Water-soluble macrocycles

For macrocycles to have biological or medicinal relevance it is importance that they are water soluble or at least amphiphilic. While this property is true of some macrocycles, such as the sulphonate derivatives of calixarenes, it is most evident in the cyclic sugars, the cyclodextrins. These compounds are of great importance in supramolecular chemistry both a volume of Comprehensive Supramolecular Chemistry [1] and an entire edition of Chemical Reviews [2] are devoted to them. 

Q-cyclodextrin an overall diameter of 14.6 A (1.46 nm) and a cavity size around 

Cyclodextrins appear to be extremely biocompatible. They are unable to significantly permeate biological membranes and are not absorbed by the gastrointestinal tract yet do not induce a response from the body s immune system. Tests on rats indicate that LD50 values for the most toxic parent compound, /7-cyclodextrin, are greater than 5 g per kg of body weight when administered orally and 0.5 g per kg of body weight when administered intravenously. This low level of toxicity, coupled to the cyclodextrins ability to form inclusion complexes, makes them ideal excipients in pharmaceutical formulations. 

Cyclodextrins can even be used to improve crop yield. Treatment of grain with cyclodextrins inhibits the production of starch-destroying amylase so that the more mature plants have a greater energy store and give up to 50 per cent higher yields. 

From a supramolecular perspective, cyclodextrins offer a preformed cavity of defined size within a water-soluble macrocycle. The interaction between guest molecules, or substituents to the cyclodextrin itself, leads to some useful results. Hydrophobic fluorescent substituents will be self-included by the macrocycle in aqueous solution until they are displaced by guests with even greater affinities [6]. The act of displacement will generate a fluorescent response that lends itself to sensor applications. It is also possible to use the hydrophobic core to induce rotaxane formation. This approach has been used by many groups, for example, Liu has recently used it to prepare water-soluble gold-polypseudorotaxanes that capture fullerenes such as C60 [7]. 

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Diederich, F., Dick, K., New water soluble macrocycles of the paracyclophane type - aggregation behavior and host-guest-interaction with hydrophobic substrates. Tetrahedron Lett. 1982, 23, 3167-3170. 

Optically pure, water-soluble macrocyclic TB tetraacid 104 has been examined as a receptor for terpenes. A H NMR study in an ND4C1/ND3 buffer at pD 9.0 in D20 showed that host 104 binds the isomeric menthols with reasonable selectivity [(-)-menthol Ka — 2.5 + 0.2 x 103M 3], ( + )-menthol Ka — 2.0 + 0.2 x 103 M ... 

Also valuable are measurements of the paramagnetic susceptibility, %M, as a function of pH of the type shown in Figure 3.14 for Fe(III)TMPyP (solid circles) and iron(III)meso tetrakis(4-sulfonatophenyl)porphyrin, Fe(III)TPPPS4 (open circles), yet another water soluble macrocycle [43]. As clearly indicated, undergoes a large decrease at about pH = 3, an effect associated with the formation of the p-oxo dimer a species that displays antiferromagnetic coupling. 

Peterson and Diederich have recently synthesized a water-soluble macrocycle containing a large hydrophobic cavity (Figure 55) [77]. This molecule has been shown to increase the water solubility of steroids severalfold. A 1 mM solution of the host was found to increase the water solubility of cholesterol to 850 /zM (from 4.7/zM in pure water). It has been suggested by these authors that further studies along these lines might lead to the development of alternative drugs for the dissolution of cholesterol deposits in vivo. 

Schwabacher et al. have studied the directionality of the cation-tr effect by measuring the association constants of guests of various sizes with cationic and anionic water-soluble macrocycles (Figure 103) [133]. These studies have provided support for ion-quadrupole interactions contributing to the binding in the anionic host. 

Synthetic organic chemistry therewith has clearly demonstrated that it is capable of designing and constructing water-soluble macrocyclic and macropolycyclic host... 

Schneider, H.-J. Guttes, D. Schneider. U. Host-guest complexes with water-soluble macrocyclic polyphenolates including induced fit and simple elements of a proton pump. J. Am. Chem. Soc. 1988.110 (19), 6449-6454. 

CDs are water soluble macrocycles containing 1,4-linked a-D-glucose units. CDs containing six, seven, and eight a-o-glucose units are labeled a-, P-, and y- CDs, respectively. The primary and secondary hydroxyl groups of CDs make... 

Cyclodextrins (CDs) have never ceased to fascinate scientists around the world due to their structures and properties [1], These inexpensive natural cyclic oligosaccharides could be obtained from the enzymatic degradation of a renewable material, namely starch. This family of water-soluble macrocycles are built up from D-(+)-glucopyranosyl units linked by a-l,4-glycosidicbonds (Fig. 2.1). In the enzymatically produced CD family, three derivatives are mainly known a-, (3-, and y-CD, constituted of six, seven, and eight glucose units, respectively (Fig. 2.1). 

The stability of the host-guest complex is significantly affected by the nature and composition of the solvent in which the processes occur. This is an important factor when the reaction is carried out in aqueous medium, where hydrophobic interactions mainly contribute to the energy of complex formation due to an increase in its stability. In this regard, the use of water-soluble macrocycles with hydrophobic cavities as components of water-soluble metal complexes in two-phase catalytic systems is of particular interest [38,39]. The catalyst, soluble in the aqueous phase, can be easily separated from the water-insoluble reaction products and reused. It should be emphasized that the activity of conventional catalysts is very low for the reactions involving substrates poorly soluble in water. Due to the formation of water-soluble inclusion host-guest complexes, the macrocyclic receptors not only influence the activity and selectivity of the reaction, but also perform the function of interfacial substrate carrier in aqueous phase. 

Water-soluble macrocyclic heterocyclophanes are good inclusion hosts for organic substrates, and such cyclophanes containing quaternary ammonium groups within the ring catalyse the hydrolysis of esters with rate enhancements of up to 20-fold. ... 

Diederich, F. and Dick, K. (1982) New Water-Soluble Macrocycles of the Paracyclophane Type Aggregation Behaviour and Host-Guest-Interaction with Hydrophobic Substrates , TetrSiedron Lett. 23, 3167-3170. 

Diederich, F. and Dick, K. (1984) A New Water-Soluble Macrocyclic Host of the Cyclophane Type Host-Guest Complexation with Aromatic Guests in Aqueous Solutitm and Acceleration of the Transport of Arenes Through an Aqueous ase , J. Am. C hem. Soc. 106, 8024-8036. 

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