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processes. This effect is known as the multivalent or cluster glycoside effect and is
of utmost importance in glycobiology [1-4].
In order to study, control, interfere, or block carbohydrate-lectin interactions,
accessing multivalent glycosystems with well-defined topologies is mandatory.
Oligomerization of monovalent derivatives, a divergent approach, has been generally
associated with the generation of polydisperse mixtures. The alternative conver-
gent strategy based on glycocoating of functionalized scaffolds, has to face limi-
tations derived from incomplete coupling reactions, resulting in structural defaults.
Moreover, both routes have often required cumbersome protecting group strategies
to avoid interference of coupling chemistry with the polyfunctionality of sugars.
This scenario has abruptly changed in the last decade with the irruption of click
chemistry [5], especially the archetypal click-type copper(I)-catalyzed azide-alkyne
cycloaddition (CuAAC) reaction [6-8], and its implementation for bioconjugation
purposes [9-12]. The bioorthogonal character of the functional groups at play and
the unique property of CuAAC as a quantitative ligation reaction have boosted the
design and synthesis of novel multivalent glycomaterials for fundamental studies on
carbohydrate-protein interactions and therapeutic applications [13-17]. This chapter
intends to provide an overview of the many classes of click multivalent glycoarchi-
tectures that can be accessed through CuAAC, with emphasis on its extraordinary
selectivity and performance. Due to space limitations, applications of CuAAC to the
modification of carbohydrates with multivalent noncarbohydrate functional elements
(e.g., elements for DNA [18-22] or toxin recognition [23, 24]) or to the preparation
of hybrid glycomaterials not intended for multivalent recognition of the sugar units
by protein receptors (e.g., hybrid glycomaterials for controlled drug release [25]) are
not discussed here.
6.2 CLICK GLYCOCLUSTERS
Low-valency glycoclusters are fundamental tools to test the influence of architectural
features on carbohydrate-protein interactions. The number of recognition elements,
their separation distances and spatial orientation, the flexibility or rigidity of the
system, and the presence of additional structural elements are parameters that can
be systematically varied in these systems. Whereas achieving full control on glyco-
cluster homogeneity maybe relatively easy for divalent or trivalent ligands built onto
achiral cores, the difficulties on warranting monodispersity increase exponentially
for higher valency platforms. The use of quantitative ligation methods then becomes
essential to prevent the presence of under-substituted side products, often susceptible
to positional isomerism in the reaction mixtures, which generally leads to unafford-
able separation problems. A seminal report by Santoyo-Gonzalez in 2003 [26], only
one year after the discovery of the catalytic version of this reaction, already illustrated
the tremendous potential of the CuAAC reaction to create multivalent glycodisplays.
By using several per-
O
-acetylated
-D-mannopyranosides with terminal alkyne agly-
cons (
1
-
3
) and complementary mono-, di-, tri-, or hexafunctionalized azide cores
(
4
-
9
), a broad series of multimannoside glycoclusters (
10
) was prepared in excellent
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