alpha-, beta-, and gamma-Cyclodextrin dimers. Molecular modeling studies by molecular mechanics and molecular dynamics simulations.

The alpha-, beta-, and gamma-cyclodextrin (CyD) dimers have been studied by molecular mechanics (MM) and molecular dynamics (MD) calculations, and the relative stability of dimers and the involved molecular interactions have been determined. Three possible orientations were considered for the alpha-, beta-, and gamma-CyD dimers: the head-to-head, the head-to-tail, and the tail-to-tail. In vacuo MM calculations were used to obtain the most stable arrangements, and MD simulations were performed over all energy minima obtained for each dimer. Results from MD always show head-to-head orientation as the most stable as a result of the larger number of intermolecular hydrogen bonds present.     

Formation process of cyclodextrin necklace-analysis of hydrogen bonding on a molecular level

By means of scanning tunneling microscopy (STM), we succeeded for the first time in the quantitative analysis of the intramolecular conformation of a supramolecule, cyclodextrin (CyD) necklace, driven by hydrogen bonding. Contrary to the current model, based on macroscopic analyses, which indicates that all CyDs are arranged in head-to-head or tail-to-tail (secondary-secondary or primary-primary hydrogen bonding) conformation, about 20% head-to-tail (primary-secondary hydrogen bonding) conformation was found to exist in the molecule. In addition, comparing the STM results with the theoretical model of the necklace formation, the formation ratio of the tail-to-tail and head-to-tail conformations due to the strength difference between primary-primary and primary-secondary hydrogen bonds of CyDs was directly obtained, for the first time, to be 2:1.     

Investigating the impact of regiochemistry in ester functionalized polyfurans

In this study, the impact of ester side group regiochemistry on electronic and conformational properties of regioregular polyfurans was explored. A derivative with alternating head-to-head and tail-to-tail orientation of the side groups was synthesized and compared with its head-to-tail analogue, and these were benchmarked against the related regioregular poly(3-hexylfurans). The study revealed that alkyl ester side groups in a head-to-head orientation will create significant steric strain as compared with linear alkyl chains with identical regiochemistry. Though the head-to-head ester side groups lead to twisting along the polymer backbone, they also produce a protective effect against photodegradation in comparison with a poly(3-hexylfuran). Altogether, the work highlights how side groups can impact conformational properties and stability of polyfurans.     

Absorption enhancement of polypeptide drugs by cyclodextrins. I. Enhanced rectal absorption of insulin from hollow-type suppositories containing insulin and cyclodextrins in rabbits.

The absorption of insulin (from porcine pancreas) from the rectum of rabbits after the administration of hollow-type suppositories containing insulin and five kinds of cyclodextrins (CyDs) was investigated. Three types of suppositories were employed: suppository I containing insulin (approximately 26 IU/mg) and various amounts of each CyD in citric buffer solution at pH 3.0 or powder in its cavity, suppository II containing CyD without insulin, and suppository III containing insulin without CyD. Without CyD, the insulin and glucose levels in plasma were unchanged, whereas a significant increase in the plasma insulin concentration and a marked decrease in the glucose levels were found following simultaneous administration of insulin and CyDs by suppository I. The enhancing effect of CyD on rectal insulin absorption (absorption-enhancing effect) by chemically modified CyDs (heptakis(2,6-di-O-methyl)-beta-CyD (DM-beta-CyD) and 2-hydroxypropyl-beta-CyD (HP-beta-CyD)) was higher than those by natural CyDs (alpha-, beta-, and gamma-CyD). The area under the plasma concentration-time curve (AUC) and Cmax of insulin significantly decreased with the preadministration (administration of CyD 6, 24 and 48 h before rectal insulin administration) of DM-beta-CyD. The absorption-enhancing effect disappeared 24 h after preadministration. These results suggest that CyDs enhance insulin absorption from the rectum, and that attenuation of the membrane transport barrier function in the rectum recovers at a maximum of 24 h after administration of CyDs.     

