Chemistry Reference
In-Depth Information
are carbohydrate-binding proteins, whose specificity depends on the size and shape
of the recognition site. By interaction with their specific oligosaccharide ligands,
intracellular lectins (for example, galectins) become functional, and thus, an optimal
transmission of certain signals take place inside the cell [5]. Extracellular lectins
are usually involved in adhesion of bacteria and other pathogens, as a first step in
infection processes [6].
A better understanding of the role of sugar-protein interactions triggering such
important biological effects requires carbohydrate-based molecules having defined
structures. Moreover, the development of efficient synthetic methodologies to con-
struct the desired molecules, as well as physiologically stable analogs, is of great
interest. And when data about the structure-function relationship is available, analogs
having specific geometries and properties can be designed.
The Huisgen 1,3-dipolar cycloaddition of azides and alkynes [7] to afford triazoles
is probably the most powerful “click” reaction to connect two distinct fragments or
residues of similar or different nature. Indeed, the reaction has shown a number
of advantages over other methods. So, by using this reaction, carbohydrates have
been linked to proteins, lipids, linkers, polymers and other sugars, giving rise to
a heterogeneous family of new compounds with promising physicochemical and
biological properties [8]. Interest for this reaction became clear after the discovery
of the advantages of Cu(I) as catalyst reported independently by Sharpless [9] and
Meldal [10] groups, the catalyzed reaction leads regioselectively under mild condi-
tions to 1,4-disubstituted-1,2,3-triazoles in high yields. This constitutes a substantial
improvement of the classical version of the thermal transformation, which affords
mixtures of 1,4- and 1,5-disubstituted triazoles.
In this catalyzed version, known as the copper(I)-catalyzed azide-alkyne cycload-
dition (CuAAC), the Cu(I) can be added as a salt (for example, CuCl), or generated
in situ
from CuSO
4
and ascorbic acid [11]. Although many groups still use Cu(I)
salts and complexes as catalysts, the most popular methodology employed nowadays
involves the CuSO
4
/ascorbic acid combination, due to its simplicity and lower cost.
Recent developments [12] showed that cyclooctynes react with azides in the absence
of copper catalysts, and therefore, the cycloaddition reaction became compatible with
living systems. However, its up-to-date limited use led us to consider it out of the
scope of this review.
The CuAAC owes its usefulness in part to its high compatibility with functional
groups (alcohols, carboxylic acids, amines) in different solvent systems including
water. In the field of carbohydrate chemistry [13], the click reaction has been used for
the synthesis of glycoconjugates [11, 14] and carbohydrate macrocycles [15] where
a sugar possessing an azido function is grafted onto a saccharide [16], a peptide [17]
or a polymeric chain [18]. Also, this methodology has recently been employed for
the synthesis of glycosidase inhibitors [19].
An important fact to be considered is that the resulting triazole ring is stable
to hydrolytic cleavage and virtually inert towards oxidation, reduction, and other
metabolic transformations [8b, 20]. In addition, 1,2,3-triazoles are interesting phar-
macophores in view of the topological and electronic similarities of triazoles and
amide bonds [21], and they can improve the binding to biologically relevant molecules
through hydrogen-bonding and/or dipole interactions [14, 22].
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