Cyclodextrins structure

Numerous examples of modiflcations to the fundamental cyclodextrin structure have appeared in the literature.The aim of much of this work has been to improve the catalytic properties of the cyclodextrins, and thus to develop so-called artificial enzymes. Cyclodextrins themselves have long been known to be capable of catalyzing such reactions as ester hydrolysis by interaction of the guest with the secondary hydroxyl groups around the rim of the cyclodextrin cavity. The replacement, by synthetic methods, of the hydroxyl groups with other functional groups has been shown, however, to improve remarkably the number of reactions capable of catalysis by the cyclodextrins. For example, Breslow and CO workersreported the attachment of the pyridoxamine-pyridoxal coenzyme group to beta cyclodextrin, and thus found a two hundred-fold acceleration of the conversion of indolepyruvic acid into tryptophan. 

Some modifications to the cyclodextrin structure have also been found to improve their complexing ability. Casu and coworkers prepared 2,3,6-tri-O-methyl and 2,6-di-O-methyl derivatives of alpha and beta cyclodextrin. They observed that tri-O-methyl-alpha cyclodextrin shows an almost ten-fold increased stability of the complex with the guest, Methyl Orange, compared with the unmodified alpha cyclodextrin. A possible reason for this increase in stability is that the methyl groups are responsible for an extension of the hydrophobic cavity of the cyclodextrin. Other workers,however, observed a much smaller enhancement of stability of complexes on methylation of the cyclodextrin, and a decrease in stability has even been reportedfor the one host-two guests complex of tropaeolin with beta cyclodextrin. Thus, the effect of methylation on the stability of a complex varies with the guest species involved, and cannot be readily predicted. 

Some other interesting modifications of the gamma cyclodextrin structure have been made by the group of Ueno and coworkers. By the... 

Figure 5. A model of the / -cyclodextrin structure. The hydroxy groups can be (partially) derivatized so as to alter the structure and also to facilitate immobilization chemistry.

Berzas Nevado et al. [138] developed a new capillary zone electrophoresis method for the separation of omeprazole enantiomers. Methyl-/ -cyclodextrin was chosen as the chiral selector, and several parameters, such as cyclodextrin structure and concentration, buffer concentration, pH, and capillary temperature were investigated to optimize separation and run times. Analysis time, shorter than 8 min was found using a background electrolyte solution consisting of 40 mM phosphate buffer adjusted to pH 2.2, 30 mM /1-cyclodextrin and 5 mM sodium disulfide, hydrodynamic injection, and 15 kV separation voltage. Detection limits were evaluated on the basis of baseline noise and were established 0.31 mg/1 for the omeprazole enantiomers. The method was applied to pharmaceutical preparations with recoveries between 84% and 104% of the labeled contents. 

Figure 6.23 Schematic representation of the packing of cyclodextrin structures, (a) Head-to-head channel type (b) head-to-tail channel type (c) cage type (d) layer type and (e) layer type composed of /TCD dimers. (Reproduced from [24] with permission of Elsevier).

Scheme 2. Cyclodextrin structural types, after Sanger. ...

The enantiomeric separation of some racemic antihistamines and antimalar-ials, namely (+/-)-pheniramine, (+/-)-bromopheniramine, (+/-)-chlorophen-iramine, (+/-)-doxylamine, and (+/-)-chloroquine, were investigated by capillary zone electrophoresis (CZE). The enantiomeric separation of these five compounds was obtained by addition of 7 mM or 1 % (w/v) of sulfated P-cyclo-dextrin to the buffer as a chiral selector. It was found that the type of substituent and degree of substitution on the rim of the cyclodextrin structure played a very important part in enhancing chiral recognition (174). The use of sulfated P-cyclo-dextrin mixtures as chiral additives was evaluated for the chiral resolution of neutral, cyclic, and bicyclic monoterpenes. While there was no resolution of the monoterpene enantiomers with the sulfated P-cyclodextrin, the addition of a-cyclodextrin resulted in mobility differences for the terpenoid enantiomers. Resolution factors of 4-25 were observed. The role of both a-cyclodextrin and sulfated P-cyclodextrin in these separations was discussed (187). The enantiomeric separation of 56 compounds of pharmaceutical interest, including anesthetics, antiarrhythmics, antidepressants, anticonvulsants, antihistamines, antimalarials, relaxants, and broncodilators, was studied. The separations were obtained at pH 3.8 with the anode at the detector end of the capillary. Most of the 40 successfully resolved enantiomers contained a basic functionality and a stereogenic carbon (173). 

