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%).     

NHC-Activations on α-, β-, γ-, and Beyond

Over the recent decades, due to the special electronic characteristics and diverse reactivities, N-heterocyclic carbene (NHC) has received significant interest in organocatalyzed reactions. The formation of Breslow intermediates by NHC can convert into acyl anion equivalent, enolates, homoenolate, acyl azolium, and vinyl enolate etc., and the cycloaddition reactions of these species has attracted lots of attention. In this review, we focus on the summry of the development of NHC-activation of carbonyl carbon (or imine carbon) in situ, α-, β-, γ-, and beyond, and the cycloaddition reaction of these species.     

Nucleation of the β-hairpin structure in a linear hybrid peptide containing α-, β- and γ-amino acids

Synthesis and conformational studies of a short linear peptide containing a pyrrole amino acid (1, Paa) and a furan amino acid (2, Faa), namely Boc-hGly-Faa-d-Pro-Gly-Paa-hGly-Faa-OMe (3), were carried out in which it was established that peptide 3 adopted a well-defined β-hairpin structure in DMSO-d₆.     

Binding behaviors of scutellarin with α-, β-, γ-cyclodextrins and their derivatives

A series of cyclodextrin/scutellarin inclusion complexes were prepared from α-cyclodextrin, β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin with scutellarin (SCU), and their inclusion complexation behaviors, such as stoichiometry, complex stability constants and inclusion mode, were investigated by means of UV/Vis spectroscopy, ¹H NMR and 2D NMR. The results showed that the SCU could be efficiently encapsulated in the cyclodextrin cavity in aqueous solution to produce complexes that were more soluble than free SCU. The enhanced binding ability of cyclodextrins towards SCU was discussed from the viewpoint of the size/shape-fit and multiple recognition mechanism between host and guest.     

Complexes of α-, β-, and γ-cyclodextrins with nitrophenols: A theoretical study of the structure and energy

Detailed quantum mechanical calculations of the interaction of cyclodextrin (α-, β-, and γ-CD) with 4-nitrophenol (I), 4-nitro-2,6-dimethylphenol (II), 4-nitro-3,5-dimethylphenol (III), and their anions (IVVI) with the formation of intercalation complexes are carried out for the first time. The calculations of the compounds are performed within the density functional theory by the hybrid Becke–Lee–Yang–Parr (B3LYP) method with LanL2DZ basis sets. For the α-CD+III and α-CD+VI complexes it is shown that a nitrophenol molecule of III and a nitrophenolate anion of VI are not contained in the α-CD torus, which agrees with the experimental equilibrium constants. It is found that the calculated equilibrium constants of the formation of guest–host complexes with phenolate anions are much larger than those of neutral molecules. The most stable CD complexes with nitrophenols and their anions should be expected for γ-CD. The β-CD complexes when the guest enters into the host cavity are formed only with compounds I, V, and VI.     

Thermal Behaviour of Anhydrous α-, β- and γ-Cyclodextrin at Low Temperature

Heat capacities of anhydrous -and -cyclodextrin were measured by adiabaticcalorimetry between 10 K and 300 K. The thermalbehaviour of the two compounds exhibits significantdifferences. -Cyclodextrin shows an anomalousexcess heat capacity in the entire region between 70 Kand 210 K. In the case of -cyclodextrin, anendothermic effect is observed at 240K. This effect isanalysed through the study of the correspondingentropy change and discussed in terms ofintramolecular organization.Using the known heat capacity values of anhydrous-CD, a comparative analysis has been developed.For each cyclodextrin, the average behaviour of abound -D-glucopyranose has been calculated andcompared. From a thermodynamic point of view, thedegree of organization of the dehydrated macrocycliccompounds could be expressed as-CD -CD -CD.     

An investigation of the complexation of a TTF derivative with α-, β- and γ-cyclodextrins in aqueous media

This Letter, describes the complexation of α-, β- and γ-cyclodextrins (1-3) with TTF derivative 4 in water. In particular, we show using ¹H, ¹³C NMR, UV-vis spectroscopy and isothermal titration calorimetry that β-cyclodextrin 2 forms an effective complex with 4. Complex 2·4 can be conveniently disassembled upon the addition of 1-adamantanol.     

Interaction of naproxen with α-, β-, and γ-hydroxypropyl cyclodextrins in solution and in the solid state

Solid combinations of naproxen with amorphous hydroxypropyl derivatives of -, -, and -cyclodextrin with an average substitution degree per anhydroglucose unit of 0.6 were investigated for thermal behaviour (differential scanning calorimetry), drug crystallinity (X-ray diffractometry), and dissolution rate (dispersed amount and rotating disc methods). Phase-solubility analysis and computer-aided molecular modelling were carried out to study the inclusion complexation of naproxen with hydroxypropyl cyclodextrins. The cavity size of the host is a selective factor for the solubilizing effect, complexing ability, and dissolution rate enhancement on naproxen, hydroxypropyl -cyclodextrin being markedly the most effective derivative. No relationship was found between the decrease in crystallinity of the drug dispersed in the amorphous carrier matrix and the geometrical features of the cyclodextrin macrocycle.     

