CLICK CHEMISTRY APPLIED TO CARBOHYDRATE-BASED DRUG DISCOVERY - Click Chemistry in Glycoscience: New Developments and Strategies - page 329

40 ◦ C, affording the corresponding MUC1 glycopeptides-TLR lipopeptides conju-
gates (Fig. 13.2, Scheme 13.8) [36].
The aberrant expression of MUC1 glycoproteins on tumor cells was also
recently explored for development of MUC1 neoglycopeptides, containing a vari-
able number of GalNAc 1- O -Thr/Ser (Tn) mimics, by 1,3-dipolar cycloaddition

reactions of unprotected sugar-azides with peptides containing one or more propar-
gyl groups (Scheme 13.9) [37]. The azido-neoglycosyl amino acid mimic (Tn)
50 was obtained by glycosylation reaction of GalNAc with 3-tosil-propanol, fol-
lowed by azide nucleophilic displacement whereas the propargylatedMUC1-derived-
peptides were prepared by incorporation of Fmoc-L-propargylglycine residues to
the pepide chain, replacing Thr/Ser at selected positions in the MUC1 sequence.
Subsequently, the click reactions were performed utilizing the catalytic sys-
tem CuSO 4 /tris(carboxyethyl)phosphine (TCEP) in 6 M guanidine hydrochloride
(GnHCl)/0.2 M Na 2 HPO 4 buffer, under microwave irradiation (25 W, 60 ◦ C, 4h),
affording a set of mono to penta-clicked MUC-1 derived neoglycopeptides, such as
51 (Scheme 13.9) [37].
Lipid A, which is a fragment of lipopolysaccharides (LPS) present on the cell
surface of Gram-negative bacteria, is known for its inherent capacity to bind to Toll-
like receptor 4 (TLR4), activating a cascade of immunological responses, including
the production of a number of cytokines and chemokines (TNF- ,TNF- , IL-6, and

IFN- ) [38]. For that reason, the design and synthesis of lipid A derivatives such as

monophosphoryl lipid A (MPLA) have been carried out in order to investigate their
potential immunostimulatory or adjuvant activity. Once they have been coupled with
peptides and carbohydrates for the assembly of multicomponent glycoconjugates,
they can pave the way for development of functional conjugate vaccines. Following
the continuous use of click chemistry to generate neoglycoconjugates as antitumor
vaccines, the synthesis of MPLA containing alkyne functionality 52 was then devel-
oped in several steps with a view to be further conjugated to the azide-derivative
of N-phenyl-acetyl GM3 (GM3NPhAc) 53 , which is an unnatural analog of GM3
ganglioside, overexpressed in tumor cells. Click reaction between 52 and 53 was then
performed utilizing CuI/DIPEA in MeOH/THF at room temperature, furnishing the
neoglycoconjugate 54 (Scheme 13.10) [39].

13.4 CLICK CHEMISTRY AND CARBOHYDRATE-BASED
ENZYME INHIBITORS

13.4.1 Fucosyltransferases (Fuc-T)

Fucosyltransferases (Fuc-T) catalyze the transfer of the L-fucose from

guanosinediphosphate- -L-fucose (GDP-fucose) to the oligosaccharide portion of

cell surface glycoconjugates, which are involved in many physiological and patholog-
ical processes such as fertilization, embryogenesis, lymphocyte trafficking, immune
responses, and cancer metastasis. By exploring the specificity of the substrate GDP-
fucose for the target enzyme, a chemical diversity of 85 GDP-triazoles containing