General cyclodextrin structure (e.g. for a-cyclodextrin, n=7) the glucose units form a bucket-like structure suitable for molecular inclusion complexation. 

In our first study we attached a pyridoxamine unit to a primary carbon of jS-cyclodextrin (structure 12). We saw that pyridoxamine alone is able to transaminate pyruvic acid to form alanine, phenylpyruvic acid to form phenylalanine, and indolepyruvic acid to form tryptophan, all with equal reactivity by competition experiments. However, when the cyclodextrin was attached to the pyridoxamine there was a 200-fold preference for the indolepyruvate over pyruvate in one-to-one competition, forming greater than 98% of tryptophan, and in the competition with phenylpynivate and pyruvate the phenyManine was formed in greater than 98% as well. Thus the ability of the substrates to bind into the cyclodextrin cavity led to striking selectivities. In addition there was some chiral induction in these processes, since )3-cyclodextrin is itself chiral, but the magnitudes of the induction were quite modest. 

Cyclodextrins are cyclic glucose oligomers consisting of six or more monomer units. The cyclodextrin structure is such that the hydrogens of C-H bonds are directed towards the inside of the cavity of the molecule and hydroxyl groups are directed towards the outside (Fig. 11-7). Therefore, the molecule has a hydrophobic cavity, which owing to its hydrophobicity can bind nonpolar molecules into host-guest complexes and transfer them into the polar phase. This property of cyclodextrins allows us to use them as components of catalytic systems in two-phase catalysis by metal complexes. [20-23, 182-196] this essentially increased the activity of these catalytic systems. 

R 45 K, Yannokopoulou and I.M. Mavridis, Threading of Long End-Functionalized Organic Molecules into Cyclodextrins Structural Analysis in Aqueous Solution by NMR Spectroscopy and in the Solid State by X-Ray Crystallography , p. 25... 

The Combined Effect of Derivatizing Cyclodextrin Structure on Chiral Selectivity Courtesy of ASTEC Inc. 

Although the cyclodextrin based GC stationary phases have already been discussed, it is now necessary to consider them in the light of their use as LC stationary phases. The three basic cyclodextrins, oc, P and Y are also used in LC but they, or their derivatives are bonded to silica gel, particles, which are then packed into a column. The cyclodextrin structure is shown in figure 8.15. 

Bonding Sites on the Cyclodextrin Structure Courtesy of Supelco Inc. 

X-ray data has indicated that the P and y structures are quite rigid whereas the a structure appears to exhibit some flexibility. Thus solute molecules, if spatially suitable, can be included and interact by dispersive, polar of ionic forces with any neighboring groups to which they are approriately close. The inclusion of a solute by the cyclodextrin structure is depicted in figure 8.16. Thus, because of the spatial differences between isomers, this can result in some interactive selectivity. This will take the form of another type of entropic contribution to the standard free energy of distribution which, as already discussed, will also induce an attending enthalpic contribution. 

The number above the peaks denote the number of substituted hydroxy propyl groups per cyclodextrin moiety. It is seen that there is a (more or less) symmetrical distribution of substituents about a mean of 6 hydroxyl groups reacted per cyclodextrin structure. There also appears to be a minimum of about 2 and a maximum of 12 substituents per moiety. This distribution, that results from substitution reaction, shows that the substituted cyclodextrin phases are not necessarily homogeneous substances and that their net chromatographic properties, including their chiral selectivity, will be the average effect of a number of differently substituted hydroxyl groups. 

As with other chiral stationary phases, dispersive interactions with the cyclodextrin structure are controlled with polar solvents, polar interaction controlled with dispersive solvents and, if ionic interactions are present, these will be controlled by both the pH and the type of buffer that is employed. Small changes in pH can be quite critical and a the effect of buffer type on chiral selectivity, under certain circumstances can be quite profound, an example of the effect of pH and buffer type is depicted in figure 8.20. 

O Mahony et al. modified cyclodextrin structurally, for enhanced siRNA deliveiy to the brain. In this study, an amphiphilic cationic p-cyclodextrin with hydrocarbon chains (C12) on the primacy face and a polar (propyl-amino) group on the secondary face was synthesized by applieation of copper(I)-catalyzed click chemistry. The results showed a signifieant inerease in siRNA delivery, with at least 80% eell viability after modification of cyclodextrin in both immortalized hypothalamic neurons and primary hippocampal neurons. Other physicoehemical properties of modified CDs were also found to be suitable for a gene deliveiy system. On the other hand, an investigation of modified amphiphilic p-cyclodextrin was done by Godinho et al. In this particular study, efficient HTT siRNA delivery with limited toxicity was reported. 

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