Scheme 11 Convergent (59 + 60) and divergent (56,57) strategies toward glycodendrimer 58.

Glycodendrimers can be synthesized by both convergent and divergent strategies. Ideally, they can be simply prepared by conjugation of active carbohydrate derivatives onto preformed dendrimers (Scheme 11). Given the commercial availability of poly(amidoamine) (PAMAM, 56) and poly(propyleneimine) (Dab, 57) dendrimers, these amine-ending dendrimers are the most heavily exploited.

Even though dendrimer surfaces can be constructed to exhibit all possible functionalities, amine-terminating groups are synthetically more appealing and have been used most extensively. The potentially useful thiolated dendrimers self-oxidize, while carboxylated dendrimers tend to form intramolecular anhydrides once activated. This last situation may cause defects upon carbohydrate attachment. Although alcohols seem also attractive, a priori, their direct use in glycosylation chemistry is hampered by potentially difficult complete anomeric stereocontrol.

Amine-functionalized dendrimers have been used in several instances. Reducing sugars (62) can be directly anchored to PAMAM dendrimers by reductive amination [97], and sugar lactones (63), readily prepared from reducing sugars by oxidation with basic iodine solutions, can be amidated [98]. Aryl [50] or glycosyl [99] isothiocyanato derivatives (64) also react rapidly and efficiently with polyaminated dendrimers, even under aqueous conditions [100]. Incorporation of chloro- or bro-moacetamido groups onto PAMAM dendrimers [XC^COCl or (ClC^CO^O] afforded highly electrophilic species that react readily with thio sugars (65) (Scheme 12). The last approach has been successfully applied in double N-alkylation when bromoacylated carbohydrate derivatives (66) were used. It simultaneously allowed increasing surface group density [66,101]. These versatile strategies gave to glycodendrimers such as 67-71 high-yielding accesses that obviously are applicable to higher oligosaccharides.

Sialylated dendrimers having modest activity in inhibition of hemagglutination of flu viruses have been prepared by using Fmoc-chemistry and l-lysine core in solid phase synthesis reactions [30,93]. Similarly, the foregoing dendrimers, together with analogous peptidomimetic-like dendrimers (72) built on 3,3'-iminobispropylamine cores [102,103] showed up to ~32-fold inhibition of binding of human a1-acid glycoprotein (orosomucoid) to the plant lectin wheat germ agglutinin or the slug lectin from Limax flavus (Scheme 13). Similar dendrimers having aryl a-d-manno-pyranosides as surface group (l-lysine core) showed ~2000-fold increased inhibition of binding of yeast mannan to concanavalin A or pea lectin [104]. Nanomolar IC50s values have been reported for sialodendrimers 73 obtained by condensation of PAMAM 56 with ^-isothiocyanatophenyl sialoside 26 [50] (Scheme 14). Additionally, dendritic 3'-sulfo-LewisX (Glc) bound to poly-l-lysine backbones inhibited the binding of E-selectin to sialyl-LewisX glycolipids 600 times better than the corresponding monomer [105]. The growth valency of the foregoing dendrimers was based on a 2" progression, where n is the generation (i.e., 2-, 4-, 8-, 16-mer, etc.). It has been deemed of interest to construct dendrimers with a 3" progression (i.e., 3-, 9-, 27-mer, etc.). To this end, we constructed sialodendrimers (74) based on a gallic acid core [106] (Scheme 15).

The inhibition of certain interactions by large variations in glycodendrimer efficacy points to the need to design multivalent neoglycoconjugates with defined geometry, valency, and shapes. The seemingly modest results observed with some plant lectins further exemplify the problem encountered in glycobiology as opposed to other drug-protein interactions. A good model to clarify these observations has

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