Synthetic Approaches to α-, β-, γ-, and δ-Lycoranes

Lycorane is a pentacyclic core presented in alkaloids isolated from the Amaryllidaceae family of herbaceous flowering plants. Members of this class of natural products have shown to display important biological properties including analgesic, antiviral, and antiproliferative activities. This review presents the known synthetic routes toward α-, β-, γ-, and δ-lycoranes. α-(19 routes), β-(10 routes), γ-(38 routes), and δ-(6 routes).     

Spectroscopic characterization of the binding and isomerization cycle of Brooker’s merocyanine with α-, β-, and γ-cyclodextrins

Complexes of Brooker’s merocyanine dye with α-, β- and γ-cyclodextrin (CD) have been characterized to determine the relative strength and thermodynamics of binding, as well as the effect of binding on the protolytic-photochemical isomerization cycle of the dye. It was found that the dye binds most tightly to β-CD, with a binding equilibrium constant of 430 M^?1, in agreement with previous results (Hamasaki et al. J. Incl. Phenom. Mol. Rec. Chem. 13, 349–359 (1992)), while α-CD and γ-CD complexes have a binding constant of approximately 110 M^?1 and 70 M^?1, respectively, determined using absorbance and fluorescence spectroscopy. The isomerization cycle for the dye in α- and γ-CD complexes was found to be the same as for the free dye. Complexation with β-CD, however, resulted in depressed trans-to-cis photoisomerization in acidic conditions followed by spontaneous cis-to-trans isomerization (with the addition of base). Thermodynamic results also indicated differences between α-CD (ΔS° = ?48 J K^?1) and β-CD (ΔS° =  +12 J K^?1) complexes. There was no temperature dependence observed for the γ-CD complexes. These results can be justified in terms of the location of the dye molecule within the cyclodextrin cavity for each of the complexes.     

Distribution of α-, β-, and γ-Phases in a Multi-flow Injection-molded Hierarchical Structure

In the current work, a custom-made vibration injection molding device that can provide oscillatory pressure was utilized to create an injection-molded hierarchical structure. Growth competition among α, β, and γ phases in the injection-molded structure can be studied because of the presence of this hierarchical structure, wherein shish-kebab and spherulite layers were arranged alternately along the thickness direction. The γ crystals only existed in layers subjected to high pressure and shear stress, whereas β crystals formed between the shear layers. The change in trend of the γ fraction was similar to that of parent-to-daughter ratio. In addition, this hierarchical and alternating crystal structure can sharply increase the mechanical properties.     

The Interactions of Titanocene Dihalides with α-, β- and γ-cyclodextrin Host Molecules

The inclusion of titanocene dihalides (X = F, Cl) into -, - and -cyclodextrin hosts was studied by NMR spectroscopy, thermal analysis and mass spectrometry. It was found that -cyclodextrin does not form inclusion complexes with titanocene halides whereas - and -cyclodextrin do form such complexes. According to the changes in NMR spectra we propose that there is a shallow penetration of a guest molecule of titanocene dihalide into the cavity in the case of -cyclodextrin, but deeper penetration in the case of -cyclodextrin. The stability of the latter inclusion complexes was studied by NMR shift titration.     

A thermodynamic study of α-, β-, and γ-cyclodextrin-complexed m-methyl red in alkaline solutions

The UV/Visible spectra of m-methyl red (m-MR) ({3-[4-(dimethyl-amino) phenylazo] benzoic acid}) were examined in basic, acidic and strongly acidic aqueous solutions. The observed spectra of m-MR were analyzed and compared with the tautomeric and resonance structures that suggested theoretically. Three isosbestic points in the spectra were observed around 508, 464 and 443 nm representing three different equilibriums between four different species of m-MR. The inclusion constant (K_f) for the inclusion of basic form of m-MR with alpha-, Beta-, and gamma-Cyclodextrin (α-, β- and γ-CD) was evaluated at different temperatures using Benesi-Hildebrand method. The values of K_f at 25 °C were found to be 8.70 × 10³, 4.93 × 10³ mol^?1 dm³ and 2.95 × 10⁷ mol^?2 dm⁶ basis on the inclusion complex ratios (m-MR:CD) of 1:1, 1:1, and 2:1 respectively. The values of the thermodynamic quantities ΔH°, ΔS°, ΔG° for the different inclusion processes were calculated by using Van’t Hoff plot. For all cases of the studied inclusion processes, these inclusions were favored through entropy and enthalpy changes.     