Theoretical study of the alpha-cyclodextrin dimer

The molecular structure, stabilization energy, and thermodynamic properties of the plausible modes of the interaction for the three possible alpha-cyclodextrin (alpha-CD) dimers (head-to-head, tail-to-tail, and head-to-tail) with a water cluster were obtained using quantum chemical methods for the first time. Nine distinct spatial arrangements were investigated. The head-to-head mode of interaction with water is preferred by more than 10 kcal.mol(-1) (BLYP/6-31G(d,p)//PM3 Gibbs free energy difference value at room temperature) in relation to the next stable structure, with a water dimer structure placed inside each cavity and cyclic water tetramers surrounding each tail end. The inter alpha-CD hydrogen bonds play a major role to stabilize the dimeric structures, with no water tetramer being found between the two alpha-CD subunits for the preferred global minimum structure. Therefore, a theoretical model aimed to describe the behavior of alpha-CD dimer, or their inclusion complexes, in the aqueous media should take into account this preference for binding of the water molecules.     

Inclusion effect and structural basis of cyclodextrins for increased extraction of medicinal alkaloids from natural medicines

The enhancing effects of alpha-, beta-, and gamma-cyclodextrins (CyDs) on the aqueous extraction of ephedrine and berberine from the natural medicines were investigated in HPLC analysis, and the greatest effect was observed for beta- and gamma-CyDs. To clarify the structural basis of such an increased extraction effect with beta-CyD, possible interaction modes of (1R,2S)-ephedrine with alpha-, beta-, and gamma-CyDs were investigated using molecular dynamic simulations in an aqueous solution system. It was shown that the wrapping model of ephedrine by beta-CyD is the most compact and thus increases the solubility most effectively, compared with those by other CyDs. The same mode could be possible for the greatest effect of gamma-CyD on the extraction of berberine from natural medicines. This clearly shows that CyDs are useful additives for the effective extraction of bioactive alkaloids from natural medicines.     

Anomalous mixing behavior of polyisobutylene/polypropylene blends: molecular dynamics simulation study

The unusual mixing behavior of polyisobutylene (PIB) with head-to-head (hhPP) and head-to-tail polypropylene (PP) is studied using large-scale molecular dynamics (MD). The heats of mixing and Flory chi parameters were computed from MD simulations of both blends using a united atom model. The chi parameters from the simulations were estimated from the structure factors using the random phase approximation in analogy with neutron scattering (SANS) experiments. MD simulations for syndiotactic hhPP/PIB predicted a lower critical solution temperature with a chi parameter in very good agreement with SANS experiments on the atactic hhPP/PIB blend. MD simulations also predicted that the isotactic PP/PIB blend was immiscible at high molecular weight in qualitative agreement with cloud point measurements on atactic PP/PIB.     

Regioselective Oligomerization of 3-(Alkylsulfanyl)thiophenes with Ferric Chloride

The action of FeCl(3) on 3-(alkylsulfanyl)thiophenes (3-(alkylthio)thiophenes) leads to the one-step formation of regioregular alpha-conjugated oligothiophenes, from trimer to octamer, depending on the solvent used and on the length of the alkyl chain. The regiochemistry of these oligomers is characterized by one inner head-to-head linkage between adjacent rings and by a variable number of lateral head-to-tail junctions. The reaction of ferric chloride with the head-to-head and head-to-tail bis(methylsulfanyl)-2,2'-bithiophenes gives the corresponding tetramers, while the reaction with the tail-to-tail counterpart affords a high molecular weight insoluble material. With the aid of theoretical calculations, these results are interpreted on the basis of the joint effects of the orienting power of the substituents and of the stability of the radical cations formed during the oxidative process.     

