Cyclodextrin Dimers and Trimers

CyD dimers and trimers have been developed to improve the binding ability for specific applications. Although the dimer linked with a short alkyl chain 1 showed higher affinity for ditopic guest molecules like p-toluidino-6-naphthalene sulfonate 

A CyD dimer 10 with a functional tether was synthesized for residue- and sequence-selective binding of nonaromatic dipeptides, binding Gly-Leu significantly better than Leu-Gly [136]. This remarkable difference in the binding between Leu-Gly and Gly-Leu can be accounted for in terms of the attractive/ repulsive interaction between the protonated amino group in the tether (-NH2 -) 

The doubly bridged dimer and trimer were prepared [138, 139]. The large binding constant of 27 000 of 15 by 13 may be due to the statistical enhancement of binding by three CyD units in the host and the entropic advantage of two-points fixation of the CyDs at the A,D-positions. In contrast, smaller association constants of 12 and 14 of 5200 and 8600 respectively have been determined for the same 

Irradiation with light of 16, with two CyD cavities linked through their secondary sides by a photochromic dithienylethene unit [140-142], switches these dimers between a relatively flexible (open) and a rigid (closed) form. Dimer 16 bound tetra-kissulfonatophenyl porphyrin (TSPP) 35 times more strongly in the open form 16b than in the closed form 16a, owing to the loss of cooperativity between the CyD cavities in the closed form. 

CyD dimers 17 and 18 can be used for transporting saccharides through a liquid membrane. The transport rate of n-ribose and methyl o-galactopyranoside through a chloroform liquid membrane was over 15 times faster with dimer 17a as the transporter than with monomer 17b [143, 144], CyD trimers 19 showed selective and strong binding to trimeric amino acid amide 21 (fCb = 3.5 x 10 M ) in spite of weak binding to 20 (JQ, = 650 M ) [30]. 

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Figure 6 Examples of supramolecular multicavity cyclodextrin dimer and trimer scaffolds.

S. Aime, E. Gianolio, F. Arena, A. Barge, K. Martina, G. Heropoulos, and G. Cravotto, New cyclodextrin dimers and trimers capable of forming supramolecular adducts with shape-specific ligands, Org. Biomol Chem., 7 (2), 370-379,2009. 

Moore, S., Askew, J.A., Gibson, G.L., Aborgrein, A., El-Agnaf, O., Allsop, D., Leung, D.K. and Breslow, R., Novel cyclodextrin dimers and trimers as inhibitors of amyloid peptide aggregation, Neurohiol Aging, 2002, 23, S105. 

Figure J4.12 Supramolecular polymers obtained by Harada and coworkers, (a) Self-inclusion complex (cyclic monomer) formed as a result of the flexibility of the linker between the hydrophobic guest and yS-cyclodextrin (CD) [47] (b) Cyclic dimer and trimer formed when more rigid linkers were applied [48] (c) Supramolecular...

The concept of cyclodextrin guest inclusion has been extended to the synthesis of a library of multicavity dimers and trimers of cyclodextrin that can bind specific guest molecules to mimic enzymes (Figure 6) Such supramolecular structures were tested with mono-, di-, and tri-substituted Gd + complexes bearing hydrophobic cyclohexyl moieties for interaction with the cyclodextrin cavities. The relaxivity enhancement increased with the number of cyclohexyl groups on the Gd + chelate. Further, the cyclodextrin trimer host-guest supramolecule with the tri-substituted Gd " " complex exhibited the greatest relaxivity... 

Sequence-selective binding of peptides and small proteins is of considerable interest. We saw that some cyclodextrin dimers could selectively doubly bind peptides in water with appropriately placed hydrophobic side chains. This built on our earlier collaborative work on the selective binding of peptides by simple cydodextrin. We then showed that we could break up a protein dimer and a protein tetramer with appropriate cydodextrin dimers in water, since such protein aggregation ordinarily involved hydrophobic side chains that our dimers could bind to. In perhaps the most striking example, our cydodextrin dimers and trimers were able to inhibit the protein aggregation involved in the formation of Alzheimer s plaques. ... 

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