolysis, nuclear magnetic resonance (NMR) spectroscopy and isothermal titration calorimetry (ITC) have been employed to study the inclusion complexes formed in aqueous solution between designed CD derivatives and two aminopenicillins, ampicillin and amoxicillin, and two antistaphylococcal penicillins, methicillin and oxacillin. Anionic and cationic thioether-substituted-β- and -γCD derivatives were thus synthesized and compared with the neutral, parent CDs for complexation with the penicillins. The synthesized derivatives were shown to present ∼20% elongated cavity space in solution.

The 'Visualized' macrocycles: Chemistry and application of fluorophore tagged cyclodextrins.

Cyclodextrins are macrocyclic molecules able to form host-guest complexes due to their hydrophobic cavity. Because of their carbohydrate nature they do not absorb light in the UV-vis region (200-800nm), but they can be converted into spectroscopically active compounds via modification with a chromophore unit. Among the chromophores, the group of fluorophores can provide high sensitivity in analytical applications (chemosensing) and low detection limit in optical imaging methods (fluorescent microscopy).

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.

Characterization of a single-isomer carboxymethyl-beta-cyclodextrin in chiral capillary electrophoresis.

In this work, the synthesis, characterization, and chiral capillary electrophoretic study of heptakis-(2,3-di-O-methyl-6-O-carboxymethyl)-β-CD (HDMCM), a single-isomer carboxymethylated CD, are presented. The pH-dependent and selector concentration-dependent enantiorecognition properties of HDMCM were investigated and discussed herein. The enantioseparation was assessed applying a structurally diverse set of noncharged, basic, and zwitterionic racemates.