Spatial arrangement of alpha-cyclodextrins in a rotaxane. Insights from free-energy calculations

The rotaxane formed by alpha-cyclodextrins (alpha-CDs) threaded onto a poly(ethylene glycol) (PEG) chain was investigated in the gas phase and in an aqueous solution by means of molecular dynamics simulations. The free-energy difference between the three possible spatial arrangements of consecutive alpha-CD--viz.. head-to-head (HH), head-to-tail (HT), and tail-to-tail, was determined using free-energy perturbation calculations. These simulations reveal that the interaction of alpha-CD with the PEG chain is very similar in the two surroundings, whereas the mutual interaction of the macrocycles is stronger in the gas phase than in the aqueous solution. Moreover, difference in the overall interaction appears to stem primarily from changes in the electrostatic contribution. Analysis of intermolecular hydrogen bonds indicates that hydrogen bonds created between alpha-CD and water molecules weaken the hydrogen-bonding interaction of adjacent alpha-CDs. Comparison of the free-energy differences characteristic of the three possible spatial arrangements of contiguous alpha-CDs reveals that the HH motif of the rotaxane is the most stable in the gas phase due to the hydrogen-bond formation between the secondary hydroxyl groups of the two alpha-CDs, and the slight preference for the HT motif in aqueous solution, which can be related to the directionality of the dipole moment borne by the macrocycles in these two motifs.     

Side-Chain Interactions in d/l Peptide Nanotubes: Studies by Crystallography,NMR Spectroscopy and Molecular Dynamics

Our understanding of the factors affecting the stability of cyclic d/l peptide (CP) nanotubes remains underdeveloped. In this work, we investigate the impact of side chain alignment, hydrophobicity and charge on CP nanotube stability through X-ray crystallography, NMR spectroscopy and molecular dynamics (MD) simulations. We characterise the distinct CP-CP alignments that can form and identify stable and unstable dimers by MD simulation. We measure H-bond half-lives of synthesised CPs by ¹H−D exchange experiments and find good correlation with predicted CP-CP stabilities. We find that hydrophobic amino acids improve CP dimer stability but experimentally reduce solubility. Charged amino acids either increase or decrease CP dimer stability depending on the relative orientation and composition of charged groups. X-ray crystal structures are solved for two CPs, revealing non-tubular folded conformations. Ultimately, this work will assist the educated design of stable tubular structures for potential applications in biomedicine.     

Circular dichroic investigation of factors that affect inclusion complexes of cyclodextrins as a drug carrier

Drug/cyclodextrin (CyD) inclusion complexes have become one of the most widely used approaches to increase aqueous solubility of poorly soluble drugs, to increase their bioavailability and stability, to reduce undesirable side effects and prevent drug–drug and drug–excipient interactions. Although drug molecules as well as CyDs exhibit detectable changes in their physicochemical properties upon complexation, to date, the interaction of CyDs with drugs is not well understood. So far, only few methods can be applied to obtain structural information on drug/CyD complexes. Circular dichroism spectroscopy (CD) has often been used to study molecular binding, nevertheless, rarely do these studies exploit the full potential of optical techniques. The objective of this article is to highlight important factors that affect drug/CyD binding interaction in particular β-CyD. On the basis of chirality, (S)-(+)-ibuprofen, meta-chlorobenzoic acid and aspirin were used to study binding interaction with β-CyD using CD. Based on CD equations for a simple 1:1 binding complex, the Levenberg–Marquadt non-linear equation was used for binding analysis and the production of simulated graphical presentations to explain the effect of various factors that influence the binding reaction and the binding curve. The results show reliability indicated by the binding constant which is in agreement with literature values. In addition, the effect of guest/host concentrations and the extent of binding on the inclusion complexes are elucidated with accuracy. This work provides useful information that can prove valuable in drug binding studies.     

Stereoprogrammed direct synthesis of calixarene-based [3]rotaxanes

Directional calixarene wheels were threaded along a bis(benzylalkylammonium) axle in a stereoprogrammed way to obtain the first examples of calixarene-based [3]rotaxanes. The base/acid treatment demonstrated that these systems act as nanosized molecular shuttles. An unprecedented switching between the tail-to-tail and head-to-head relative orientation of the calix-wheels was observed.     

