Chemistry Reference
In-Depth Information
Therefore, the purpose of this chapter is to provide a general overview of the
potential application of CuAAC reactions in the synthesis of bioactive carbohydrate-
based ligands for lectins (galectins and selectins), antitumor vaccines and sub-
strates/inhibitors for fucosyltransferases, manosyltransferases, glucosidases, neu-
raminidase and
trans
-sialidase, all of them built up from a common 1,4-disubstituted
1,2,3-triazole scaffold.
13.2 CLICK CHEMISTRY AND CARBOHYDRATE-BASED LIGANDS
FOR LECTINS (GALECTINS AND SELECTINS)
Lectins are carbohydrate-specific proteins that act as recognition molecules in various
biological systems. These proteins bind to carbohydrates reversibly and with high
specificity to mono/oligosaccharides, being also known as glycan-binding proteins.
They are expressed by animals, plants, fungi, bacteria, and viruses and are involved
in several biological and pathological processes [7, 8]. The carbohydrate recognition
capability inherent to lectins is often associated to a distinct polypeptide region in
these proteins, denominated Carbohydrate RecognitionDomain (CRD) [9-11]. Based
on the amino acid sequence and structural homology of their CRDs, animal lectins
are classified into different families (types) identified as S-, C-, I-, M-, L-, P-, and
R-types [11]. In this chapter, we will focus on the development of specific ligands
to galectins (S-type) and selectins (C-type) by means of different strategies utilizing
Cu(I)-assisted 1,3-dipolar azide-alkyne cycloaddition (CuAAC) reactions.
13.2.1 Galectins
Galectins, existing in the form of 15 different subtypes in mammals, share primary
structural homology in their CRDs, which are constituted by approximately 135
amino acid residues. Through specific interactions with only few CRD residues,
galectins are able to bind to
-galactose molecules, especially those found in
N
-
acetyl-lactosamine (LacNAc) sequences. Thus, terminal
-galactose residues and
the size of the poly-lactosamine chain seem to represent critical requirements for the
carbohydrate recognition capacity of these lectins [12].
Galectins are expressed by a variety of cell types and can participate in cell-cell and
cell-extracellular matrix interactions, besides modulating several cellular functions
[13, 14]. Therefore, these proteins may play an essential role in the development of
inflammatory response, autoimmune diseases, atherosclerosis, infectious processes,
and cancer [13, 15]. Galectins, mainly subtypes -1 and -3, are overexpressed in several
types of tumor cells and are then involved in important functions related to cancer,
such as tumorigenesis, neoplastic transformation, tumor cell survival, angiogenesis,
tumor metastasis, and regulation of apoptosis. Moreover, they can help tumors to
escape from immune surveillance through modulation of immune and inflammatory
responses [16, 17].
Taking into account the low affinities of naturally occurring carbohydrate ligands
for galectins, besides their lowphysiological stabilities due to acid sensitive glycosidic
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