Glycodendrimers

Owing to the weakness of carbohydrate receptor-protein interactions, in order to attain biological meaningful affinities for the receptor, carbohydrates very often need to be clustered and expressed in multiple copies. For this purpose glycodendrimers, which are multivalent glycoconjugates with well-defined chemical structures, have received recent attention for their considerable potential as tools for studying cell-surface protein-carbohydrate interactions, because of the affinity enhancement obtained by multivalency. 

The importance of these structures is clear by observing the numerous biomedical applications7711 that have been suggested for such compounds including inhibition of viral and bacterial infections, tumor eradication by stimulating the immune response, preventing toxin binding, and many others. Selected examples have been chosen to illustrate these potentialities. 

Glyco-coated dendrimers possess a core structure of varied chemical nature, with a number of peripheral groups to which carbohydrate moieties are attached. The most common core structures are based on polyaminoamides (PAMAM) or poly(propyleneimine) (Astramol ) with a primary amine at the periphery, and these are commercially available. Polyamides based on N,N-bis(3-aminopropyl)glycine and A,Ar-bis(3-aminopropyl)succinic acid have also been prepared.78 

Examples of glyco-coated dendrimers are the sialylated dendrimers79 that have been developed to prevent infection by the influenza virus. This infection is mediated by the interaction of viral glycoprotein hemagglutinin and the sialic acid residues present on cell-surface glycoproteins and glycolipids. 

A G4 PAMAM dendrimer conjugate80 (Fig. 16) has been synthesized, and in vivo studies have demonstrated its ability to protect against experimental infection by influenza A X-31 H3N2 virus in mice. In this case the glycodendrimer not only showed increased binding affinity due to the multivalency, but also facilitated the delivery of sialic acid, preventing enzymatic breakdown in vivo, and diminishing the cytotoxicity. 

Frechet and coworkers have popularized poly(aryl ether) dendrimers and polyester dendrimers (Fig. 13.7), which have been widely used (Hawker and Frechet 1990 Dire et al. 1998). Addition of the aromatic rings adds rigidity to the dendiimer framework that is lacking in the PPI and PAMAM dendrimers. The polyester dendrimers may be more like the PPIs and PAMAMs in terms of rigidity, but the ester linkages enable degradation of the polyester dendrimers by esterases in vivo. Thus, the biological stability of the PAMAMs and the polyester frameworks is quite different. 

Drug and DNA delivery, photodynamic therapy, boron neutron capture therapy, and magnetic resonance imaging are some areas in which appropriately functionalized dendrimers are being evaluated (Jang and Kataoka 2005 Svenson and Tomalia 2005 Yang and Kao 2006). In one particularly nice example, polylysine 

1) Sequential addition of isothlocyanato mannose and isothiocyanalo giucose derivatives. 

Sixteen is the difference that is predicted using E q. (1), which was proposed by Mammen et al. (1998). 

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Equation 11 has been popularly used for example to investigate the molecular weights of carboxymethylchitins [51-53], glycodendrimers [54,55], galactomannans [56], beta-glucans [57,58] and alginates [59]. 

Fig. 1. Steps involved in the discovery of optimized multivalent glycodendrimers.

Fig. 2. Common scaffolds used in the design of glycoclusters and glycodendrimers.

Fig. 26. Majoral-type glycodendrimers built around a cyclophosphazene core (P3N3).195...

The preparation of biocompatible SWNTs, noncovalently functionalized with bioactive glycodendrimers, has been reported (Scheme 29).253 A bifunctional dendritic scaffold 284 was built using the 2,2-bis(hydroxymethyl)propanoic acid as a building block 281, which was linked to an azidopyrene tail (280) capable of binding the surface... 

Fig. 35. Self-assembled glycodendrimers around a Fe(II)-bipyridyl complex.267...

FIG. 36. Self-assembled glycodendrimers using chelating metal cations and divalent bipyridine... 

SCHEME 41. Mannosylated glycodendrimers on a bipyridine core for ruthenium complexation.279... 

SCHEME 43. Glycodendrimers scaffolded on hydrophobic repeating-units, forming stacked aggregates in aqueous solutions.280,281... 

SCHEME 45. AB2-sugar scaffold used in glycodendrimer synthesis.319... 

HG. 51. Azides and propargylated dendrons for the rapid assembly of glycodendrimers. 

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