Enhancing effect of cyclodextrins on nasal absorption of insulin and its duration in rabbits.

The absorption of insulin (from porcine pancreas) in rabbits after the nasal administration of aqueous preparations containing insulin and five kinds of cyclodextrins (CyDs) in phosphate buffer solution at pH 7.0 was investigated. Without CyD, the insulin and glucose levels in plasma were unchanged, whereas a marked increase in the plasma levels of insulin and a decrease in glucose concentrations were observed following the simultaneous administration of insulin and CyD such as alpha- and heptakis (2,6-di-O-methyl)-beta-CyD (DM-beta-CyD). The largest enhancing effect on the nasal absorption of insulin was obtained by DM-beta-CyD. To evaluate the duration of the absorption-enhancing effect of CyDs, preadministration (administration of CyD 0.5, 6, 12 and 24 h before insulin administration) was performed. The area under plasma concentration-time curve (AUC) and Cmax of insulin significantly decreased with the preadministration of DM-beta-CyD 6, 12 and 24 h before nasal administration. The absorption-enhancing effect disappeared 24h after the preadministration. These findings demonstrate that CyDs enhance the nasal absorption of insulin, and the recovery of the membrane transport barrier function in nasal mucosa is achieved, at the latest, 24 h after the administration of CyDs.     

Interactions of cyclodextrins with aromatic amino acids: a basis for protein interactions

Cyclodextrins (CyD) have proven effects on the stability of proteins and can be used in the formulation of aggregation prone therapeutic proteins. This effect stems from specific interactions between the CyD (preferably β-CyD) and solvent exposed amino acid residues. Here the interaction with hydrophobic aromatic amino acid residues stands out and the interaction between CyDs and these amino acid residues holds the key to understanding the observed effects, which CyDs exerts on proteins and peptides. Here we present a comparative study of the interactions between free and peptide bound aromatic amino acids and their derivatives with α, β and γ-CyDs using NMR spectroscopy. We propose a novel, quantitative means of assessing the penetration depth of guest molecules in CyD cavities, the penetration gauge Π, and apply it to the observed interaction patterns from ROESY NMR spectra. We demonstrate that the penetration depths of the aromatic rings within the CyDs rely highly on the nature of the remainder of the guest molecule. Thus the presence of charges, neighboring amino acids and the specific positioning on the surface of a protein highly influences the penetration depth and geometry of guest–CyD interactions.     

Two-phase channel structures based on alpha-cyclodextrin-polyethylene glycol inclusion complexes

Wide-angle X-ray scattering observations of alpha-cyclodextrin (CD)-poly(ethylene glycol) (PEG) inclusion complexes (ICs) have shown for the first time that two crystalline columnar modifications (forms I and II) are produced in the process of their formation. This was made possible by precise azimuthal X-ray diffraction scanning of oriented IC samples. Form I is characterized by CDs threaded onto PEG chains and arranged along channels in the order head-to-head/tail-to-tail, while form II is formed by unbound CDs also arranged into columns in a head-to-tail and also possibly a head-to-head/tail-to-tail manner, probably as a result of template crystallization on the form I IC crystals. It was shown that similar structural peculiarities are inherent for channel structures based on ICs obtained with PEG with a wide range of molecular weights (MWs). The characteristic feature of ICs based on PEG, especially with MW > 8000, is the presence of unbound polymer in the composition of the complex. The amount of unbound PEG was shown to rise with increasing MW of PEG, resulting in greater imperfections in the IC crystalline structure. The polyblock structure of ICs based on alpha-CD and PEG was therefore proposed.     