The Synthesis of Substituted α, β-Butenolides from γ-Hydroxy-α, β-Acetylenic Esters

Abstract

The α, β-butenolide ring system is found in a number of physiologically important natural products² and there has been recent interest in the development of methods of synthesis of compounds of this type.³ It is well known that α, β-unsubstituted butenolides may be prepared by catalytic hydrogenation of γ-hydroxy acetylenic acids.^4,5b Recently, an excellent route of γ-hydroxy acetylenic esters which involves the addition of the lithium acetylide salts of propiolic esters to aldehydes⁵ and ketones⁶ has become available. We have carried out the addition of ethyl lithiopropiolate (1) to cyclohexanone (2) and 4-t-butylcyclohexanone (3) and wish to report the conversion of these adducts into corresponding β-methyl or β-methyl-α-allyl-α, β-butenolides.     

Investigation on the Interaction of Bendazac with β-, Hydroxypropyl-β-, and γ-, yclodextrins

The interactions of Bendazac, a topical non-steroidal anti-inflammatory drug, with-cyclodextrin, hydroxypropyl--cyclodextrin and -cyclodextrinwere investigated to evaluate possibilities to improve the drug's poor water solubilityand eventually to enhance the topical delivery of Bendazac. Phase solubility studiesdemonstrated the ability of the selected cyclodextrins to complex with Bendazac andincrease drug solubility. The amount of solubilized Bendazac increased linearly withthe addition of each cyclodextrin according toA_L type plots. ¹³C-NMR studiesshowed that the Bendazac A-ring was included in the cavity of the three cyclodextrins.The -cyclodextrin was also able to include the B-ring of Bendazac, forminga complex where one drug molecule fitted into two cyclodextrin molecules. Equimolarsolid systems of the drug with each cyclodextrin carrier were prepared using varioustechniques (physical mixing, spray-drying and freeze-drying). The results of differential scanning calorimetry and Fourier transform infrared analysis, performed on the solid systems, demonstrated that freeze-dried and spray-dried products had a high degree of amorphization and agreed with the hypothesis of the existence of drug–cyclodextrin interaction in the solid state. The cyclodextrins tested were able to improve the dissolution of Bendazac. The dissolution profile of the drug was also affected by the physico-chemical properties of each solid system, the freeze-dried products being the most rapidly dissolving forms.     

Stabilization of β-hairpin structures via inter-strand π-π and hydrogen bond interactions in α-, β-, γ-hybrid peptides

Synthesis and conformational studies of α-, β-, γ-hybrid peptides containing a pyrrole amino acid (Paa, 1) and a furan amino acid (Faa, 2), namely Boc-β-Phe-Faa-d-Pro-Gly-Paa-β-HGly-Faa-OMe (3) and Boc-Paa-β-Phe-Faa-d-Pro-Gly-Paa-β-HGly-Faa-OMe (4), were carried out and they adopt β-hairpin structures stabilized via inter-strand π-π and hydrogen bonding interactions.     

Effect of pH and α-, β- and γ-cyclodextrin on the spectral properties of etoricoxib: spectroscopic and molecular dynamics study

The spectral properties of etoricoxib (ETR) at pH 2.0, 6.0 and 10.0 in the presence of cyclodextrins (CDs) were investigated. The absorption spectrum of ETR in acidic medium exhibited two bands centered at 236 and 273 nm, while in basic medium it exhibited two bands centered at 236 and 285 nm. No change in the spectrum was observed in the presence of CDs. The fluorescence emission spectra of ETR in acidic and basic media exhibited one band at 380 nm and another one at 484 nm. The emission band at 484 nm was enhanced when ETR was complexed with β-CD and γ-CD at pH 2.0, 6.0 and 10.0, while the band at 380 nm was enhanced selectively when ETR was complexed with α-CD at pH 2.0. Molecular dynamics simulations computations revealed that at pH 2.0, the sulfonyl moiety of H₂ETR²⁺ is preferentially included within the α-CD cavity, which is believed to cause the enhancement of the band at 380 nm. Moreover, at pH 6.0 and 10.0, the enhancement of the band at 484 nm was related to the inclusion of the chloropyridinyl and methylpyridinyl groups of the bipyridine moiety of HETR⁺ and ETR within β-CD and γ-CD cavities. Benesi–Hildebrand analysis showed that the ETR/β-CD complex adopts a 1:1 stoichiometry with association constant of K ₁₁?=?64.8 at pH 2.0, K ₁₁?=?105.4 at pH 6.0 and K ₁₁?=?520.5 at pH 10.0.