Towards the stability limit of cyclic diphosphonium bis-ylides

A typology of molecules containing two phosphonium ylide groups (bis-ylides) is proposed, versus the bridge length (fused, ω- and α-bisylides) and their relative topographical orientations (head-to-head, tail-to-tail or head-to-tail). The formal electrostatic constraint occurring in the head-to-head series is systematically addressed for cyclic representatives based on the o-bis(diphenylphosphonio)benzene framework. After a survey of previously reported results in the fused and β-bis-ylide series, emphasis is given to the cyclic α-bis-ylides. The non-substituted, non-stabilized version escaped isolation through spontaneous fragmentation to bis(diphenylphosphino)benzene and acetylene. Inspired by this result, the reverse process was employed for the generation of stabilized representatives with ethoxycarbonyl and benzoyl substituents at the ylidic carbon atoms. The stability and stereochemistry of the obtained head-to-head α-bis-ylides was investigated by NMR techniques and reproduced and analyzed by DFT calculations. The role of electrostatics in determining structural and reactivity features of cyclically constrained species is here illustrated.     

Role of ions on structure and stability of a synthetic gramicidin ion channel in solution. A molecular dynamics study

We performed a molecular dynamics (MD) simulation to the investigate structure and stability of a synthetic gramicidin-like peptide in solution with and without ions. The starting structures of the MD simulations were taken from two recently solved NMR structures of this peptide in isotropic solution, which forms stable monomers or dimers in the presence or absence of ions, respectively. The monomeric structure is channel-like and is assumed to be stabilized by the presence of two Cs(+) ions bound in the channel, each one close to one channel entrance. In our MD simulations, we observed how the Cs(+) ions bind in the channel formed by the monomeric gramicidin-like peptide using implicit solvent and explicit ions with a concentration of 2 M. MD simulations were performed with and without explicit ions but with an implicit solvent model defined by the generalized Born approximation, which was used to mimic the dielectric properties of the solvent and to speed up the computations.     

Expanding the registry of aromatic amide foldamers: folding, photochemistry and assembly using diaza-anthracene units

The synthesis of various 1,8-diaza-4,5-dialkoxy-2,7-anthracene dicarboxylic acid derivatives and their incorporation into cyclic and helically folded aromatic oligoamides are reported. The ability of the diaza-anthracene monomers to undergo photoaddition or head-to-tail photodimerization was investigated in the solid state and in solution. Quantitative conversion of a monomer diester to the corresponding head-to-tail photodimer could be achieved in the solid state without protection from oxygen. The formation of an emissive excimer between two diaza-anthracene units appended at the end of a helically folded oligomer was demonstrated. Intramolecular photodimerization was not observed in this compound, possibly due to the low thermal stability of the head-to-head photoadduct. A cyclic oligoamide composed of two diaza-anthracene and two pyridine units was shown to adopt a flat conformation and to form columnar stacks in the solid state. Longer, noncyclic oligoamides composed of one or two diaza-anthracene units were shown to adopt helical conformations that exist preferentially as double helical dimers.     

New Acyclic Dimers of Cholic Acid with Oxamide and Hydrazide Spacers

Summary. Three new acyclic dimers of cholic acid with oxamide and isomeric hydrazide (N,N′-diacylhydrazine) spacers were obtained. The oxamide spacers bind two identical steroidal subunits through position 3 (head-to-head dimer) or position 23 (tail-to-tail dimer). In the case of a third dimer the hydrazine moiety binds two molecules of cholic acid through position 24 (tail-to-tail dimer).     

Polymerization of ordered tail-to-tail vinyl stearate bilayers

This study is a continuation of previous work done in this laboratory which has demonstrated the possibility of polymerizing built-up monomer multilayers in the solid state. In the present work, the formation, structure, and solid-state polymerization of multilayers of vinyl stearate which can be built up by the method of Langmuir and Blodgett were studied. A new technique to polymerize such films under the water surface was developed. This made possible the formation of poly(vinyl stearate) multilayers with different molecular orientations through bilayer polymerization. The mechanism of deposition and the structure and properties of head-to-tail and head-to-head, tail-to-tail poly(vinyl stearate) multilayers were investigated by using Fourier-Transform infrared spectroscopy, x-ray diffraction, and electron diffraction.